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Abstract Roles of liver-specific genes (LSGs) in tumor initiation and progression are rarely explored in hepatocellular carcinoma (HCC). Here we show that LSGs are generally downregulated in HCC tumor tissues compared to non-HCC liver tissues, and low-LSG HCCs show poor prognosis and the activated c-Myc pathway. Among the c-Myc- and patient prognosis-associated LSGs, PGRMC1 significantly blocks c-Myc-induced orthotopic HCC formation. The role of PGRMC1 depends on its localization to the endoplasmic reticulum (ER) membrane, where PGRMC1 interacts with PERK through their ER luminal domains. This interaction in turn activates PERK in an ER stress-independent manner, which phosphorylates eIF2α and consequently inhibits c-Myc protein translation. In HCC patients, PGRMC1 level is significantly reduced in tumor tissues and negatively associated with the c-Myc signature. Patients with low-PGRMC1 in their tumors have poor prognosis. Collectively, deregulated LSGs in HCC are associated with the c-Myc pathway activation and PGRMC1 blocks c-Myc-induced hepatic carcinogenesis through promoting ER stress-independent PERK activation. more...

Abstract Background Gastric cancer (GC) is known for its high heterogeneity, presenting challenges in current clinical treatment strategies. Accurate subtyping and in-depth analysis of the molecular heterogeneity of GC at the molecular level are still not fully understood. Methods This study categorized GC into two subtypes based on apoptosis-related genes (ARGs) and investigated differences in tumor immune microenvironment, intratumoral microorganisms distribution, gene expression, and signaling pathways. Key prognostic genes related to apoptosis in GC were identified through random survival forest analysis, and their specific signaling mechanisms were explored. Expression levels of key genes were validated through PCR in paired GC tissues and cancer cell lines. Moreover, biological functions of these key genes were verified in vitro experiments. Results A consistent clustering of GC was conducted using 161 apoptosis-related genes (ARGs), resulting in the identification of two subtypes, C1 and C2. Subsequently, significant differences were found in the tumor immune microenvironment, intratumoral microorganisms, gene expression, signaling pathways, and protein interaction networks between the two subtypes. GPX3, PLAT, and CAV1 were identified as key prognostic genes related to apoptosis in GC, with a focus on their impact on disease progression-related pathways. Furthermore, PCR assays validated that these three key genes exhibited significantly low expression levels in both GC cell lines and tissues. Finally, knocking down key genes expression significantly promoted cell proliferation, colony formation and invasion of GC. Conclusions Our study conducted a comprehensive analysis of the molecular characteristics of ARGs in GC, revealed their association with the tumor immune microenvironment and intratumoral microorganisms. These findings provide new ideas for the molecular classification of GC. more...

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features. Methods Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1–3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1–3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells. Results The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)–Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis. Conclusions RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features. more...

Orthotopic implantation in vivo is the ultimate target of tissue-engineering organoids research, aiming to achieve sustaining survival after implantation. However, the limited representation of a complex microenvironment in implanted accepter hampers a comprehensive understanding of long-term maintenance of tissue-engineering organoids, especially in liver. In this research, we developed a 3D bioprinting method using gelatin methacryloyl (GelMA) hydrogel to fabricate lobule-like hepatorganoids, which faithfully mimic the structure of hepatic lobules with lower level of hypoxia (lobule vs 60°, 90°, control; 0.4880 vs 1.009, 0.6778, 0.8704; p more...

Bile duct lesion, including benign (eg. occlusion, cholelithiasis, dilatation, malformation) and malignant (cholangiocarcinoma) diseases, is a frequently encountered challenge in hepatobiliary diseases, which can be repaired by interventional or surgical procedures. A viable cure for bile duct lesions is implantation with biliary stents. Despite the placement achieved by current clinical biliary stents, the creation of functional and readily transplantable biliary stents remains a formidable obstacle. Excellent biocompatibility, stable mechanics, and absorbability are just a few benefits of using bioengineered biliary stents, which can also support and repair damaged bile ducts that drain bile. Additionally, cell sources & organoids derived from the biliary system that are loaded onto scaffolds can encourage bile duct regeneration. Therefore, the implantation of bioengineered biliary stent is considered as an ideal treatment for bile duct lesion, holding a broad potential for clinical applications in future. In this review, we look back on the development of conventional biliary stents, biodegradable biliary stents, and bioengineered biliary stents, highlighting the crucial elements of bioengineered biliary stents in promoting bile duct regeneration. After providing an overview of the various types of cell sources & organoids and fabrication methods utilized for the bioengineering process, we present the in vitro and in vivo applications of bioengineered biliary ducts, along with the latest advances in this exciting field. Finally, we also emphasize the ongoing challenges and future development of bioengineered biliary stents. more...

Background Circular RNAs (circRNAs) are identified as a novel family of endogenous RNA molecules through ‘back-splicing’ and covalently linked at the 5′ and 3′ ends. Emerging researches have demonstrated circRNAs are stable and abundant in exosomes called exosomal circRNAs (exo-circRNA).Materials and methods We searched recent studies and references to summary the research progress of exosomal circRNA.Results Recent studies have revealed that exosome-derived circRNAs including exo-CDR1as, exo-circRanGAP1, exo-circIAR play vital roles in cell proliferation and apoptosis, epithelial mesenchymal transition, invasion and metastasis, angiogenesis, immune evasion, cellular crosstalk, cancer cachexia through a variety of biological mechanisms, such as serving as microRNA sponges, interacting with RNA binding proteins, regulating gene transcription, N6-Methyladenosine modification and so on. Due to their characteristics of origin, structure, properties and biological functions, exo-circRNAs are expected to apply in precious diagnosis and prognostic indicators, improving drug and radiation resistance and sensitivity, becoming biological therapeutic targets.Conclusion We summarize the update of digestive malignancies associated exo-circRNAs in biogenesis, biological functions, molecular mechanisms, clinical implications, potential applications and experimental technique in order to effectively promote transformation and application in the future. more...

Abstract RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy. more...

Abstract Background Gastric cancer (GC) is one of the most common malignant tumors worldwide. Nevertheless, GC still lacks effective diagnosed and monitoring method and treating targets. This study used multi omics data to explore novel biomarkers and immune therapy targets around sphingolipids metabolism genes (SMGs). Method LASSO regression analysis was performed to filter prognostic and differently expression SMGs among TCGA and GTEx data. Risk score model and Kaplan-Meier were built to validate the prognostic SMG signature and prognostic nomogram was further constructed. The biological functions of SMG signature were annotated via multi omics. The heterogeneity landscape of immune microenvironment in GC was explored. qRT-PCR was performed to validate the expression level of SMG signature. Competing endogenous RNA regulatory network was established to explore the molecular regulatory mechanisms. Result 3-SMGs prognostic signature (GLA, LAMC1, TRAF2) and related nomogram were constructed combing several clinical characterizes. The expression difference and diagnostic value were validated by PCR data. Multi omics data reveals 3-SMG signature affects cell cycle and death via several signaling pathways to regulate GC progression. Overexpression of 3-SMG signature influenced various immune cell infiltration in GC microenvironment. RBP-SMGs-miRNA-mRNAs/lncRNAs regulatory network was built to annotate regulatory system. Conclusion Upregulated 3-SMGs signature are excellent predictive diagnosed and prognostic biomarkers, providing a new perspective for future GC immunotherapy. more...

Abstract Helicobacter pylori (H. pylori) resistance is the most important risk factor for eradication failure. However, in most regions, antibiotic resistance rates of H. pylori in patients with different types of gastric mucosal lesions are still unclear. An 8-year clinical retrospective cohort study involving 2847 patients was performed. In this study, we first summarized and compared the resistance status of H. pylori in different years, ages, sexes, and gastric diseases. The resistance profiles of amoxicillin (AMX), clarithromycin (CLR), levofloxacin (LVX) and furazolidone (FR) and their changing trends in the clinic were described. Then, multiple antibiotic resistance in different gastric diseases and years were described and compared. The relationship between proton pump inhibitor (PPI) medication history and antibiotic resistance in H. pylori was also explored. Finally, an antibiotic resistance risk model was constructed for clinical resistance risk prediction. The overall resistance rates of AMX, CLR, LVX and FR in gastric diseases were 8.18%, 38.11%, 43.98%, and 13.73%, respectively. The mono resistance, double resistance, triple resistance, and quadruple resistance rates were 30.17%, 25.96%, 6.46%, and 0.63%, respectively. Compared with the period from 2014 to 2016, the rates of mono-resistance and multiple resistance all showed relatively downward trends in the past 5 years. Factors including age, sex, type of gastric lesions and recent PPI treatment history are associated with the antibiotic resistance rate of H. pylori. Atrophic gastritis is an important clinical feature of high-risk antibiotic resistance in H. pylori-infected patients. Patients with atrophic gastritis have higher risk of resistant strains infection. In this study, our data provide the association between antibiotic resistance of H. pylori and gastritis pattern, which indicate the higher risk of resistant strain infection if the patients with atrophic gastritis, PPI history and older age. more...

As a low-cost green building warm in winter and cool in summer, silo-cave has gradually declined in recent years for its low safety and inconvenient living condition. In the calling of energy-saving buildings worldwide, the popularization potentiality of the silo-cave in the condition of scientific design depends on its safety, comfort, and economy. In view of the lack of safety analysis with creep effect and economy evaluation, the displacement field and mechanical analyses after excavation of the silo-cave are conducted based on its simulated creep, and a series of corresponding reinforcement measures are provided to make it to be a safety silo-cave. Meanwhile, the popularization potentiality of the safety silo-cave is evaluated by budgeting its real building and living costs and comparing with those of the counterpart ground house. The results show that the building cost index and living cost index of the safety silo-cave are just 59.41% and 43.69% of those of the ground house. The research results indicate that the safety silo-cave has a great advantage and potential to be widely popularized in the modern society that advocates eco-friendly and low-carbon, which has a significant meaning for policy makers and architectural designers of green residence in suitable rural region. more...

The rapid spread of oil pollution owing to river flow has vast consequences for human activities and ecosystems within the affected river basin. In the context of the profound impact of oil spills on river basins, an integrated riverine oil spill impact assessment framework is proposed. The framework combines a risk-matrix approach with an oil trajectory model and the environmental sensitivity index (ESI) methodology to estimate the impact level of the affected river basin. The framework was applied in simulation to the middle reaches of the Nenjiang River, China, to evaluate the impact of a hypothetical oil spill accident during different seasons. Our findings revealed similar propagation trends of the oil and impact level maps during normal water and flood seasons, largely owing to the regulating function of a downstream dam. Specifically, the oil front edge spread over 2 km/h along the initial 30-km downstream segment in normal water and flood seasons, and the speed slowed to 1.2 km/h in the dry season. The length of the polluted river during normal water and flood seasons was approximately 1.4 times that in the dry season, with contaminated zone lengths averaging 0.45, 0.61, and 0.82 km in the dry, normal water, and flood seasons, respectively. The output impact-level maps, which highlight the severely affected areas over time after the spill, are especially useful for decision makers. This framework is shown to be a valuable tool for quantitatively evaluating the dynamic impacts that a river basin may face following an oil spill, and is particularly useful for facilitating the initial emergency response. more...

The increasing public demand for fresh products has catalyzed the requirement for cold chain logistics distribution systems. However, challenges such as temperature control and delivery delays have led a significant product loss and increased costs. To improve the current situation, a novel approach to optimize cold chain logistics distribution for fresh products will be presented in the paper, utilizing a hybrid Tabu-Grey wolf optimizer (TGWO) algorithm. The proposed hybrid approach combines Tabu search (TS) and Grey wolf optimizer (GWO), employing TS for exploration and GWO for exploitation, aiming to minimize distribution costs in total and establish efficient vehicle scheduling schemes considering various constraints. The effectiveness of the TGWO algorithm is demonstrated through experiments and case studies compared to other heuristic algorithms. Comparative analysis against traditional optimization methods, including Particle swarm optimization (PSO), Whale optimization algorithm (WOA), and original GWO, highlights its superior efficiency and solution quality. This study contributes theories by demonstrating the efficacy of hybrid optimization techniques in complex supply chain networks and dynamic market environments. The practical implication lies in the implementation of TGWO to bolster distribution efficiency, cost reduction, and product quality maintenance throughout the logistics process, offering valuable insights for operational and strategic improvements by decision-makers. However, the study has limitations in generalizability and assumptions, suggesting future research areas including exploring new search operators, applying additional parameters, and using the algorithm in diverse real-life scenarios to improve its effectiveness and applicability. more...

Abstract Background Gastric cancer (GC) carries significant morbidity and mortality globally. An increasing number of studies have confirmed that circular RNA (circRNA) is tightly associated with the carcinogenesis and development of GC, especially acting as a competing endogenous RNA for miRNAs. Objective Our study aimed to construct the circRNA-miRNA-mRNA regulatory network and analyze the function and prognostic significance of the network using bioinformatics tools. Methods We first downloaded the GC expression profile from the Gene Expression Omnibus database and identified differentially expressed genes and differentially expressed circRNAs. Then, we predicted the miRNA-mRNA interaction pairs and constructed the circRNA-miRNA-mRNA regulatory network. Next, we established a protein-protein interaction network and analyzed the function of these networks. Finally, we primarily validated our results by comparison with The Cancer Genome Atlas cohort and by performing qRT-PCR. Results We screened the top 15 hub genes and 3 core modules. Functional analysis showed that in the upregulated circRNA network, 15 hub genes were correlated with extracellular matrix organization and interaction. The function of downregulated circRNAs converged on physiological functions, such as protein processing, energy metabolism and gastric acid secretion. We ascertained 3 prognostic and immune infiltration-related genes, COL12A1, COL5A2, and THBS1, and built a nomogram for clinical application. We validated the expression level and diagnostic performance of key prognostic differentially expressed genes. Conclusions In conclusion, we constructed two circRNA-miRNA-mRNA regulatory networks and identified 3 prognostic and screening biomarkers, COL12A1, COL5A2, and THBS1. The ceRNA network and these genes could play important roles in GC development, diagnosis and prognosis. more...

Improving the forage quality of alfalfa in terms of digestibility and crude content is essential for any alfalfa quality breeding programs. Arabidopsis thaliana orphan gene QQS (Qua-Quine Starch) has been shown to improve protein content and alter carbohydrate composition in different food crops. However, there are significant differences in agronomic traits and nutritional conditions between alfalfa and other food crops. To explore the biological function and molecular mechanisms of QQS in alfalfa, we generated QQS transgenic plants and their segregated population (T1 generation), and evaluated their performance under normal- and nitrogen-deficient conditions. Our findings indicate that QQS can significantly enhance the total nitrogen and crude protein content of alfalfa and increase nodule weight under low-nitrogen conditions. Furthermore, QQS transgenic lines also showed reduced levels of neutral detergent fiber (NDF) and lignin, improving forage digestibility. By RNA sequencing and RT-qPCR analysis, we found that QQS affected the expression of genes involved in carbon and nitrogen metabolism, lignin biosynthesis and amino acid biosynthesis and degradation pathways in alfalfa. In addition, QQS also improved alfalfa biomass yield by increasing branch number and plant height in both greenhouse and field conditions. Our results demonstrate that QQS as a useful molecular tool can improve alfalfa biomass yield and overall forage quality and could have significant implications for the alfalfa breeding industry in satisfying the constant demands for high-quality and high-yielding forage. more...

Background: Hepatocellular carcinoma (HCC) remains notorious for its high malignancy, poor prognosis and high mortality. The exploration of novel therapeutic agents for HCC has remained challenging due to its complex aetiology. Therefore, it is necessary to elucidate the pathogenesis and mechanism of HCC for clinical intervention.Methods: We collected data from several public data portals and systematically analysed the association between transcription factors (TFs), eRNA-associated enhancers and downstream targets. We next filtered the prognostic genes and established a novel prognosis-related nomogram model. Moreover, we explored the potential mechanisms of the identified prognostic genes. The expression level was validated by several ways.Results: We first constructed a significant TF-enhancer-target regulatory network and identified DAPK1 as a coregulatory differentially expressed prognosis-related gene. We combined common clinicopathological factors and built a prognostic nomogram model for HCC. We found that our regulatory network was correlated with the processes of synthesizing various substances. Moreover, we explored the role of DAPK1 in HCC and found that it was associated with immune cell infiltration and DNA methylation. Several immunostimulators and targeting drugs could be promising immune therapy targets. The tumor immune microenvironment was analyzed. Finally, the lower DAPK1 expression in HCC was validated via the GEO database, UALCAN cohort, and qRT-PCR.Conclusion: In conclusion, we established a significant TF-enhancer-target regulatory network and identified downregulated DAPK1 as an important prognostic and diagnostic gene in HCC. Its potential biological functions and mechanisms were annotated using bioinformatics tools. more...

Circular RNAs (circRNAs), a class of endogenous RNA molecules, are produced by alternative splicing of precursor RNA and are covalently linked at the 5′ and 3′ ends. Recent studies have revealed that dysregulated circRNAs are closely related to the occurrence and progression of gastrointestinal malignancies. Accumulating evidence indicates that circRNAs, including circPVT1, circLARP4, circ-SFMBT2, cir-ITCH, circRNA_100782, circ_100395, circ-DONSON, hsa_circ_0001368, circNRIP1, circFAT1(e2), circCCDC66, circSMARCA5, circ-ZNF652, and circ_0030235 play important roles in the proliferation, differentiation, invasion, and metastasis of cancer cells through a variety of mechanisms, such as acting as microRNA sponges, interacting with RNA-binding proteins, regulating gene transcription and alternative splicing, and being translated into proteins. With the characteristics of high abundance, high stability, extensive functions, and certain tissue-, time- and disease-specific expressions, circRNAs are expected to provide novel perspectives for the diagnoses and treatments of gastrointestinal malignancies. more...

Bile duct injury is a common complication of hepatobiliary surgeries in clinical practice with poorly satisfactory treatment outcomes. Implanting a tissue-engineered tubular scaffold for supporting and replacing defected native bile duct is an important treatment option for bile duct injury. Here a dual-layer tubular scaffold with poly (lactic-co-glycolic acid) (PLGA) inner layer and gelatin methacrylate (GelMA)/poly (ethylene glycol) diacrylate (PEGDA) outer layer was fabricated using a two-stage molding method for bile duct regeneration. Further, induced mesenchymal stem cells (MSC)-derived cholangiocyte-like cells were embedded in the outer layer during fabrication. The inner layer of PLGA offered adequate mechanical strength for the scaffold, and the outer layer of GelMA/PEGDA provided excellent biocompatibility and conditions for the MSCs and their induced differentiation. Moreover, cholic acid and its derivates are believed to induce MSC-cholangiocyte differentiation in two-dimensional culture and could affect the MSCs transforming to cholangiocyte-like cells in the hydrogel. Induced-MSC-laden GelMA/PEGDA-PLGA dual-layer tubular scaffold and PLGA single-layer scaffold were transplanted into animal models for assessing the repair effect on bile duct injury. After 12 wk, induced-MSC-laden dual-layer tubular scaffold promoted bile duct repairing and enhanced more intact biliary epithelium regenerating compared to PLGA single-layer scaffold. Therefore, the induced-MSC-laden dual-layer tubular scaffold with superior biocompatibility and distinct function of inducing differentiation exerted a satisfactory effect on bile duct regeneration and could provide an ideal option for the clinical treatment of bile duct injury in the future. more...

Abstract Objective Poststroke aphasia (PSA) has a high prevalence and requires a long recovery period, severely impairing life and work. Its existing behavioral interventions, principally speech and language therapy, are limited by numerous factors. The aims of this study are to evaluate the efficacy and safety of DL‐3‐N‐butylphthalein (NBP) and explore its mechanism in the treatment of ischemic PSA. Methods Patients hospitalized in the Second Hospital of Hebei Medical University in China were randomly administered NBP soft capsules or placebo orally for 6 months from July 1, 2021, to February 25, 2023. Language skills were assessed using the Western Aphasia Battery‐Aphasia Quotient (WAB‐AQ). We collected plasma samples and detected neurotransmitters by liquid chromatography‐mass spectrometry. Results In total, 118 out of 124 patients were included in the outcome analysis. Compared with the control group, AQ values in the NBP group significantly improved at 6 months (U = 1187.5, p = 0.003). After eliminating baseline interference, NBP treatment was independently associated with the 6‐month AQ improvement [mean difference (MD) 0.106, 95% confidence interval (CI) 0.018, 0.195, p = 0.019]. We observed no statistically significant difference between the groups in abnormal liver function at 1 month [relative risk (RR) 1.07, 95% CI 0.89, 1.28] and 6 months [RR 0.99, 95% CI 0.86, 1.42]. Statistically significant differences were observed in tyrosine (p = 0.043) and 5‐hydroxytryptophan (p = 0.041) between the two groups. Interpretation NBP treatment might promote the recovery of WAB‐AQ in patients with ischemic PSA by increasing levels of monoamine neurotransmitters. more...

The content of stannous chloride is one of the key indicators for the quality control of Technetium [99mTc] radiopharmaceutical injection Kits，which directly affects the clinical use of Technetium [99mTc] radiopharmaceuticals. Consequently，it is crucial to choose the appropriate analytical method for its accurate determination. By comparing the quality standards of radiopharmaceuticals included in the 2020 edition of the Chinese Pharmacopoeia and other related literature，the characteristics，determination principles and applications of commonly used methods for the determination of stannous chloride，including potentiometric analysis，spectrophotometry and high-performance liquid chromatography，were analyzed and summarized. This work provided technical reference for the establishment of a more scientific and rational quality standard for Technetium [99mTc] radiopharmaceutical injection kits. more...

Previous studies indicated that the SNARC effect can stably present in numerical cognition, however how the orientation influence the SNARC effect when Arabic numbers were rotated to left or right space remains unclear. The present study rotated Arabic numbers 45° to the left or right space and randomly and centrally presented those rotated numbers for participants systematically to investigate above question in orientation task (experiment 1), parity task (experiment 2), and magnitude task (experiment 3) respectively. The results found that 1) the SNARC effect was absent, but orientation spatial association effect was present in the orientation classification task. 2) the SNARC effect was only present in the orientation-response consistent condition, but absent in the orientation-response inconsistent condition in the numerical parity task (experiment 2) and numerical magnitude classification task (experiment 3). From these results, it can be concluded that 1) rotating numbers to left or right can substantially influence the SNARC effect; 2) how rotated orientation influence the SNARC effect was moderated by the task performed when numbers were rotated to left or right space. These results imply that the additional cue can substantially influence the SNARC effect in processing of numbers and support the working memory account. more...

Abstract Melanoma is a malignant skin tumor. This study aimed to explore and assess the effect of novel biomarkers on the progression of melanoma. Differently expressed genes (DEGs) were screened from GSE3189 and GSE46517 datasets of Gene Expression Omnibus database using GEO2R. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted based on the identified DEGs. Hub genes were identified and assessed using protein–protein interaction networks, principal component analysis, and receiver operating characteristic curves. Quantitative real-time polymerase chain reaction was employed to measure the mRNA expression levels. TIMER revealed the association between aldehyde dehydrogenase 2 (ALDH2) and tumor immune microenvironment. The viability, proliferation, migration, and invasion were detected by cell counting kit-8, 5-ethynyl-2′-deoxyuridine, wound healing, and transwell assays. Total 241 common DEGs were screened out from GSE3189 and GSE46517 datasets. We determined 6 hub genes with high prediction values for melanoma, which could distinguish tumor samples from normal samples. ALDH2, ADH1B, ALDH3A2, DPT, EPHX2, and GATM were down-regulated in A375 and SK-MEL-2 cells, compared with the human normal melanin cell line (PIG1 cells). ALDH2 was selected as the candidate gene in this research, presenting a high diagnostic and predictive value for melanoma. ALDH2 had a positive correlation with the infiltrating levels of immune cells in melanoma microenvironment. Overexpression of ALDH2 inhibited cell viability, proliferation, migration, and invasion of A375/SK-MEL-2 cells. ALDH2 is a new gene biomarker of melanoma, which exerts an inhibitory effect on melanoma. more...

We are examining a second-order system of non-stiff Initial Value Problems (IVP), focusing on a scenario where the first derivatives are not present. In the realm of solving IVPs, Runge-Kutta-Nyström (RKN) pairs have proven to be highly effective. In order to achieve a pair with eighth and sixth order accuracy, we need to find a solution to a well-defined set of equations regarding the coefficients. Traditionally, pairs are constructed to go through eight stages per step. However, we propose a novel approach with nine stages per step, which enables the creation of pairs with orders $ 8 $ and $ 6 $ that have notably smaller truncation errors. Our paper introduces a new pair that, as expected, outperforms existing pairs of the same orders in a range of important problems. more...

This paper reviews the field of cascaded metasurfaces, which are advanced optical devices formed by stacking or serially arranging multiple metasurface layers. These structures leverage near-field and far-field electromagnetic (EM) coupling mechanisms to enhance functionalities beyond single-layer metasurfaces. This review comprehensively discusses the physical principles, design methodologies, and applications of cascaded metasurfaces, focusing on both static and dynamic configurations. Near-field-coupled structures create new resonant modes through strong EM interactions, allowing for efficient control of light properties like phase, polarization, and wave propagation. Far-field coupling, achieved through greater interlayer spacing, enables traditional optical methods for design, expanding applications to aberration correction, spectrometers, and retroreflectors. Dynamic configurations include tunable devices that adjust their optical characteristics through mechanical motion, making them valuable for applications in beam steering, varifocal lenses, and holography. This paper concludes with insights into the potential of cascaded metasurfaces to create multifunctional, compact optical systems, setting the stage for future innovations in miniaturized and integrated optical devices. more...

Background and objective: Cerebral edema (CED) is a serious complication of acute ischemic stroke (AIS), especially in patients with large hemispheric infarction (LHI). Herein, a deep learning-based approach is implemented to extract CSF from T2-Weighted Imaging (T2WI) and evaluate the relationship between quantified cerebrospinal fluid and outcomes. Methods: Patients with acute LHI who underwent magnetic resonance imaging (MRI) were included. We used a deep learning algorithm to segment the CSF from T2WI. The hemispheric CSF ratio was calculated to evaluate its relationship with the degree of brain edema and prognosis in patients with LHI. Results: For the 93 included patients, the left and right cerebrospinal fluid regions were automatically extracted with a mean Dice similarity coefficient of 0.830. Receiver operating characteristic analysis indicated that hemispheric CSF ratio was an accurate marker for qualitative severe cerebral edema (area under receiver-operating-characteristic curve 0.867 [95% CI, 0.781–0.929]). Multivariate logistic regression analysis of functional prognosis showed that previous stroke (OR = 5.229, 95% CI 1.013–26.984), ASPECT≤6 (OR = 13.208, 95% CI 1.136–153.540) and low hemispheric CSF ratio (OR = 0.966, 95% CI 0.937–0.997) were significantly associated with higher chances for unfavorable functional outcome in patients with LHI. Conclusions: Automated assessment of CSF volume provides an objective biomarker of cerebral edema that can be leveraged to quantify the degree of cerebral edema and confirm its predictive effect on outcomes after LHI. more...

Abstract Neural interfaces for stable access to the spinal cord (SC) electrical activity can benefit patients with motor dysfunctions. Invasive high‐density electrodes can directly extract signals from SC neuronal populations that can be used for the facilitation, adjustment, and reconstruction of motor actions. However, developing neural interfaces that can achieve high channel counts and long‐term intraspinal recording remains technically challenging. Here, a biocompatible SC hyperflexible electrode array (SHEA) with an ultrathin structure that minimizes mechanical mismatch between the interface and SC tissue and enables stable single‐unit recording for more than 2 months in mice is demonstrated. These results show that SHEA maintains stable impedance, signal‐to‐noise ratio, single‐unit yield, and spike amplitude after implantation into mouse SC. Gait analysis and histology show that SHEA implantation induces negligible behavioral effects and Inflammation. Additionally, multi‐unit signals recorded from the SC ventral horn can predict the mouse's movement trajectory with a high decoding coefficient of up to 0.95. Moreover, during step cycles, it is found that the neural trajectory of spikes and low‐frequency local field potential (LFP) signal exhibits periodic geometry patterns. Thus, SHEA can offer an efficient and reliable SC neural interface for monitoring and potentially modulating SC neuronal activity associated with motor dysfunctions. more...

The highly infectious Delta variant strain of SARS-CoV-2 remains globally dominant and undermines COVID-19 vaccines. Rapid detection of the Delta variant is crucial for the identification and quarantine of infected individuals. In this study, our aim was to design and validate a genotyping RT-LAMP method to detect Delta variants specifically. R203M in the N gene of SARS-CoV-2 was chosen as the Delta variant-specific mutation for genotyping. To target the R203M-harboring region and the conserved sequence of the N gene, two sets of primers were designed, and a Cq (quantification cycle) ratio-based RT-LAMP for SARS-CoV-2 and R203M detection was developed by analyzing the significant discrepancy in amplification efficiency of the two sets of primers. We validated the RT-LAMP method on 498 clinical specimens in parallel with RT-qPCR, and 84 Delta variants from 198 positive samples were determined by sequencing. Compared with traditional RT-qPCR analyses, RT-LAMP appears to be 100% accurate in detecting SARS-CoV-2 clinical samples. RT-LAMP has a good ability to distinguish between Delta and non-Delta variants under a Cq ratio threshold of 1.80. Furthermore, the AUC (area under the curve) of this method was 1.00; the sensitivity, specificity and accuracy were all 100%. In summary, we have proposed a rapid, accurate and cost-effective RT-LAMP method to detect SARS-CoV-2 and Delta variants, which may facilitate the surveillance of COVID-19. more...

As one of the main approaches to implement phase gradient in metasurfaces, Pancharatnam-Berry (PB) phase originated from the spin–orbit interaction (SOI) of light has attracted enormous interest during the past several decades. Different from classical PB phase in linear optics that equals to twice the rotational angle of anisotropic elements for half wave plate distance and circular polarization, the recently proposed generalized PB phase indicates that phase gradient equals to multiple times the rotation angle could be achieved by high-order symmetry metallic meta atoms. Here, we show that the generalized PB phase can also be implemented in all-dielectric metasurfaces with higher efficiency than their metallic counterparts. Besides, by merging generalized PB phase and propagation phase, several functional devices are designed that the symmetric performance of PB phase can be decoupled. Moreover, a detailed comparison between meta atoms with C2, C3, and C6 rotational symmetries is conducted to illustrate the difference between classical and generalized PB phase. These results may further supplement the concept of generalized PB phase and could find many applications in optics and photonics.. more...

Objective: To investigate the distribution of axial length (AL) and posterior staphyloma (PS) in congenital cataract (CC) patients. The correlation between AL and the concentration of tissue transglutaminase (TGM2) in the aqueous humor (AH) of cataractous eyes was also evaluated. Methods: Cross-sectional data were collected from 499 children with CC who underwent phacoemulsification, anterior vitrectomy, and IOL implantation. AL measured by IOLMaster or A-scan ultrasonography and the presence of PS examined by B-scan ultrasonography were recorded. TGM2 levels in AH of 15 CC patients with normal axial length (NAL) and 15 CC patients with PS or long axial length (LAL) were measured by enzyme-linked immunosorbent assay. Results: The presence of PS in congenital cataractous eyes was 11.02%, and the presence of PS + LAL in congenital cataractous eyes was 29.06%. The AH levels of TGM2 in the cataractous group with NAL were lower than those in the cataractous group with PS or LAL (P more...

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL. more...

Abstract Background Tumor deposits (TDs) have been identified as an independent prognostic factor in gastric cancer (GC). However, the associated clinicopathological factors and how to simply and reasonably incorporate TD into the TNM staging system remain undetermined. The aim of the current study was therefore to assess the significance of TD among radically resected GC patients. Methods We retrospectively reviewed 1915 patients undergoing radical resection between 2007 and 2012. The patients were classified into two groups according to TD status (absent vs. present), and the clinicopathologic characteristics, DFS, and OS were compared. Associations of TD presence with other clinicopathologic factors were evaluated by logistic regression analysis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors for DFS and OS in the primary cohort. Propensity score matching (PSM) was performed to reduce the possibility of selection bias according to the presence of TD. External validation of previously proposed modified staging systems incorporating TD was conducted. Results The detection rate of TD was 10.5% (201/1915). The presence of TD was significantly related to unfavorable clinicopathologic variables, including advanced T and N categories. According to the multivariate Cox regression analysis, the presence of TD was identified as an independent prognostic factor for DFS and OS in the primary cohort (both P < 0.001). In the after-PSM cohort, TD presence also significantly shortened DFS and OS. In the external validation, one system that incorporated TD into the pTNM stage had the best performance. Conclusions The presence of TD was significantly associated with poor survival in radically resected GC patients. The incorporation of TD into the TNM staging system can further improve the predictive capability. A multicenter cohort with a large sample size is needed to determine the appropriate method of incorporation. more...