Adaptation in Unstable Environments and Global Gene Losses: Small but Stable Gene Networks by the May-Wigner Theory.

Although gene loss is common in evolution, it remains unclear whether it is an adaptive process. In a survey of seven major mangrove clades that are woody plants in the intertidal zones of daily environmental perturbations, we noticed that they generally evolved reduced gene numbers. We then focused on the largest clade of Rhizophoreae and observed the continual gene set reduction in each of the eight species. A great majority of gene losses are concentrated on environmental interaction processes, presumably to cope with the constant fluctuations in the tidal environments. Genes of the general processes for woody plants are largely retained. In particular, fewer gene losses are found in physiological traits such as viviparous seeds, high salinity, and high tannin content. Given the broad and continual genome reductions, we propose the May-Wigner theory (MWT) of system stability as a possible mechanism. In MWT, the most effective solution for buffering continual perturbations is to reduce the size of the system (or to weaken the total genic interactions). Mangroves are unique as immovable inhabitants of the compound environments in the land-sea interface, where environmental gradients (such as salinity) fluctuate constantly, often drastically. Extending MWT to gene regulatory network (GRN), computer simulations and transcriptome analyses support the stabilizing effects of smaller gene sets in mangroves vis-à-vis inland plants. In summary, we show the adaptive significance of gene losses in mangrove plants, including the specific role of promoting phenotype innovation and a general role in stabilizing GRN in unstable environments as predicted by MWT.

The interaction between the histone acetyltransferase complex Hat1-Hat2 and transcription factor AmyR provides a molecular brake to regulate amylase gene expression.

The chromatin structure is generally regulated by chromatin remodelers and histone modifiers, which affect DNA replication, repair, and levels of transcription. The first identified histone acetyltransferase was Hat1/KAT1, which belongs to lysine (K) acetyltransferases. The catalytic subunit Hat1 and the regulatory subunit Hat2 make up the core HAT1 complex. In this study, the results of tandem affinity purification and mass spectrometry and bimolecular fluorescence complementation proved that the Penicillium oxalicum PoHat1-Hat2 is the transcriptional cofactor of the sequence-specific transcription factor PoAmyR, a transcription activator essential for the transcription of amylase gene. ChIP-qPCR results demonstrated that the complex PoHat1-Hat2 is recruited by PoAmyR to the promoters of prominent amylase genes Poamy13A and Poamy15A and performs histone H4 lysine12 acetylation. The result of the yeast two-hybrid test indicated that PoHat2 is the subunit that directly interacts with PoAmyR. PoHat1-Hat2 acts as the molecular brake of the PoAmyR-regulating transcription of amylase genes. A putative model for amylase gene regulation by PoAmyR-Hat2-Hat1 was constructed. Our paper is the first report that the Hat1-Hat2 complex acts as a cofactor for sequence-specific TF to regulate gene expression and explains the mechanism of TF AmyR regulating amylase genes expression.

Investigation of the association between the Toll-like receptor 1 rs4833095 variation and gastric adenocarcinoma recurrence.

BACKGROUND: Toll-like receptors (TLRs) are a family of transmembrane receptors that play key roles in identifying invading pathogens and activating innate immunity. TLR1 has been reported to be associated with the risk of gastric cancer (GC) but that was based on only a simple statistical analysis. METHODS: We genotyped the TLR1 in 526 GC patients to investigate the association between the variation and gastric cancer survival by the multiplex polymerase chain reaction and sequencing method. The rs4833095 variation (chr4:38798089 [GRCh38. p14], T > C) in the TLR1 gene was genotyped in 526 patients who underwent GC resection. The associations between genotype, survival, and recurrence were investigated. The potential role of TLR1 in stomach cancer was investigated using clinical data from formalin-fixed, paraffin-embedded tissue samples. RESULTS: Patients with the T/C and C/C genotypes of rs4833095 had a lower risk of recurrence than those with the T/T genotype. Recurrence-free periods were substantially longer in patients with the T/C or C/C genotypes (22.6 and 22.3 months, respectively) than in those with the T/T genotype (20.7 months). Patients with the T/C or C/C genotype, low expression levels of VEGF1, high expression levels of ERBB2 and ERCC1, the absence of cancer nodules, a tumor size of less than 5 cm, and poor differentiation had a considerably reduced risk of recurrence. CONCLUSIONS: TLR1 rs4833095 was correlated with the postresection prognosis of patients with gastric cancer, suggesting that TLR1 may have a role in the onset or progression of gastric cancer.

The evolution history of an allotetraploid mangrove tree analysed with a new tool Allo4D.

Mangrove species are broadly classified as true mangroves and mangrove associates. The latter are amphibious plants that can survive in the intertidal zone and reproduce naturally in terrestrial environments. Their widespread distribution and extensive adaptability make them ideal research materials for exploring adaptive evolution. In this study, we de novo assembled two genomes of mangrove associates (the allotetraploid Barringtonia racemosa (2n = 4x = 52) and diploid Barringtonia asiatica (2n = 2x = 26)) to investigate the role of allopolyploidy in the evolutionary history of mangrove species. We developed a new allotetraploid-dividing tool Allo4D to distinguish between allotetraploid scaffold-scale subgenomes and verified its accuracy and reliability using real and simulated data. According to the two subgenomes of allotetraploid B. racemosa divided using Allo4D, the allopolyploidization event was estimated to have occurred approximately one million years ago (Mya). We found that B. racemosa, B. asiatica, and Diospyros lotus shared a whole genome duplication (WGD) event during the K-Pg (Cretaceous-Paleozoic) period. K-Pg WGD and recent allopolyploidization events contributed to the speciation of B. racemosa and its adaptation to coastal habitats. We found that genes in the glucosinolates (GSLs) pathway, an essential pathway in response to various biotic and abiotic stresses, expanded rapidly in B. racemosa during polyploidization. In summary, this study provides a typical example of the adaptation of allopolyploid plants to extreme environmental conditions. The newly developed tool, Allo4D, can effectively divide allotetraploid subgenomes and explore the evolutionary history of polyploid plants, especially for species whose ancestors are unknown or extinct.

Identification of prognostic signatures in remnant gastric cancer through an interpretable risk model based on machine learning: a multicenter cohort study.

OBJECTIVE: The purpose of this study was to develop an individual survival prediction model based on multiple machine learning (ML) algorithms to predict survival probability for remnant gastric cancer (RGC). METHODS: Clinicopathologic data of 286 patients with RGC undergoing operation (radical resection and palliative resection) from a multi-institution database were enrolled and analyzed retrospectively. These individuals were split into training (80%) and test cohort (20%) by using random allocation. Nine commonly used ML methods were employed to construct survival prediction models. Algorithm performance was estimated by analyzing accuracy, precision, recall, F1-score, area under the receiver operating characteristic curve (AUC), confusion matrices, five-fold cross-validation, decision curve analysis (DCA), and calibration curve. The best model was selected through appropriate verification and validation and was suitably explained by the SHapley Additive exPlanations (SHAP) approach. RESULTS: Compared with the traditional methods, the RGC survival prediction models employing ML exhibited good performance. Except for the decision tree model, all other models performed well, with a mean ROC AUC above 0.7. The DCA findings suggest that the developed models have the potential to enhance clinical decision-making processes, thereby improving patient outcomes. The calibration curve reveals that all models except the decision tree model displayed commendable predictive performance. Through CatBoost-based modeling and SHAP analysis, the five-year survival probability is significantly influenced by several factors: the lymph node ratio (LNR), T stage, tumor size, resection margins, perineural invasion, and distant metastasis. CONCLUSIONS: This study established predictive models for survival probability at five years in RGC patients based on ML algorithms which showed high accuracy and applicative value.

Equisetin protects from atherosclerosis in vivo by binding to STAT3 and inhibiting its activity.

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound isolated from fungus of marine sponge origin, which has antibacterial, anti-inflammatory, lipid-lowering, and weight loss effects. Whether EQST has anti-atherosclerotic activity has not been reported. In this study, we revealed that EQST displayed anti- atherosclerosis effects through inhibiting macrophage inflammatory response, lipid uptake and foam cell formation in vitro, and finally ameliorated high-fat diet (HFD)-induced atherosclerosis in AopE-/- mice in vivo. Mechanistically, EQST directly bound to STAT3 with high-affinity by forming hydrophobic bonds at GLN247 and GLN326 residues, as well as hydrogen bonds at ARG325 and THR346 residues. EQST interacted with STAT3 physically, and functionally inhibited the transcription activity of STAT3, thereby regulating atherosclerosis. Therefore, these results supports EQST as a candidate for developing anti-atherosclerosis therapeutic agent.

Progress in Identification of UDP-Glycosyltransferases for Ginsenoside Biosynthesis.

Ginsenosides, the primary pharmacologically active constituents of the Panax genus, have demonstrated a variety of medicinal properties, including anticardiovascular disease, cytotoxic, antiaging, and antidiabetes effects. However, the low concentration of ginsenosides in plants and the challenges associated with their extraction impede the advancement and application of ginsenosides. Heterologous biosynthesis represents a promising strategy for the targeted production of these natural active compounds. As representative triterpenoids, the biosynthetic pathway of the aglycone skeletons of ginsenosides has been successfully decoded. While the sugar moiety is vital for the structural diversity and pharmacological activity of ginsenosides, the mining of uridine diphosphate-dependent glycosyltransferases (UGTs) involved in ginsenoside biosynthesis has attracted a lot of attention and made great progress in recent years. In this paper, we summarize the identification and functional study of UGTs responsible for ginsenoside synthesis in both plants, such as Panax ginseng and Gynostemma pentaphyllum, and microorganisms including Bacillus subtilis and Saccharomyces cerevisiae. The UGT-related microbial cell factories for large-scale ginsenoside production are also mentioned. Additionally, we delve into strategies for UGT mining, particularly potential rapid screening or identification methods, providing insights and prospects. This review provides insights into the study of other unknown glycosyltransferases as candidate genetic elements for the heterologous biosynthesis of rare ginsenosides.

Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1.

Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions2-4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility5-7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF18,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.

Transcription Factor MITF Inhibits the Transcription of CPT1B to Regulate Fatty Acid ß-Oxidation and Thus Affects Stemness in Lung Adenocarcinoma Cells.

INTRODUCTION: Cancer stem cells (CSCs) play critical roles in lung adenocarcinoma (LUAD) progression, and fatty acid oxidation is key for CSC growth and survival. Therefore, investigating the molecular mechanisms regulating fatty acid ß-oxidation in LUAD is important for its treatment. METHODS: Bioinformatics analysis assessed CPT1B and MITF expression and their correlation in LUAD tissues, as well as the pathways enriched by CPT1B. qRT-PCR assessed expression of CPT1B and MITF, while CCK-8 and sphere-forming assays were used to measure cell viability and stemness, respectively. Dual staining detected lipid accumulation, while kits were used to measure fatty acid ß-oxidation and glycerol content. qRT-PCR was used to assay expression of lipid oxidation genes. Western blot was used to examine expression of stem cell-related markers. Dual-luciferase assay and ChIP assay were used to verify the binding relationship between MITF and CPT1B. RESULTS: CPT1B was found to be highly expressed in LUAD and enriched in linoleic acid metabolism pathway and α-linolenic acid metabolism pathway. Functional experiments showed that CPT1B could promote stemness in LUAD cells by regulating fatty acid ß-oxidation. Additionally, CPT1B was found to be regulated by the upstream transcription factor MITF, which was lowly expressed in LUAD and could downregulate CPT1B expression. Rescue experiments revealed that CPT1B/MITF axis could affect stemness in LUAD cells by regulating fatty acid ß-oxidation. CONCLUSION: Transcription factor MITF inhibited transcription of CPT1B to regulate fatty acid ß-oxidation, thereby suppressing stemness in LUAD cells. MITF and CPT1B may become new targets for LUAD.

A portable intelligent hydrogel platform for multicolor visual detection of HAase.

Hyaluronidase (HAase) is an important endoglycosidase involved in numerous physiological and pathological processes, such as apoptosis, senescence, and cancer progression. Simple, convenient, and sensitive detection of HAase is important for clinical diagnosis. Herein, an easy-to-operate multicolor visual sensing strategy was developed for HAase determination. The proposed sensor was composed of an enzyme-responsive hydrogel and a nanochromogenic system (gold nanobipyramids (AuNBPs)). The enzyme-responsive hydrogel, formed by polyethyleneimine-hyaluronic acid (PEI-HA), was specifically hydrolyzed with HAase, leading to the release of platinum nanoparticles (PtNPs). Subsequently, PtNPs catalyzed the mixed system of 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2 to produce TMB2+ under acidic conditions. Then, TMB2+ effectively etched the AuNBPs and resulted in morphological changes in the AuNBPs, accompanied by a blueshift in the localized surface plasmon resonance peak and vibrant colors. Therefore, HAase can be semiquantitatively determined by directly observing the color change of AuNBPs with the naked eye. On the basis of this, the method has a linear detection range of HAase concentrations between 0.6 and 40 U/mL, with a detection limit of 0.3 U/mL. In addition, our designed multicolor biosensor successfully detected the concentration of HAase in human serum samples. The results showed no obvious difference between this method and enzyme-linked immunosorbent assay, indicating the good accuracy and usability of the suggested method.

Genomic analysis of Nypa fruticans elucidates its intertidal adaptations and early palm evolution.

Nypa fruticans (Wurmb), a mangrove palm species with origins dating back to the Late Cretaceous period, is a unique species for investigating long-term adaptation strategies to intertidal environments and the early evolution of palms. Here, we present a chromosome-level genome sequence and assembly for N. fruticans. We integrated the genomes of N. fruticans and other palm family members for a comparative genomic analysis, which confirmed that the common ancestor of all palms experienced a whole-genome duplication event around 89 million years ago, shaping the distinctive characteristics observed in this clade. We also inferred a low mutation rate for the N. fruticans genome, which underwent strong purifying selection and evolved slowly, thus contributing to its stability over a long evolutionary period. Moreover, ancient duplicates were preferentially retained, with critical genes having experienced positive selection, enhancing waterlogging tolerance in N. fruticans. Furthermore, we discovered that the pseudogenization of Early Methionine-labelled 1 (EM1) and EM6 in N. fruticans underly its crypto-vivipary characteristics, reflecting its intertidal adaptation. Our study provides valuable genomic insights into the evolutionary history, genome stability, and adaptive evolution of the mangrove palm. Our results also shed light on the long-term adaptation of this species and contribute to our understanding of the evolutionary dynamics in the palm family.

Adaptation to a new environment with pre-adaptive genomic features - Evidence from woody plants colonizing the land-sea interface.

Adaptation to new environments is a key evolutionary process which presumably involves complex genomic changes. Mangroves, a collection of approximately 80 woody plants that have independently invaded intertidal zones >20 times, are ideal for studying this process. We assembled near-chromosome-scale genomes of three Xylocarpus species as well as an outgroup species using single-molecule real-time sequencing. Phylogenomic analysis reveals two separate lineages, one with the mangrove Xylocarpus granatum and the other comprising a mangrove Xylocarpus moluccensis and a terrestrial Xylocarpus rumphii. In conjunction with previous studies, we identified several genomic features associated with mangroves: (i) signals of positive selection in genes related to salt tolerance and root development; (ii) genome-wide elevated ratios of non-synonymous to synonymous substitution relative to terrestrial relatives; and (iii) active elimination of long terminal repeats. These features are found in the terrestrial X. rumphii in addition to the two mangroves. These genomic features, not being strictly mangrove-specific, are hence considered pre-adaptive. We infer that the coastal but non-intertidal habitat of X. rumphii may have predisposed the common ancestor to invasion of true mangrove habitats. Other features including the preferential retention of duplicated genes and intolerance to pseudogenization are not found in X. rumphii and are likely true adaptive features in mangroves. In conclusion, by studying adaptive shift and partial shifts among closely related species, we set up a framework to study genomic features that are acquired at different stages of the pre-adaptation and adaptation to new environments.

Where whole-genome duplication is most beneficial: Adaptation of mangroves to a wide salinity range between land and sea.

Whole-genome duplication (WGD) is believed to increase the chance of adaptation to a new environment. This conjecture may apply particularly well to new environments that are not only different but also more variable than ancestral habitats. One such prominent environment is the interface between land and sea, which has been invaded by woody plants, collectively referred as mangroves, multiple times. Here, we use two distantly related mangrove species (Avicennia marina and Rhizophora apiculata) to explore the effects of WGD on the adaptive process. We found that a high proportion of duplicated genes retained after WGD have acquired derived differential expression in response to salt gradient treatment. The WGD duplicates differentially expressed in at least one copy usually (>90%) diverge from their paralogues' expression profiles. Furthermore, both species evolved in parallel to have one paralogue expressed at a high level in both fresh water and hypersaline conditions but at a lower level at medium salinity. The pattern contrasts with the conventional view of monotone increase/decrease as salinity increases. Differentially expressed copies have thus probably acquired a new role in salinity tolerance. Our results indicate that the WGD duplicates may have evolved to function collaboratively in coping with different salinity levels, rather than specializing in the intermediate salinity optimal for mangrove plants. In conclusion, WGD and the retained duplicates appear to be an effective solution for adaptation to new and unstable environments.

CircPIM3 regulates taxol resistance in non-small cell lung cancer via miR-338-3p/TNFAIP8 axis.

Numerous work has revealed the involvement of circular RNA (circRNA) in regulating chemotherapy resistance. Here, we investigate circPIM3 role in taxol (Tax) resistance in non-small cell lung cancer (NSCLC). CircPIM3, microRNA (miR)-338-3p and tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) expression were detected via quantitative real-time PCR, western blot or immunohistochemistry assay. Tax resistance was evaluated using cell counting kit-8, cell proliferation was measured by colony formation assay, cell cycle and apoptosis were examined via flow cytometry. The interplay between miR-338-3p and circPIM3 or TNFAIP8 was confirmed by dual-luciferase reporter assay. Finally, the effect of circPIM3 on Tax resistance in NSCLC in vivo was investigated by xenograft models. CircPIM3 and TNFAIP8 were upregulated in Tax-resistant NSCLC tissue and cell samples. Reducing circPIM3 expression inhibited Tax resistance, proliferation and induced cycle arrest and apoptosis in Tax-resistant NSCLC cells. Mechanically, circPIM3 absence led to downregulation of TNFAIP8 via absorbing miR-338-3p. Additionally, circPIM3 depletion increased Tax sensitivity of NSCLC in vivo. Silencing of circPIM3 suppressed Tax resistance in Tax-resistant NSCLC cells through regulation of the miR-338-3p/TNFAIP8 axis.

Chromosomal-Scale Genome Assemblies of Two Coastal Plant Species, Scaevola taccada and S. hainanensis-Insight into Adaptation Outside of the Common Range.

While most of the species in Goodeniaceae family, excluding the Scaevola genus, are endemic to Australasia, S. taccada and S. hainanensis have expanded their distribution range to the tropical coastlines of the Atlantic and Indian Oceans. S. taccada appears to be highly adapted to coastal sandy lands and cliffs, and it has become invasive in places. S. hainanensis is found mainly in salt marshes near mangrove forests, and is at risk of extinction. These two species provide a good system to investigate adaptive evolution outside the common distribution range of this taxonomic group. Here, we report their chromosomal-scale genome assemblies with the objective of probing their genomic mechanisms related to divergent adaptation after leaving Australasia. The scaffolds were assembled into eight chromosome-scale pseudomolecules, which covered 90.12% and 89.46% of the whole genome assembly for S. taccada and S. hainanensis, respectively. Interestingly, unlike many mangroves, neither species has undergone whole-genome duplication. We show that private genes, specifically copy-number expanded genes are essential for stress response, photosynthesis, and carbon fixation. The gene families that are expanded in S. hainanensis and contracted in S. taccada might have facilitated adaptation to high salinity in S. hainanensis. Moreover, the genes under positive selection in S. hainanensis have contributed to its response to stress and its tolerance of flooding and anoxic environments. In contrast, compared with S. hainanensis, the more drastic copy number expansion of FAR1 genes in S. taccada might have facilitated its adaptation to the stronger light radiation present in sandy coastal lands. In conclusion, our study of the chromosomal-scale genomes of S. taccada and S. hainanensis provides novel insights into their genomic evolution after leaving Australasia.

The efficacy and feasibility of neoadjuvant immunotherapy plus chemotherapy followed by McKeown minimally invasive oesophagectomy for locally advanced oesophageal squamous cell carcinoma.

Introduction: In immunotherapy, antibodies are activated to block immune checkpoints, resist tumour immunosuppression, shrink tumours and prevent a recurrence. As the science behind tumour immunotherapy continuously develops and improves, neoadjuvant immunotherapy bears more prominent advantages: antigen exposure not only enhances the degree of tumour-specific T-cell response but also prolongs the duration of actions. In this study, we evaluated the efficacy and safety of McKeown minimally invasive oesophagectomy (McKeown MIO) following neoadjuvant immunotherapy combined with chemotherapy (NICT) in patients with locally advanced oesophageal cancer (OC). Patients and Methods: In this retrospective study, 94 patients underwent either NICT or neoadjuvant chemotherapy (NCT) followed by MIO at our institution from January 2020 to October 2022. We assessed the therapy-related adverse events and perioperative outcomes and compared them between the two groups. Results: After completing at least two cycles of neoadjuvant therapy, all patients underwent McKeown MIO with negative margins within 4-7 weeks. Demographic data of the two cohorts were similar. Regarding perioperative characteristics, the median intraoperative blood loss was 50 ml in the NICT group, lower than that of the NCT group (100 ml, P < 0.05). In addition, the NICT group had significantly more harvested lymph nodes than the NCT group (P < 0.05). No significant differences were found in post-operative complications. The rate of objective response rate in the NICT group was higher than that in the NCT group (88.3% vs. 58.8%). Regarding tumour regression, the number of patients with TRG Grades 1-3 in the NICT group was more than that in the NCT. Adverse events experienced by the two groups included anaemia and elevated transaminase. We found no difference in the adverse events between the two groups. Conclusions: This study showed the efficacy and feasibility of NICT followed by McKeown MIO in treating locally advanced OC.

Surface-Enhanced Electrochemiluminescence Imaging for Multiplexed Immunoassays of Cancer Markers in Exhaled Breath Condensates.

Recently we have demonstrated that the surface plasmon of noble metal nanoparticles can effectively enhance the ECL intensity of Ru(bpy)32+, and we named this detection principle as surface-enhanced electrochemiluminescence (SEECL-I). However, SEECL based on photomultiplier tube (PMT) detection can only detect one target at a time, which is not suitable for multiple targets detection. In this work, we combined our previous developed SEECL with a bioimaging device to develop a novel multiplexed immunassay for simultaneous and fast analysis of cancer markers. A core-shell nanocomposite consisted of gold-silicon dioxide nanoparticles doped with Ru(bpy)32+(Au@SiO2-Ru) with strong ECL emission was employed as ECL label due to the localized surface plasmon resonance (LSPR) of AuNPs, which can significantly enhance the ECL emission of Ru(bpy)32+. The ECL signals from the 4 × 4 electrode arrays were collected using the constant potential method (current-time curve method) imaging with a sCOMS camera. As a proof-of-concept application, we demonstrated the use of the proposed SEECL-I for simultaneous detection of carcinoembryonic antigen (CEA), neuron specific enolase (NSE), and squamous cell carcinoma antigen (SCC) in exhaled breath condensates (EBCs) with low detection limit (LOD) of 0.17, 0.33, and 0.33 pg/mL (S/N = 3), respectively. The results demonstrated that the proposed SEECL-I strategy can provide a high sensitivity, fast analysis, and high-throughput platform for clinical diagnosis of cancer markers in EBCs.

MENDA: a comprehensive curated resource of metabolic characterization in depression.

Depression is a seriously disabling psychiatric disorder with a significant burden of disease. Metabolic abnormalities have been widely reported in depressed patients and animal models. However, there are few systematic efforts that integrate meaningful biological insights from these studies. Herein, available metabolic knowledge in the context of depression was integrated to provide a systematic and panoramic view of metabolic characterization. After screening more than 10 000 citations from five electronic literature databases and five metabolomics databases, we manually curated 5675 metabolite entries from 464 studies, including human, rat, mouse and non-human primate, to develop a new metabolite-disease association database, called MENDA (http://menda.cqmu.edu.cn:8080/index.php). The standardized data extraction process was used for data collection, a multi-faceted annotation scheme was developed, and a user-friendly search engine and web interface were integrated for database access. To facilitate data analysis and interpretation based on MENDA, we also proposed a systematic analytical framework, including data integration and biological function analysis. Case studies were provided that identified the consistently altered metabolites using the vote-counting method, and that captured the underlying molecular mechanism using pathway and network analyses. Collectively, we provided a comprehensive curation of metabolic characterization in depression. Our model of a specific psychiatry disorder may be replicated to study other complex diseases.

miR-6071 inhibits hepatocellular carcinoma progression via targeting PTPN11.

Hepatocellular carcinoma (HCC) is a deadly malignancy. Liver cancer stem cells (LCSCs) participated in HCC progression and caused failure of chemotherapy. However, the underlying mechanism for the LCSCs regulation was unclear. In this study, we found that miR-6071 expression was decreased in LCSCs. Gain-of-function assays showed that miR-6071 overexpression repressed LCSCs self-renewal and tumorigenesis and inhibited HCC cells proliferation and migration. In mechanism, bioinformatics and luciferase reporter assay demonstrated that miR-6071 targeted 3'UTR of PTPN11 mRNA. Pearson analysis revealed a negative correlation between miR-6071 expression and PTPN11 levels in HCC tissue samples. Further study showed that PTPN11 interference and specific inhibitors IACS-13909 abrogated the discrepancy of self-renewal ability, proliferation, migration and tumorigenicity capacity between miR-6071 overexpression HCC cells and control cells. Moreover, upregulation of miR-6071 sensitized HCC cells to lenvatinib treatment. Clinical cohort analysis revealed that HCC patients with high miR-6071 expression got more survival benefit from postoperative lenvatinib treatment than patients with low miR-6071 levels. In conclusion, our study demonstrated a regulation mechanism of LCSCs, a target against LSCSs, and a biomarker for postoperative lenvatinib treatment.

Integrative Analysis of Transcriptomic and Metabolomic Data for Identification of Pathways Related to Matrine-Induced Hepatotoxicity.

Matrine (MT) is a major bioactive compound extracted from Sophorae tonkinensis. However, the clinical application of MT is relatively restricted due to its potentially toxic effects, especially hepatotoxicity. Although MT-induced liver injury has been reported, little is known about the underlying molecular mechanisms. In this study, transcriptomics and metabolomics were applied to investigate the hepatotoxicity of MT in mice. The results indicated that liver injury occurred when the administration of MT (30 or 60 mg/kg, i.g) lasted for 2 weeks, including dramatically increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc. The metabolomic results revealed that steroid biosynthesis, purine metabolism, glutathione metabolism, and pyruvate metabolism were involved in the occurrence and development of MT-induced hepatotoxicity. Further, the transcriptomic data indicated that the downregulation of NSDHL with CYP51, FDFT1, and DHCR7, involved in steroid biosynthesis, resulted in a lower level of cholic acid. Besides, Gstps and Nat8f1 were related to the disorder of glutathione metabolism, and HMGCS1 could be treated as the marker gene of the development of MT-induced hepatotoxicity. In addition, other metabolites, such as taurine, flavin mononucleotide (FMN), and inosine monophosphate (IMP), also made a contribution to the boosting of MT-induced hepatotoxicity. In this work, our results provide clues for the mechanism investigation of MT-induced hepatotoxicity, and several biomarkers (metabolites and genes) closely related to the liver injury caused by MT are also provided. Meanwhile, new insights into the understanding of the development of MT-induced hepatotoxicity or other monomer-induced hepatotoxicity were also provided.