Size-Optimized Layered Double Hydroxide Nanoparticles Promote Neural Progenitor Cells Differentiation of Embryonic Stem Cells Through the Regulation of M6A Methylation.

Purpose: The committed differentiation fate regulation has been a difficult problem in the fields of stem cell research, evidence showed that nanomaterials could promote the differentiation of stem cells into specific cell types. Layered double hydroxide (LDH) nanoparticles possess the regulation function of stem cell fate, while the underlying mechanism needs to be investigated. In this study, the process of embryonic stem cells (ESCs) differentiate to neural progenitor cells (NPCs) by magnesium aluminum LDH (MgAl-LDH) was investigated. Methods: MgAl-LDH with diameters of 30, 50, and 100 nm were synthesized and characterized, and their effects on the cytotoxicity and differentiation of NPCs were detected in vitro. Dot blot and MeRIP-qPCR were performed to detect the level of m6A RNA methylation in nanoparticles-treated cells. Results: Our work displayed that LDH nanoparticles of three different sizes were biocompatible with NPCs, and the addition of MgAl-LDH could significantly promote the process of ESCs differentiate to NPCs. 100 nm LDH has a stronger effect on promoting NPCs differentiation compared to 30 nm and 50 nm LDH. In addition, dot blot results indicated that the enhanced NPCs differentiation by MgAl-LDH was closely related to m6A RNA methylation process, and the major modification enzyme in LDH controlled NPCs differentiation may be the m6A RNA methyltransferase METTL3. The upregulated METTL3 by LDH increased the m6A level of Sox1 mRNA, enhancing its stability. Conclusion: This work reveals that MgAl-LDH nanoparticles can regulate the differentiation of ESCs into NPCs by increasing m6A RNA methylation modification of Sox1.

Application of Bioactive Materials for Osteogenic Function in Bone Tissue Engineering.

Bone tissue defects present a major challenge in orthopedic surgery. Bone tissue engineering using multiple versatile bioactive materials is a potential strategy for bone-defect repair and regeneration. Due to their unique physicochemical and mechanical properties, biofunctional materials can enhance cellular adhesion, proliferation, and osteogenic differentiation, thereby supporting and stimulating the formation of new bone tissue. 3D bioprinting and physical stimuli-responsive strategies have been employed in various studies on bone regeneration for the fabrication of desired multifunctional biomaterials with integrated bone tissue repair and regeneration properties. In this review, biomaterials applied to bone tissue engineering, emerging 3D bioprinting techniques, and physical stimuli-responsive strategies for the rational manufacturing of novel biomaterials with bone therapeutic and regenerative functions are summarized. Furthermore, the impact of biomaterials on the osteogenic differentiation of stem cells and the potential pathways associated with biomaterial-induced osteogenesis are discussed.

ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases.

Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.

Spinal Nmur2-positive Neurons Play a Crucial Role in Mechanical Itch.

The dorsal spinal cord is crucial for the transmission and modulation of multiple somatosensory modalities, such as itch, pain, and touch. Despite being essential for the well-being and survival of an individual, itch and pain, in their chronic forms, have increasingly been recognized as clinical problems. Although considerable progress has been made in our understanding of the neurochemical processing of nociceptive and chemical itch sensations, the neural substrate that is crucial for mechanical itch processing is still unclear. Here, using genetic and functional manipulation, we identified a population of spinal neurons expressing neuromedin U receptor 2 (Nmur2+) as critical elements for mechanical itch. We found that spinal Nmur2+ neurons are predominantly excitatory neurons, and are enriched in the superficial laminae of the dorsal horn. Pharmacogenetic activation of cervical spinal Nmur2+ neurons evoked scratching behavior. Conversely, the ablation of these neurons using a caspase-3-based method decreased von Frey filament-induced scratching behavior without affecting responses to other somatosensory modalities. Similarly, suppressing the excitability of cervical spinal Nmur2+ neurons via the overexpression of functional Kir2.1 potassium channels reduced scratching in response to innocuous mechanical stimuli, but not to pruritogen application. At the lumbar level, pharmacogenetic activation of these neurons evoked licking and lifting behaviors. However, ablating these neurons did not affect the behavior associated with acute pain. Thus, these results revealed the crucial role of spinal Nmur2+ neurons in mechanical itch. Our study provides important insights into the neural basis of mechanical itch, paving the way for developing novel therapies for chronic itch. PERSPECTIVE: Excitatory Nmur2+ neurons in the superficial dorsal spinal cord are essential for mechanical but not chemical itch information processing. These spinal Nmur2+ neurons represent a potential cellular target for future therapeutic interventions against chronic itch. Spinal and supraspinal Nmur2+ neurons may play different roles in pain signal processing.

Deep whole-genome analysis of 494 hepatocellular carcinomas.

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1-3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4-8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications.

Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions.

Despite considerable efforts to identify human liver cancer genomic alterations that might unveil druggable targets, the systematic translation of multiomics data remains challenging. Here, we report success in long-term culture of 64 patient-derived hepatobiliary tumor organoids (PDHOs) from a Chinese population. A divergent response to 265 metabolism- and epigenetics-related chemicals and 36 anti-cancer drugs is observed. Integration of the whole genome, transcriptome, chromatin accessibility profiles, and drug sensitivity results of 64 clinically relevant drugs defines over 32,000 genome-drug interactions. RUNX1 promoter mutation is associated with an increase in chromatin accessibility and a concomitant gene expression increase, promoting a cluster of drugs preferentially sensitive in hepatobiliary tumors. These results not only provide an annotated PDHO biobank of human liver cancer but also suggest a systematic approach for obtaining a comprehensive understanding of the gene-regulatory network of liver cancer, advancing the applications of potential personalized medicine.

Positive Correlation Between Motor Function and Neuropathic Pain-Like Behaviors After Spinal Cord Injury: A Longitudinal Study of Mice.

Abstract With the recovery of motor function, some spinal cord injury (SCI) patients still suffer from severe pain-like behaviors symptoms. Whether motor function correlates with neuropathic pain-like behaviors remain unclear. In this study, a longitudinal cohort study of mice with moderate thoracic 10 contusion was performed to explore the characteristics of neuropathic pain-like behaviors and its correlation with motor function in different sexes. Pain-like behaviors data up to 42 days post-injury (dpi) were collected and compared. Mice of both sexes were divided into three groups based on their Basso Mouse Scale at 42 dpi. There was no significant difference in motor function recovery between the sexes. Female mice showed more significant mechanical allodynia than males at 14 dpi, which was sustained until 42 dpi without significant dynamic changes. However, males showed a gradually worsening state and more severe mechanical allodynia than females at 28 dpi, and then the differences disappeared. Interestingly, male mice obtained more severe cold hyperalgesia symptoms than females. Additionally, we found that there was a correlation between the occurrence of mechanical allodynia and cold and thermal hyperalgesia. Importantly, motor function recovery was positively associated with the outcomes of neuropathic pain-like behaviors after SCI, which was more obvious in female mice. Our data not only revealed the characteristics of neuropathic pain-like behaviors but also clarified the correlations between motor function recovery and neuropathic pain-like behaviors after SCI. These findings may provide new opinions and suggestions for promoting the clinical diagnosis and treatment of neuropathic pain-like behaviors after SCI.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid ß (Aß)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aß phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.

Development of a nomogram model for prediction of new adjacent vertebral compression fractures after vertebroplasty.

BACKGROUND: Vertebroplasty is the main minimally invasive operation for osteoporotic vertebral compression fracture (OVCF), which has the advantages of rapid pain relief and shorter recovery time. However, new adjacent vertebral compression fracture (AVCF) occurs frequently after vertebroplasty. The purpose of this study was to investigate the risk factors of AVCF and establish a clinical prediction model. METHODS: We retrospectively collected the clinical data of patients who underwent vertebroplasty in our hospital from June 2018 to December 2019. The patients were divided into a non-refracture group (289 cases) and a refracture group (43 cases) according to the occurrence of AVCF. The independent predictive factors for postoperative new AVCF were determined by univariate analysis, least absolute shrinkage and selection operator (LASSO) logistic regression, and multivariable logistic regression analysis. A nomogram clinical prediction model was established based on relevant risk factors, and the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were used to evaluate the prediction effect and clinical value of the model. After internal validation, patients who underwent vertebroplasty in our hospital from January 2020 to December 2020, including a non-refracture group (156 cases) and a refracture group (21 cases), were included as the validation cohort to evaluate the prediction model again. RESULTS: Three independent risk factors of low bone mass density (BMD), leakage of bone cement and "O" shaped distribution of bone cement were screened out by LASSO regression and logistic regression analysis. The area under the curve (AUC) of the model in the training cohort and the validation cohort was 0.848 (95%CI: 0.786-0.909) and 0.867 (95%CI: 0.796-0.939), respectively, showing good predictive ability. The calibration curves showed the correlation between prediction and actual status. The DCA showed that the prediction model was clinically useful within the whole threshold range. CONCLUSION: Low BMD, leakage of bone cement and "O" shaped distribution of bone cement are independent risk factors for AVCF after vertebroplasty. The nomogram prediction model has good predictive ability and clinical benefit.

The impact of carbon information disclosure quality on the financial performance based on UNC combination weight and FA: evidence from public companies in China's electric power industry.

As a significant carbon emitter, China has set a target in 2020 of "carbon peaking and carbon neutrality." This target presents stricter criteria for the company's carbon information disclosure quality (CIDQ). Meantime, financial performance (FP) is a primary consideration for companies and their stakeholders. Therefore, this paper selected public companies in the electric power industry (EPI), which are the first to be integrated into the carbon emissions trading market, to research the impact of CIDQ on FP. Theoretically, this paper enhances the conclusions regarding the impact of CIDQ on FP, which might serve as a reference for future research, and practically, this paper can reduce management resistance to carbon information disclosure in pursuing profit, facilitate the co-improvement of CIDQ and FP, contribute in achieving China's target of "carbon peaking and carbon neutrality." First, this paper constructed a CIDQ evaluation index system by analyzing the characteristics of diverse sub-sectors within the EPI, which can make the CIDQ evaluation system more rational, and then evaluated it using a comprehensive evaluation method based on uncertain normal cloud (UNC) combination weight, which can reflect the ambiguity and uncertainty of the information obtained during the process of evaluating the company's CIDQ, and broaden the thought process for evaluating the CIDQ. Furthermore, the paper used factor analysis (FA) to evaluate FP, effectively resolving the issue of massive data while preserving the essential information of financial indicators. Finally, the paper concluded by analyzing the impact of the CIDQ on FP using a multiple linear regression model. The results indicated that the CIDQ by electric public companies has a positive impact on solvency and profitability, a negative impact on operating capacity, and a non-significant impact on development capacity. In response to these conclusions, this paper proposed corresponding suggestions at the government, society, and company levels.

Integrated Multi-Omics Landscape of Liver Metastases.

BACKGROUND & AIMS: Lack of thorough knowledge about the complicated immune microenvironment (IM) within a variety of liver metastases (LMs) leads to inappropriate treatment and unsatisfactory prognosis. We aimed to characterize IM subtypes and investigate potential mechanisms in LMs. METHODS: Mass cytometry was applied to characterize immune landscape of a primary liver cancers and liver metastases cohort. Transcriptomic and whole-exome sequencing were used to explore potential mechanisms across distinct IM subtypes. Single-cell transcriptomic sequencing, multiplex fluorescent immunohistochemistry, cell culture, mouse model, Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used for validation. RESULTS: Five IM subtypes were revealed in 100 LMs and 50 primary liver cancers. Patients featured terminally exhausted (IM1) or rare T-cell-inflamed (IM2 and IM3) immune characteristics showed worse outcome. Increased intratumor heterogeneity, enriched somatic TP53, KRAS, APC, and PIK3CA mutations and hyperactivated hypoxia signaling accounted for the formation of vicious subtypes. SLC2A1 promoted immune suppression and desert via increasing proportion of Spp1+ macrophages and their inhibitory interactions with T cells in liver metastatic lesions. Furthermore, SLC2A1 promoted immune escape and LM through inducing regulatory T cells, including regulatory T cells and LAG3+CD4+ T cells in primary colorectal cancer. CONCLUSIONS: The study provided integrated multi-omics landscape of LM, uncovering potential mechanisms for vicious IM subtypes and confirming the roles of SLC2A1 in regulating tumor microenvironment remodeling in both primary tumor and LM lesions.

The origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after spinal cord injury.

Accaumulating studies focus on the effects of C3-positive A1-like phenotypes and S100A10-positive A2-like phenotypes of reactive astrocytes on spinal cord injury (SCI), however the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI remain poorly understood. Through transgenic mice and lineage tracing, we aimed to determine the origins of C3- and S100A10-positive reactive astrocytes. Meanwhile, the distribution and dynamic changes in C3- and S100A10-positive reactive astrocytes were also detected in juvenile and adult SCI mice models and cultured astrocytes. Combing with bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq) and bioinformatic analysis, we further explored the dynamic transcripts changes of C3- and S100A10-positive reactive astrocytes after SCI. We confirmed that resident astrocytes produced both C3- and S100A10-positive reactive astrocytes, whereas ependymal cells regenerated only S100A10-positive reactive astrocytes in lesion area. Importantly, C3-positive reactive astrocytes were predominantly activated in adult SCI mice, while S100A10-positive reactive astrocytes were hyperactivated in juvenile mice. Furthermore, we observed that C3- and S100A10-positive reactive astrocytes had a dynamic transformation process at different time in vitro and vivo, and a majority of intermediate states of C3- and S100A10-positive reactive astrocytes were found during transformation. RNA-seq and scRNA-seq results further confirmed that the transcripts of C3-positive reactive astrocytes and their lipid toxicity were gradually increased with time and age. In contrast, S100A10-positive reactive astrocytes transcripts increased at early time and then gradually decreased after SCI. Our results provide insight into the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI, which would be valuable resources to further target C3- and S100A10-positive reactive astrocytes after SCI.

Single-cell atlas of diverse immune populations in the advanced biliary tract cancer microenvironment.

Immunotherapies have been explored in treating solid tumors, albeit with disparate clinical effects in distinct cancer types. Systematic interrogation of immune cells in the tumor microenvironment (TME) is vital to the prediction of immunotherapy response and the development of innovative immunotherapeutics. To comprehensively characterize the immune microenvironment in advanced biliary tract cancer (BTC), we utilized single-cell RNA sequencing in unselected viable cells from 16 matched samples, and identified nineteen cell subsets from a total of 45,851 cells, in which exhausted CD8+ T cells, macrophages, and dendritic cells (DCs) in BTC were shown to augment and communicate within the TME. Transcriptional profiles coupled with T cell receptor (TCR) sequences revealed that exhausted CD8+ T cells retained clonal expansion and high proliferation in the TME, and some of them highly expressed the endoplasmic reticulum stress (ER) response gene, XBP1, indicating the role of ER stress in remodeling TME. Functional assays demonstrated that XBP1 and common immune checkpoints (PD1, TIGIT) were significantly upregulated in CD8+ T cells cocultured within the TME of BTC cells (GBC-SD, HCCC-9810). When treating the coculture groups with the specific inhibitor of IRE1α-XBP1 (4µ8C), the downregulation of TIGIT was observed in the treatment group. Collectively, comprehensive transcriptome profiling provides deep insights into the immune atlas in advanced BTC, which might be instrumental in exploring innovative immunotherapy strategies.

Microalgae simultaneously promote antibiotic removal and antibiotic resistance genes/bacteria attenuation in algal-bacterial granular sludge system.

This study investigated the effects of microalgae growth on antibiotic removal and the attenuation of antibiotic resistance genes (ARGs)/ARGs host bacteria in algal-bacterial granular sludge (ABGS) system. In the presence of tetracycline (TC) and sulfadiazine (SDZ) mixture (2-4 mg/L), microalgae could grow on bacterial granular sludge (BGS) to form ABGS, with a chlorophyll-a content of 7.68-8.13 mg/g-VSS being achieved. The removal efficiencies of TC and SDZ by ABGS were as high as 79.0 % and 94.0 %, which were 4.3-5.0 % higher than those by BGS. Metagenomic analysis indicated that the relative abundances of TC/SDZ- related ARGs and mobile genetic elements (MGEs) in BGS were 56.1 % and 22.1 % higher than those in ABGS. A total of 26 ARGs were detected from the granules, and they were identified to associate with 46 host bacteria. 13 out of 26 ARGs and 13 out of 46 hosts were shared ARGs and hosts, respectively. The total relative abundance of host bacteria in BGS was 30.8 % higher than that in ABGS. Scenedesmus and Chlorella were the dominant microalgae that may reduce the diversity of ARGs hosts. Overall, ABGS is a promising biotechnology for antibiotic-containing wastewater treatment.

Hepatobiliary Tumor Organoids Reveal HLA Class I Neoantigen Landscape and Antitumoral Activity of Neoantigen Peptide Enhanced with Immune Checkpoint Inhibitors.

Neoantigen-directed therapy lacks preclinical models recapitulating neoantigen characteristics of original tumors. It is urgent to develop a platform to assess T cell response for neoantigen screening. Here, immunogenic potential of neoantigen-peptides of tumor tissues and matched organoids (n = 27 pairs) are analyzed by Score tools with whole genome sequencing (WGS)-based human leukocyte antigen (HLA)-class-I algorithms. The comparisons between 9203 predicted neoantigen-peptides from 2449 mutations of tumor tissues and 9991 ones from 2637 mutations of matched organoids demonstrate that organoids preserved majority of genetic features, HLA alleles, and similar neoantigen landscape of original tumors. Higher neoantigen load is observed in tumors with early stage. Multiomics analysis combining WGS, RNA-seq, single-cell RNA-seq, mass spectrometry filters out 93 candidate neoantigen-peptides with strong immunogenic potential for functional validation in five organoids. Immunogenic peptides are defined by inducing increased CD107aCD137IFN-γ expressions and IFN-γ secretion of CD8 cells in flow cytometry and enzyme-linked immunosorbent assay assays. Nine immunogenic peptides shared by at least two individuals are validated, including peptide from TP53R90S . Organoid killing assay confirms the antitumor activity of validated immunogenic peptide-reactive CD8 cells, which is further enhanced in the presence of immune checkpoint inhibitors. The study characterizes HLA-class-I neoantigen landscape in hepatobiliary tumor, providing practical strategy with tumor organoid model for neoantigen-peptide identification in personalized immunotherapy.

Bioactive 2D nanomaterials for neural repair and regeneration.

Biomaterials have provided promising strategies towards improving the functions of injured tissues of the nervous system. Recently, 2D nanomaterials, such as graphene, layered double hydroxides (LDHs), and black phosphorous, which are characterized by ultrathin film structures, have attracted much attention in the fields of neural repair and regeneration. 2D nanomaterials have extraordinary physicochemical properties and excellent biological activities, such as a large surface-area-to-thickness ratio, high levels of adhesion, and adjustable flexibility. In addition, they can be designed to have superior biocompatibility and electrical or nano-carrier properties. To date, many 2D nanomaterials have been used for synaptic modulation, neuroinflammatory reduction, stem cell fate regulation, and injured neural cell/tissue repair. In this review, we discuss the advances in 2D nanomaterial technology towards novel neurological applications and the mechanisms underlying their unique features. In addition, the future outlook of functional 2D nanomaterials towards addressing the difficult issues of neuropathy has been explored to introduce a promising strategy towards repairing and regenerating the injured nervous system.

Neurogenesis potential of oligodendrocyte precursor cells from oligospheres and injured spinal cord.

Severe traumatic spinal cord injury (SCI) leads to long-lasting oligodendrocyte death and extensive demyelination in the lesion area. Oligodendrocyte progenitor cells (OPCs) are the reservoir of new mature oligodendrocytes during damaged myelin regeneration, which also have latent potential for neurogenic regeneration and oligospheres formation. Whether oligospheres derived OPCs can differentiate into neurons and the neurogenesis potential of OPCs after SCI remains unclear. In this study, primary OPCs cultures were used to generate oligospheres and detect the differentiation and neurogenesis potential of oligospheres. In vivo, SCI models of juvenile and adult mice were constructed. Combining the single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), bioinformatics analysis, immunofluorescence staining, and molecular experiment, we investigated the neurogenesis potential and mechanisms of OPCs in vitro and vivo. We found that OPCs differentiation and oligodendrocyte morphology were significantly different between brain and spinal cord. Intriguingly, we identify a previously undescribed findings that OPCs were involved in oligospheres formation which could further differentiate into neuron-like cells. We also firstly detected the intermediate states of oligodendrocytes and neurons during oligospheres differentiation. Furthermore, we found that OPCs were significantly activated after SCI. Combining scRNA-seq and bulk RNA-seq data from injured spinal cord, we confirmed the neurogenesis potential of OPCs and the activation of endoplasmic reticulum stress after SCI. Inhibition of endoplasmic reticulum stress could effectively attenuate OPCs death. Additionally, we also found that endoplasmic reticulum may regulate the stemness and differentiation of oligospheres. These findings revealed the neurogenesis potential of OPCs from oligospheres and injured spinal cord, which may provide a new source and a potential target for spinal cord repair.

The effect of biliary obstruction, biliary drainage and bile reinfusion on bile acid metabolism and gut microbiota in mice.

BACKGROUND & AIMS: Preoperative obstructive jaundice is usually associated with higher post-operative mortality. Although external biliary drainage (EBD) has been widely used to relieve obstructive jaundice, the role of bile reinfusion after EBD is still controversial. The aim of our study was to study the effects of biliary obstruction, biliary drainage and bile reinfusion on bile acid metabolism and gut microbiota. METHODS: Firstly, we created a mice bile drainage collection (BDC) model to simulate the process of biliary obstruction, drainage and bile reinfusion. Then, we analysed the faecal, serum, liver and bile samples to investigate the effects of the process on bile acid profiles and gut microbiota. Finally, we evaluated the clinical effects of bile reinfusion. RESULTS: We evaluated the bile acid profiles of faeces, serum, liver and bile of normal mice. During biliary obstruction, secondary bile acids can still be produced, and increased in the liver and serum of mice. Compared with no bile reinfusion, bile reinfusion was beneficial to the recovery of T-ωMCA in the liver and bile, and can restore the colon crypt length shortened by biliary obstruction. Only Ruminococcus_1 proliferated when the biliary obstruction lasted for 12 days. In the clinic, bile reinfusion cannot accelerate the patient's perioperative recovery or prolong long-term survival. CONCLUSION: We have successfully created a mice bile drainage collection model. Short-term bile reinfusion can partially benefit the recovery of the secondary bile acids in the liver and bile, but hardly benefit the patient's perioperative recovery or long-term survival. (247 words).

Comprehensive analysis of spatial architecture in primary liver cancer.

Heterogeneity is the major challenge for cancer prevention and therapy. Here, we first constructed high-resolution spatial transcriptomes of primary liver cancers (PLCs) containing 84,823 spots within 21 tissues from seven patients. The progressive comparison of spatial tumor microenvironment (TME) characteristics from nontumor to leading-edge to tumor regions revealed that the tumor capsule potentially affects intratumor spatial cluster continuity, transcriptome diversity, and immune cell infiltration. Locally, we found that the bidirectional ligand-receptor interactions at the 100-µm-wide cluster-cluster boundary contribute to maintaining intratumor architecture and the PROM1+ and CD47+ cancer stem cell niches are related to TME remodeling and tumor metastasis. Last, we proposed a TLS-50 signature to accurately locate tertiary lymphoid structures (TLSs) spatially and unveiled that the distinct composition of TLSs is shaped by their distance to tumor cells. Our study provides previous unknown insights into the diverse tumor ecosystem of PLCs and has potential benefits for cancer intervention.

Discovery of a Carbamoyl Phosphate Synthetase 1-Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis.

BACKGROUND AND AIMS: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS: A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.