Colorectal cancer (CRC) remains the most prevalent malignancy of the digestive system globally and ranks second in cancer-related deaths worldwide. Metabolic reprogramming is one of the hallmarks of cancer. Aspartate is a proteinogenic non-essential amino acid with several essential functions in cancer cells. SLC1A3 is the main aspartate transporter, but its role in CRC needs to be elucidated. We found that SLC1A3 is significantly overexpressed in CRC tissues compared to adjacent normal tissues, and elevated SLC1A3 expression is associated with poor prognosis. Further, SLC1A3 could enhance the proliferation, invasion, migration of CRC cells and organoids by activating the DAG/PKC/MDM2 signaling axis. In addition, we revealed that SLC1A3 in CRC cells could induce the immunosuppressive M2 phenotype of macrophages via upregulating IL17c and CSF2. In sum, these findings suggest that SLC1A3 plays a dual role in CRC progression and may represent a promising target for therapeutic intervention.

From 2020 to 2022, colorectal cancer (CRC) cases increased, making it the third most common cancer and the second leading cause of cancer-related deaths worldwide. Early detection remains a significant challenge due to the lack of reliable diagnostic biomarkers. This study aimed to develop a robust gene diagnostic model for CRC using publicly available databases, such as GEO and GEPIA2. The approach integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and the application of 113 machine learning combinations derived from 12 algorithms. The most effective model was then validated using independent datasets, which included analyses such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI) networks, and receiver operating characteristic (ROC) curves, along with assessments of immune infiltration and tumor-node-metastasis (TNM) staging. Notably, the glmBoost + RF algorithm identified an eight-gene diagnostic model with high precision, pinpointing key genes such as CLDN1, IFITM1, and FOXQ1, which exhibited strong diagnostic performance (AUC > 0.9). Furthermore, Mendelian randomization (MR) analysis suggested that IFITM1 may be a potential causal gene for CRC, with significant associations to immune cell profiles and established roles in immune regulation and tumor progression. Collectively, these findings highlight IFITM1, SCGN, and FOXQ1 as promising early diagnostic biomarkers and therapeutic targets for CRC, laying a foundation for future research focused on enhancing early detection and intervention strategies in colorectal cancer management.

The current understanding and a standardized assessment or treatment guidelines for keloids are not fully established, highlighting the need for an objective method to gauge keloid severity and treatment outcomes. This study investigated the clinical utility of multimodal ultrasound, integrating Shear Wave Elastography (SWE) and Angio planewave ultrasensitive imaging (AP), to assess keloid severity and treatment responses in 58 keloids across 31 patients. Keloids were categorized into mild, moderate, and severe based on Vancouver Scar Scale (VSS) scores. The results revealed significant differences in keloid thickness, elasticity parameters, and blood flow levels among severity groups, with the AP technique demonstrated superior sensitivity in detecting keloid microcirculation. Additionally, the study evaluated the therapeutic response to Strontium-90 Yttrium-90 isotope applicator treatment in 28 keloids, categorizing them into 13 good responders and 15 poor responders based on improvements observed in their VSS scores. Good responders demonstrated marked improvements post-treatment, including significant flattening of the keloids, decreased stiffness, and normalization of blood flow levels. In contrast, poor responders exhibited minimal changes in keloid thickness, stiffness, and blood flow signals following treatment. These findings underscore the effectiveness of multimodal ultrasound in evaluating treatment responses in keloid management. In conclusion, multimodal ultrasound, focusing on SWE and AP modalities, offers a promising tool for comprehensive assessment, with potential to enhance keloid evaluation and track treatment responses across varying therapeutic interventions, thereby facilitating optimized clinical management and guiding personalized treatment. The study was successfully registered on ClinicalTrials.gov on 12/09/2023, with the Identifier NCT06034587.

Colorectal cancer (CRC) is a prevalent type of cancer affecting the digestive system, characterized by a complex and not fully understood development process. Inflammation and metabolic processes are thought to play significant roles in both the initiation and progression of this disease. This study aimed to clarify the causal relationships between CRC and specific inflammatory proteins, immune cell types, and metabolites, while also exploring potential bidirectional associations and identifying possible therapeutic targets. We employed Mendelian Randomization (MR) analysis to investigate a wide array of biological factors, including 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell characteristics, and 1,400 metabolites. Additionally, we utilized bioinformatics techniques such as constructing Protein-Protein Interaction (PPI) networks, performing Gene Ontology (GO) enrichment, and conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Our results indicated significant associations between CRC and 104 circulating proteins, 5 inflammatory proteins, 24 immune cell traits, and 28 metabolites. Through subnetwork analysis, we identified 15 central proteins, among which Tissue Inhibitor of Metalloproteinase 1 (TIMP1) showed notable variability in expression. This finding was computationally validated through survival analysis data from the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases. Furthermore, molecular docking studies confirmed TIMP1 as a promising drug target, demonstrating stable interactions with compounds such as meclizine and megestrol. Overall, this research enhances our understanding of CRC pathogenesis by emphasizing the roles of inflammation, immune response, and metabolic pathways, and it suggests TIMP1 as a particularly promising target for future therapeutic development.

Background Fibrotic scar formation is a critical pathological change impacting tissue reconstruction and functional recovery after ischemic stroke. The regulatory mechanisms behind fibrotic scarring in the central nervous system (CNS) remain largely unknown. While macrophages are known to play a role in fibrotic scar formation in peripheral tissues, the involvement of microglia, the resident immune cells of the CNS, in CNS fibrosis requires further exploration. The Sonic Hedgehog (Shh) signaling pathway, pivotal in embryonic development and tissue regeneration, is also crucial in modulating fibrosis in peripheral tissues. However, the impact and regulatory mechanisms of Shh on fibrotic scar formation post-ischemic stroke have not been thoroughly investigated. Methods This study explores whether Shh can regulate fibrotic scar formation post-ischemic stroke and its underlying mechanisms through in vivo and in vitro manipulation of Shh expression. Results Our results showed that Shh expression was upregulated in the serum of acute ischemic stroke patients, as well as in the serum, CSF, and ischemic regions of MCAO/R mice. Moreover, the upregulation of Shh expression was positively correlated with fibrotic scar formation and M2 microglial polarization. Shh knockdown inhibited fibrotic scar formation and M2 microglial polarization while aggravating neurological deficits in MCAO/R mice. In vitro, adenoviral knockdown or Smoothened Agonist (SAG) activation of Shh expression in BV2 cells following OGD/R regulated their polarization and influenced the expression of TGFβ1 and PDGFA, subsequently affecting fibroblast activation. Conclusion These results suggest that Shh regulates M2 microglial polarization and fibrotic scar formation after cerebral ischemia.

In this paper, Si-based composites coated by a multi-component layer have been synthetically prepared, via a solvothermal process, mechanical ball milling, and subsequent high-temperature calcination. The multi-component surface layer consists of an amorphous SiOx/C layer with well dispersion of TiC and TiB2 nanocrystals and amorphous TiOx and B2O3. The introduction of titanium and boron species is beneficial for the improvement of mechanical stability of the coating layer and ensures the structural integrity of the electrode during cycling, consequently leading to excellent electrochemical performances. Therefore, the obtained Si-based composites exhibit much better high-rate performances and cycling stability than Si and Si/C electrodes. Si-based composites from 2.94 mmol tetrabutyl titanate deliver specific capacities of 1377, 1361, 1247, 1104, 949, 833, 669, and 526 mAh·g−1 at 0.1, 0.2, 0.5, 1.0, 2.0, 3.0, 5.0, and 8.0 A·g−1, respectively, and capacity retention of 76.7

Background and Purpose: Ischemic stroke is a leading cause of mortality and disability globally, necessitating accurate prediction of intra-hospital mortality (IHM) for improved patient care. This study aimed to develop a practical nomogram for personalized IHM risk prediction in ischemic stroke patients. Methods: A retrospective study of 422 ischemic stroke patients (April 2020 - December 2021) from Chongqing Medical University's First Affiliated Hospital was conducted, with patients divided into training (n=295) and validation (n=127) groups. Data on demographics, comorbidities, stroke risk factors, and lab results were collected. Stroke severity was assessed using NIHSS, and stroke types were classified by TOAST criteria. Least absolute shrinkage and selection operator (LASSO) regression was employed for predictor selection and nomogram construction, with evaluation through ROC curves, calibration curves, and decision curve analysis. Results: LASSO regression and multivariate logistic regression identified four independent IHM predictors: age, admission NIHSS score, chronic obstructive pulmonary disease (COPD) diagnosis, and white blood cell count (WBC). A highly accurate nomogram based on these variables exhibited excellent predictive performance, with AUCs of 0.958 (training) and 0.962 (validation), sensitivities of 93.2% and 95.7%, and specificities of 93.1% and 90.9%, respectively. Calibration curves and decision curve analysis validated its clinical applicability. Conclusion: Age, admission NIHSS score, COPD history, and WBC were identified as independent IHM predictors in ischemic stroke patients. The developed nomogram demonstrated high predictive accuracy and practical utility for mortality risk estimation. External validation and prospective studies are warranted for further confirmation of its clinical efficacy.

Background and purpose: Clinically, the ability to identify individuals at risk of ischemic stroke remains limited. This study aimed to develop a nomogram model for predicting the risk of acute ischemic stroke. Methods: In this study, we conducted a retrospective analysis on patients who visited the Department of Neurology, collecting important information including clinical records, demographic characteristics, and complete hematological tests. Participants were randomly divided into training and internal validation sets in a 7:3 ratio. Based on their diagnosis, patients were categorized as having or not having ischemic stroke (ischemic and non-ischemic stroke groups). Subsequently, in the training set, key predictive variables were identified through multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression methods, and a nomogram model was constructed accordingly. The model was then evaluated on the internal validation set and an independent external validation set through area under the receiver operating characteristic curve (AUC-ROC) analysis, a Hosmer-Lemeshow goodness-of-fit test, and decision curve analysis (DCA) to verify its predictive efficacy and clinical applicability. Results: Eight predictors were identified: age, smoking status, hypertension, diabetes, atrial fibrillation, stroke history, white blood cell count, and vitamin B12 levels. Based on these factors, a nomogram with high predictive accuracy was constructed. The model demonstrated good predictive performance, with an AUC-ROC of 0.760 (95% confidence interval [CI]: 0.736–0.784). The AUC-ROC values for internal and external validation were 0.768 (95% CI: 0.732–0.804) and 0.732 (95% CI: 0.688–0.777), respectively, proving the model’s capability to predict the risk of ischemic stroke effectively. Calibration and DCA confirmed its clinical value. Conclusions: We constructed a nomogram based on eight variables, effectively quantifying the risk of ischemic stroke.

OBJECTIVES:Clinical manifestations of vitamin B12 deficiency are varied and may result in missed or delayed diagnosis. This investigation explores the diverse clinical manifestations and demographic characteristics of vitamin B12 deficiency in neurology outpatients, aiming to enhance timely diagnosis and outcomes. METHODS:The severity of vitamin B12 deficiency was classified as absolute (≤150 pg/mL) or borderline deficiency (150-300 pg/mL). We conducted a retrospective analysis of 165 outpatients with vitamin B12 deficiency at the department of neurology between May 2020 and May 2021. RESULT:Absolute vitamin B12 deficiency was found in 23.0% of the patients. The most common age range was 50-60 years, the most common cause was vegetarianism, and the most common symptom was headache. Epileptiform symptoms were more likely to occur in younger patients (<20 years old) with vitamin B12 deficiency, whereas psychiatric symptoms were more likely to occur in older patients (>70 years old). Vegetarians, salivation, and nonmegaloblastic anemia were more obvious in patients with absolute vitamin B12 deficiency, whereas headaches often showed borderline B12 deficiency. CONCLUSIONS:The clinical characteristics of vitamin B12 deficiency are complex and nonspecific. The diagnosis should be based on multiple factors.

In this work, rutile-phase Ti0.95Nb0.95O4/C (TNO/C) composites with different carbon contents were obtained through solvothermal method and subsequent calcination. The effect of carbon component on the microstructure and electrochemical performances of TNO/C composites were investigated. The results indicate more oxygen vacancies, and higher contents of Nb4+ and Ti3+ can be obtained under higher carbon content, leading to enhanced conductivity. Besides serving as conductive agent, carbon component in TNO/C composites also acts as an active component for Li+ storage, and pseudocapacitance provided by carbon component increases with the increasing of its relative content. Therefore, TNO/C-27.0 composites with the highest carbon content in the as-prepared composites deliver the highest reversible capacities at different current densities and excellent cycling capability of 488 mAh·g−1 at 0.3 A·g−1 after 300 cycles and 331 mAh·g−1 at 1.0 A·g−1 after 500 cycles.

In this study, composites with Co8FeS8 nanoparticles encapsulated in N-doped carbon tubes/carbon structure (Co8FeS8/NCTs@C) were developed, wherein NCTs and C serve as supporting carrier and surface coating layer, respectively. The synergistic effect of NCTs and C effectively avoids aggregation of Co8FeS8 nanoparticles, improves the conductivity and ensures the integrity of electrodes during cycling. Therefore, Co8FeS8/NCTs@C shows excellent performance as anode of Li-ion batteries. Their specific capacities at 0.1, 0.2, 0.3, 0.5, 1.0 and 2.0 A·g−1 are 1002, 871, 822, 760, 678 and 602 mAh·g−1, respectively. Moreover, the specific capacities are 1032 mAh·g−1 at 0.3 A·g−1 after 140 cycles and 878 mAh·g−1 at 1.0 A·g−1 after 300 cycles.

Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a concentric circle structure with two α rings and two β rings overlapped. The proteasome 20S can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits (such as 19S, 11S, and 200PA), which is performed by its active subunit β1, β2, and β5. The proteasome can degrade misfolded, excess proteins to maintain homeostasis. At the same time, it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth. Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-κB and p53, cell cycle, immune regulation, and drug resistance. Proteasome-encoding genes have been found to be overexpressed in a variety of tumors, providing a potential novel target for cancer therapy. In addition, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma. More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma, non-small cell lung cancer, glioblastoma, and neuroblastoma. However, proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors. Therefore, further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

Loss of E-cadherin (ECAD) is required in tumor metastasis. Protein degradation of ECAD in response to oxidative stress is found in metastasis of hepatocellular carcinoma (HCC) and is independent of transcriptional repression as usually known. Mechanistically, protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344. The activation of PKA kinase activity subsequently induces RNF25 phosphorylation at Ser450 to initiate RNF25-catalyzed degradation of ECAD. Functionally, RNF25 repression induces ECAD protein expression and inhibits HCC metastasis in vitro and in vivo. Altogether, these results indicate that RNF25 is a critical regulator of ECAD protein turnover, and PKA is a necessary redox sensor to enable this process. This study provides some mechanistic insight into how oxidative stress-induced ECAD degradation promotes tumor metastasis of HCC.

The moderate formation of the fibrotic scar plays an important role in functional recovery after stroke. M2a macrophages have been identified as an important source of early fibrosis after cerebral ischemia. However, the underlying mechanisms by which macrophages interact with fibroblasts in this context remain largely unknown. Therefore, our study aimed to further investigate the potential mechanisms underlying the effects of macrophages on fibroblasts following ischemic stroke. In vitro and in vivo, recombinant rat interleukin 4 (IL4) was used to induce macrophages to polarize into M2a macrophages. In vitro, primary Sprague-Dawley newborn rat meningeal-derived fibroblasts were treated with PU.1 knockdown, the PU.1 inhibitor DB1976 or the mTOR inhibitor rapamycin, which were then co-cultured with M2a macrophage conditioned medium (MCM). In vivo, Sprague-Dawley adult rats were infected with negative control adenoviruses or PU.1-shRNA adenoviruses. Ten days after infection, an injury model of middle cerebral artery occlusion/reperfusion (MCAO/R) was constructed. Subsequently, IL4 was injected intracerebroventricularly to induce M2a macrophages polarization. In vitro, M2a MCM upregulated PU.1 expression and promoted the differentiation, proliferation, migration and extracellular matrix generation of fibroblasts, which could be reversed by treatment with the PU.1 inhibitor DB1976 or PU.1 knockdown. In vivo, PU.1 expression in fibroblasts was increased within ischemic core following MCAO/R, and this upregulation was further enhanced by exposure to IL4. Treatment with IL4 promoted fibrosis, increased angiogenesis, reduced apoptosis and infarct volume, as well as mitigated neurological deficits after MCAO/R, and these effects could be reversed by PU.1 knockdown. Furthermore, both in vivo and in vitro studies showed that IL4 treatment increased the levels of phosphorylated Akt and mTOR proteins, which were markedly decreased by PU.1 knockdown. Additionally, the use of an mTOR inhibitor rapamycin obviously suppressed the migration and differentiation of fibroblasts, and Col1 synthesis. In conclusion, our findings suggest for the first time that M2a macrophages, at least in part, regulate fibrosis and affect the outcome after cerebral ischemic stroke via the PU.1/mTOR signaling pathway in fibroblasts.

RNA-binding protein (RBP) plays pivotal roles in the malignant progression of cancer by regulating gene expression. In this paper, we aimed to develop RBP-based prognostic signature and identify critical hub RBPs in bladder cancer (BLCA). Firstly, a risk model based on differentially expressed RBP gens (DERBPs) between normal and tumor tissues was successfully established, which can predict the tumor stromal score and drug sensitivity. Then two another RBP risk models based on miRNA-correlated RBPs or lncRNA-correlated RBPs were also established, and RBMS3 was identified as the overlapping gene in the three models. Data from multiple bioinformatics databases revealed that RBMS3 was an independent prognostic factor for overall survival (OS), and was associated with an immunosuppressive tumor microenvironment (TME) in BLCA. Further, Single-cell RNA-Seq (scRNA-Seq) data and the human protein altas (HPA) database showed that RBMS3 expression (both mRNA and protein) were up-regulated in BLCA tumor and tumor stromal cells. Finally, RBMS3 was shown to be associated with worse response to BLCA immunotherapy. Overall, RBMS3 is a key prognostic RBP with TME remodeling function and may serve as a target for BLCA immunotherapy.

Circadian rhythm disruption impacts the efficiency of both chemotherapy and immunotherapy, yet identifying the key factors involved remains challenging. Circadian rhythm disruption can trigger aberrant fibroblasts activation, suggesting potential roles of cancer-associated fibroblasts (CAFs) in addressing this issue. In this paper, TCGA-BLCA patients were classified into two subgroups based on the expression of core circadian rhythm genes (CCRGs). The CCRG-based subgroups showed distinct fibroblast-related signals, from which a risk model composed of five fibroblast-related genes was finally established with excellent survival prognostic value in both TCGA and GEO datasets. The risk model was positively associated with the infiltration of CAFs and can efficiently predict the immunotherapy response in BLCA. Besides, high-risk score was associated with reduced sensitivity to a majority of traditional chemotherapeutic drugs such as oxaliplatin and gemcitabine. Further, the correlation between CCRGs and the risk genes was analyzed. Among the five risk genes, FAM20C displayed the most extensive correlation with the CCRGs and exhibited the strongest connection with CAFs infiltration. Moreover, FAM20C independently served as a predictor for the response to immunotherapy in BLCA. In conclusion, this study has identified a circadian-based signature for evaluating CAFs infiltration and predicting the efficacy of chemotherapy and immunotherapy. The central gene FAM20C has emerged as a promising candidate which merits further investigations.

Colorectal cancer (CRC) is one of the most common and deadly malignancies worldwide, and immune regulation plays a critical role in its development. This study investigates the causal relationships between uveitis, specific immune cell traits, and CRC using Mendelian Randomization (MR) analyses. A total of 21 single nucleotide polymorphisms (SNPs) associated with uveitis were identified, and the analysis revealed that a 1 log-odds increase in uveitis was linked to a statistically significant 3.0% reduction in CRC odds (IVW OR = 0.970, 95% CI: 0.946-0.995, P = 0.021). This protective effect was also observed using the weighted median approach (OR = 0.963, 95% CI: 0.931-0.997, P = 0.034), reinforcing the robustness of the findings. Furthermore, both univariable and multivariable MR analyses highlighted the significant causal influence of specific immune cell traits on CRC odds. Notably, the levels of extracellular monocyte HLA-DR expression emerged as a critical factor, with an associated increase in CRC odds (IVW OR = 1.084, 95% CI: 1.008-1.165, P = 0.030). The proportion of CRC odds mediated by the levels of extracellular monocyte HLA-DR expression, calculated as the ratio of the indirect effect to the total effect using estimates from multivariable MR analyses, was approximately 34.1%(95% CI: 10.23-58.04%). These findings underscore the complex interplay between immune regulation and carcinogenesis, offering insights into potential mechanisms underlying CRC development and suggesting avenues for targeted prevention and therapeutic strategies.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Numerous studies have shown that metabolic reprogramming is crucial for the development of HCC. Carbamoyl phosphate synthase 1 (CPS1), a rate-limiting enzyme in urea cycle, is an abundant protein in normal hepatocytes, however, lacking systemic research in HCC. It is found that CPS1 is low-expressed in HCC tissues and circulating tumor cells, negatively correlated with HCC stage and prognosis. Further study reveals that CPS1 is a double-edged sword. On the one hand, it inhibits the activity of phosphatidylcholine-specific phospholipase C to block the biosynthesis of diacylglycerol (DAG), leading to the downregulation of the DAG/protein kinase C pathway to inhibit invasion and metastasis of cancer cells. On the other hand, CPS1 promotes cell proliferation by increasing intracellular S-adenosylmethionin to enhance the m6A modification of solute carrier family 1 member 3 mRNA, a key transporter for aspartate intake. Finally, CPS1 overexpressing adeno-associated virus can dampen HCC progression. Collectively, this results uncovered that CPS1 is a switch between HCC proliferation and metastasis by increasing intracellular aspartate level.

Elucidating cellular architecture and cell-type evolution across species is central to understanding immune system function and susceptibility to disease. Adaptive immunity is a shared trait of the common ancestor of cartilaginous and bony fishes. However, evolutionary features of lymphocytes in these two jawed vertebrates remain unclear. Here, we present a single-cell RNA sequencing atlas of immune cells from cartilaginous (white-spotted bamboo shark) and bony (zebrafish and Chinese tongue sole) fishes. Cross-species comparisons show that the same cell types across different species exhibit similar transcriptional profiles. In the bamboo shark, we identify a phagocytic B cell population expressing several pattern recognition receptors, as well as a T cell sub-cluster co-expressing both T and B cell markers. In contrast to a division by function in the bony fishes, we show close linkage and poor functional specialization among lymphocytes in the cartilaginous fish. Our cross-species single-cell comparison presents a resource for uncovering the origin and evolution of the gnathostome immune system.