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Liver cirrhosis occurs as a consequence of many chronic liver diseases that are prevalent worldwide. Here we characterize the gut microbiome in liver cirrhosis by comparing 98 patients and 83 healthy control individuals. We build a reference gene set for the cohort containing 2.69 million genes, 36.1% of which are novel. Quantitative metagenomics reveals 75,245 genes that differ in abundance between the patients and healthy individuals (false discovery rate < 0.0001) and can be grouped into 66 clusters representing cognate bacterial species; 28 are enriched in patients and 38 in control individuals. Most (54%) of the patient-enriched, taxonomically assigned species are of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis. Biomarkers specific to liver cirrhosis at gene and function levels are revealed by a comparison with those for type 2 diabetes and inflammatory bowel disease. On the basis of only 15 biomarkers, a highly accurate patient discrimination index is created and validated on an independent cohort. Thus microbiota-targeted biomarkers may be a powerful tool for diagnosis of different diseases.

Cross-talk between the brain and cervical lymph nodes (CLNs) is crucial in brain pathologies. However, the precise roles and the mechanisms of CLNs in brain damage during subarachnoid hemorrhage (SAH) remain unclear. In this study, mandibular lymph node (part of CLNs) removal attenuates brain damage in SAH mouse models. Notably, the extravasated erythrocytes following SAH are significantly engulfed by lymphatic endothelial cells (LECs) in CLNs. Single-cell RNA sequencing reveals that the differentially expressed genes in medullary LECs are enriched in lysosomes after SAH, with a notable upregulation of Ctss (which encodes cathepsin S). Importantly, the deficiency of cathepsin S specifically in LECs, achieved through transgenic mice, or the use of a cathepsin S inhibitor, significantly reduces neuroinflammation and neurological deficits induced by SAH. These findings elucidate mechanisms of how CLNs participate in brain injury following SAH in mice. Targeting this process may offer effective therapeutic strategies to alleviate SAH-related pathologies. Crosstalk between the brain and CLNs is critical in brain pathologies. Here, the authors show in a mouse model that extravasated erythrocytes following SAH are degraded by cathepsin S of medullary LECs in CLNs, which plays an important role in SAH pathology.

SOX2 is an important stem cell marker and plays important roles in development and carcinogenesis. However, the role of SOX2 in Epithelial-Mesenchymal Transition has not been investigated. We demonstrated, for the first time, that SOX2 is involved in the Epithelial-Mesenchymal Transition (EMT) process as knock downof SOX2 in colorectal cancer (CRC) SW620 cells induced a Mesenchymal-Epithelial Transition (MET) process with recognized changes in the expression of key genes involved in the EMT process including E-cadherin and vimentin. In addition, we provided a link between SOX2 activity and the WNT pathway by showing that knock down of SOX2 reduced the WNT pathway activity in colorectal cancer (CRC) cells. We further demonstrated that SOX2 is involved in cell migration and invasion in vitro and in metastasis in vivo for CRC cells, and that the process might be mediated through the MMP2 activity. Finally, an IHC analysis of 44 cases of colorectal cancer patients suggested that SOX2 is a prognosis marker for metastasis of colorectal cancers.

ObjectiveStem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells’ activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application.DesignWe used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells’ activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry.ResultsAll pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs’ cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models.ConclusionsOur results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

Background: Differential diagnosis of patients with suspected infections is particularly difficult, but necessary for prompt diagnosis and rational use of antibiotics. A substantial proportion of these patients have non-infectious diseases that include malignant tumors. This study aimed to explore the clinical value of metagenomic next-generation sequencing (mNGS) for tumor detection in patients with suspected infections.Methods: A multicenter, prospective case study involving patients diagnosed with suspected infections was conducted in four hospitals in Shanghai, China between July 2019 and January 2020. Based upon mNGS technologies and chromosomal copy number variation (CNV) analysis on abundant human genome, a new procedure named Onco-mNGS was established to simultaneously detect pathogens and malignant tumors in all of the collected samples from patients.Results: Of 140 patients screened by Onco-mNGS testing, 115 patients were diagnosed with infections; 17 had obvious abnormal CNV signals indicating malignant tumors that were confirmed clinically. The positive percent agreement and negative percent agreement of mNGS testing compared to clinical diagnosis was 53.0% (61/115) and 60% (15/25), vs. 20.9% (24/115) and 96.0% (24/25), respectively, for conventional microbiological testing (both P <0.01). Klebsiella pneumoniae (14.8%, 9/61) was the most common pathogen detected by mNGS, followed by Escherichia coli (11.5%, 7/61) and viruses (11.5%, 7/61). The chromosomal abnormalities of the 17 cases included genome-wide variations and local variations of a certain chromosome. Five of 17 patients had a final confirmed with malignant tumors, including three lung adenocarcinomas and two hematological tumors; one patient was highly suspected to have lymphoma; and 11 patients had a prior history of malignant tumor.Conclusion: This preliminary study demonstrates the feasibility and clinical value of using Onco-mNGS to simultaneously search for potential pathogens and malignant tumors in patients with suspected infections.

Autonomous systems have been widely deployed in various field applications, such as inspection, exploration, and aerial videography using micro aerial vehicles (MAVs), and highway pilot (HWP), rush-hour pilot (RHP), robo-taxi in field of intelligent vehicles. For accomplishing such missions in challenging environments, navigation functionality is essential. In this thesis, Autonomous systems have been widely deployed in various field applications, such as inspection, exploration, and aerial videography using micro aerial vehicles (MAVs), and highway pilot (HWP), rush-hour pilot (RHP), robo-taxi in field of intelligent vehicles. For accomplishing such missions in challenging environments, navigation functionality is essential. In this thesis, we study practical and efficient planning methods for autonomous systems, which can achieve full autonomy in real-world complex environments. Our study covers both low-level motion planning problems and high-level decision-making (i.e., behavior planning) problems, targeting for safe and smooth autonomous navigation with minimum user intervention. We investigate the navigation problem for two different platforms, namely, quadrotors for MAVs, and autonomous vehicles (AVs), which have significant practical impacts while illustrating different focuses and functionalities. We start with a novel kinodynamic motion planning method for quadrotors, which achieves safe and efficient replanning in unknown cluttered 3-D environments. Leveraging the knowledge of motion planning for quadrotors, we further study the planning problem for autonomous vehicles in highly dynamic environments. Different from the motion planning for quadrotors, planning for AVs requires reasoning about other dynamic traffic participants and social compliance. To this end, a novel behavior prediction method is proposed to understand the behaviors of other traffic participants in the real world. The behavior prediction is then tightly incorporated into our proposed decision-making framework which generates robust decisions efficiently. The output decision is subsequently utilized by our novel motion planning module to generate a smooth and safe trajectory for closed-loop execution. We assemble all the individual modules into a complete and robust planning system which is validated in real-world dense city traffic.

Hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and the mechanisms of its development and progression remain unclear. The aim of this study was to define the characteristics of peripheral blood mononuclear cell microRNAs in patients with HBV-ACLF. In this study, novel microRNA (miRNA) biomarkers of peripheral blood mononuclear cells (PBMCs) in patients with HBV-ACLF were characterised by high-throughput sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). The results showed 78 miRNAs were significantly differentially expressed in patients with HBV-ACLF compared to patients with chronic hepatitis B (CHB) and healthy controls. Among patients with HBV-ACLF, 17 dysregulated miRNAs increased or decreased more than 4-fold, of which eight miRNAs had higher expression levels than median level. qRT-PCR validation demonstrated that six miRNAs (hsa-miR-21-5p, hsa-miR-34c-5p, hsa-miR-143-3p, hsa-miR-143-5p, hsa-miR-374a-3p and hsa-miR-542-3p) may be useful as novel biomarkers for the diagnosis of HBV-ACLF. Five novel miRNAs (L-miR-1~5) were detected and two (L-miR-1 and L-miR-3) were significantly differentially expressed in patients with HBV-ACLF. Conclusions: The miRNA expression profile of PBMCs is altered in patients with HBV-ACLF and a signature of six miRNAs may be a promising biomarker for HBV-ACLF progression.

Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is essential to elucidate the pathogenesis of HBV-ACLF and identify HBV-ACLF-specific biomarkers. In this study, high-throughput sequencing was performed to characterize the transcriptome of PMBCs from patients with HBV-ACLF. Specifically, 2381 differentially expressed genes (DEGs) and 776 differentially expressed transcripts were identified through comparisons with patients with chronic hepatitis B (CHB) and healthy controls. Gene Ontology (GO) analysis identified 114 GO terms that were clustered into 12 groups. We merged 10 dysregulated genes selected from these grouped GO terms and non-clustered terms with four significant genes with a specificity of >0.8 in the HBV-ACLF patients to obtain a set of 13 unique genes. The quantitative real-time polymerase chain reaction (qRT-PCR) validation of the top six genes (CYP19A1, SEMA6B, INHBA, DEFT1P, AZU1 and DEFA4) was consistent with the results of messenger ribonucleic acid (mRNA) sequencing. A further receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curves of the six genes were all >0.8, which indicated their significant diagnostic potentials for HBV-ACLF. Conclusion: The transcriptome characteristics of PBMCs are altered in patients with HBV-ACLF, and six genes may serve as biomarkers of HBV-ACLF.

[...]we aimed to search detectable biomarkers to predict the outcome of HBV-ACLF.