Appraisal of surgical outcomes and oncological efficiency of intraoperative adverse events in robotic radical gastrectomy for gastric cancer.

BACKGROUND: Surgical quality control is a crucial determinant of evaluating the tumor efficacy. OBJECTIVE: To assess the ClassIntra grade for quality control and oncological outcomes of robotic radical surgery for gastric cancer (GC). METHODS: Data of patients undergoing robotic radical surgery for GC at a high-volume center were retrospectively analyzed. Patients were categorized into two groups, the intraoperative adverse event (iAE) group and the non-iAE group, based on the occurrence of intraoperative adverse events. The iAEs were further classified into five sublevels (ranging from I to V according to severity) based on the ClassIntra grade. Surgical performance was assessed using the Objective Structured Assessment of Technical Skill (OSATS) and the General Error Reporting Tool. RESULTS: This study included 366 patients (iAE group: n = 72 [19.7%] and non-iAE group: n = 294 [80.3%]). The proportion of ClassIntra grade II patients was the highest in the iAE group (54.2%). In total and distal gastrectomies, iAEs occurred most frequently in the suprapancreatic area (50.0% and 54.8%, respectively). In total gastrectomy, grade IV iAEs were most common during lymph node dissection in the splenic hilum area (once for bleeding [grade IV] and once for injury [grade IV]). The overall survival (OS) and disease-free survival of the non-iAE group were significantly better than those of the iAE group (Log rank P < 0.001). Uni- and multi-variate analyses showed that iAEs were key prognostic indicators, independent of tumor stage and adjuvant chemotherapy (P < 0.001). CONCLUSION: iAEs in patients who underwent robotic radical gastrectomy significantly correlated with the occurrence of postoperative complications and a poor long-term prognosis. Therefore, utilization and inclusion of ClassIntra grading as a crucial surgical quality control and prognostic indicator in the routine surgical quality evaluation system are recommended.

IL-33/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity.

BACKGROUND: Interleukin-33 (IL-33), defined as "alarming", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction. METHODS: C57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized. RESULTS: We discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo. CONCLUSIONS: These results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling. Video Abstract.

GJA1 reverses arsenic-induced EMT via modulating MAPK/ERK signaling pathway.

Arsenic is known as a well-established human carcinogen. Gap Junction Protein Alpha 1 (GJA1) is a multifunction protein that forms gap junction channels and is important for intercellular communication. Recently, its aberrant expression has been shown to associate with cancer recurrence and metastatic spread. However, whether GJA1 plays a role in arsenic carcinogenesis remains unknown. Here, we demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to sodium arsenite promoted epithelial-mesenchymal transition (EMT) via increasing the expression of EMT inducer S100A4 and activation of MAPK/ERK signaling. In vitro and in vivo experiments showed that chronic exposure to sodium arsenite reduced GJA1 expression. Forced expression of GJA1 inhibited sodium arsenite-induced EMT via suppressing MAPK/ERK signaling whereas GJA1 knockdown produced an opposite effect. Intriguingly, chronic exposure to sodium arsenite increased autophagy flux. Inhibition of autophagy by pharmacological intervention or genetic deletion of autophagy core gene Beclin-1 upregulated GJA1 expression. These results suggested that GJA1 restrained the carcinogenic effect of sodium arsenite by limiting MAPK/ERK signaling, and GJA1 expression was decreased by arsenic-activated autophagy. In addition, interventions directed at enhancing the level or functional activity of GJA1 could be of preventive and therapeutic interest.

Lipopolysaccharide facilitates immune escape of hepatocellular carcinoma cells via m6A modification of lncRNA MIR155HG to upregulate PD-L1 expression.

Recent studies have suggested that the initiation and progression of hepatocellular carcinoma (HCC) are closely associated with lipopolysaccharide (LPS) of intestinal bacteria. However, the role of LPS in immune regulation of HCC remains largely unknown. An orthotopic Hepa1-6 tumor model of HCC was constructed to analyze the effect of LPS on the expression of immune checkpoint molecules PD-1 and PD-L1. Then we verified the regulation of PD-L1 by LPS in HCC cells. Based on the previous finding that lncRNA MIR155HG regulates PD-L1 expression in HCC cells, we analyzed the relationship of LPS signaling pathway molecules with PD-L1 and MIR155HG by bioinformatics. The molecular mechanism of MIR155HG regulating PD-L1 expression induced by LPS was investigated by RNA pull-down followed by mass spectrometry, RNA immunoprecipitation, fluorescence in situ hybridization, and luciferase reporter assay. Finally, the HepG2 xenograft model was established to determine the role of MIR155HG on PD-L1 expression in vivo. We showed that LPS induced PD-1 and PD-L1 expression in mouse tumor tissues and induced PD-L1 expression in HCC cells. Mechanistically, upregulation of METTL14 by LPS promotes the m6A methylation of MIR155HG, which stabilizes MIR155HG relying on the "reader" protein ELAVL1 (also known as HuR)-dependent pathway. Moreover, MIR155HG functions as a competing endogenous RNA (ceRNA) to modulate the expression of PD-L1 by miR-223/STAT1 axis. Our results suggested that LPS plays a critical role in immune escape of HCC through METTL14/MIR155HG/PD-L1 axis. This study provides a new insight for understanding the complex immune microenvironment of HCC. 1. LPS plays a critical role in immune escape of HCC, especially HCC with cirrhosis. 2. Our study reveals that LPS regulates PD-L1 by m6A modification of lncRNA in HCC. 3. MIR155HG plays an important role in LPS induced PD-L1 expression. 4. LPS-MIR155HG-PD-L1 regulatory axis provides a new target for the treatment of HCC.

The NanDeSyn database for Nannochloropsis systems and synthetic biology.

Nannochloropsis species, unicellular industrial oleaginous microalgae, are model organisms for microalgal systems and synthetic biology. To facilitate community-based annotation and mining of the rapidly accumulating functional genomics resources, we have initiated an international consortium and present a comprehensive multi-omics resource database named Nannochloropsis Design and Synthesis (NanDeSyn; http://nandesyn.single-cell.cn). Via the Tripal toolkit, it features user-friendly interfaces hosting genomic resources with gene annotations and transcriptomic and proteomic data for six Nannochloropsis species, including two updated genomes of Nannochloropsis oceanica IMET1 and Nannochloropsis salina CCMP1776. Toolboxes for search, Blast, synteny view, enrichment analysis, metabolic pathway analysis, a genome browser, etc. are also included. In addition, functional validation of genes is indicated based on phenotypes of mutants and relevant bibliography. Furthermore, epigenomic resources are also incorporated, especially for sequencing of small RNAs including microRNAs and circular RNAs. Such comprehensive and integrated landscapes of Nannochloropsis genomics and epigenomics will promote and accelerate community efforts in systems and synthetic biology of these industrially important microalgae.

Culture-Free Identification and Metabolic Profiling of Microalgal Single Cells via Ensemble Learning of Ramanomes.

Microalgae are among the most genetically and metabolically diverse organisms on earth, yet their identification and metabolic profiling have generally been slow and tedious. Here, we established a reference ramanome database consisting of single-cell Raman spectra (SCRS) from >9000 cells of 27 phylogenetically diverse microalgal species, each under stationary and exponential states. When combined, prequenching ("pigment spectrum" (PS)) and postquenching ("whole spectrum" (WS)) signals can classify species and states with 97% accuracy via ensemble machine learning. Moreover, the biosynthetic profile of Raman-sensitive metabolites was unveiled at single cells, and their interconversion was detected via intra-ramanome correlation analysis. Furthermore, not-yet-cultured cells from the environment were functionally characterized via PS and WS and then phylogenetically identified by Raman-activated sorting and sequencing. This PS-WS combined approach for rapidly identifying and metabolically profiling single cells, either cultured or uncultured, greatly accelerates the mining of microalgae and their products.

Protein and metabolic profiles of tyrosine kinase inhibitors co-resistant liver cancer cells.

Hepatocellular Carcinoma (HCC) patients often develop resistance to tyrosine kinase inhibitors (TKIs) like sorafenib (SR) and lenvatinib (RR). We established HCC cell lines resistant to these drugs and analyzed the correlation between protein and metabolite profiles using bioinformatics. Our analysis revealed overexpression of MISP, CHMP2B, IL-18, TMSB4X, and EFEMP1, and downregulation of IFITM3, CA4, AGR2, and SLC51B in drug-resistant cells. Differential signals are mainly enriched in steroid hormone biosynthesis, cell adhesion, and immune synapses, with metabolic pathways including cytochrome P450 drug metabolism, amino acid metabolism, and glycolysis. Proteomics and metabolomics analysis showed co-enrichment signals in drug metabolism, amino acids, glucose metabolism, ferroptosis, and other biological processes. Knocking down MISP, CHMP2B, IL-18, TMSB4X, and EFEMP1 significantly reduced drug resistance, indicating their potential as therapeutic response biomarkers. This study characterizes protein and metabolic profiles of drug-resistant HCC cells, exploring metabolite-protein relationships to enhance understanding of drug resistance mechanisms and clinical treatment.

Single-cell atlas reveals characteristic changes in intrahepatic HBV-specific leukocytes.

IMPORTANCE: Hepatitis B virus (HBV)-specific CD8+ T cells play a central role in the clearance of virus and HBV-related liver injury. Acute infection with HBV induces a vigorous, multifunctional CD8+ T cell response, whereas chronic one exhibits a weaker response. Our study elucidated HBV-specific T cell responses in terms of viral abundance rather than the timing of infection. We showed that in the premalignant stage, the degree of impaired T cell function was not synchronized with the viral surface antigen, which was attributed the liver's tolerance to the virus. However, after the development of hepatocellular carcinoma, T cell exhaustion was inevitable, and it was marked by the exhaustion of the signature transcription factor TOX.

Unpacking the complexity of nuclear IL-33 (nIL-33): a crucial regulator of transcription and signal transduction.

Interleukin-33 (IL-33) (NF-HEV), a chromatin-associated nuclear cytokine, is a member of the IL-1 family. IL-33 possesses a nuclear localization signal and a homeodomain (a structure resembling a helix-turn-helix) that can bind to nuclear chromatin. Research has revealed that IL-33 can function as a nuclear factor to regulate various biological processes. This review discusses the cellular localization, functional effects, and immune regulation of full length IL-33 (FLIL-33), cytokine IL-33 (sIL-33) and nuclear IL-33 (nIL-33). In addition, the post-translational modifications of nIL-33 and the hypothesis of using nIL-33 as a treatment method were also summarized. A multidisciplinary approach is required which integrates methods and techniques from genomics, proteomics, cell biology and immunology to provide comprehensive insights into the function and therapeutic potential of nIL-33.

XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial-mesenchymal transition in hepatocellular carcinoma.

Emerging studies have suggested that exportin-1 (XPO1) plays a pivotal role in hepatocellular carcinoma (HCC). However, the underlying mechanism of XPO1 in HCC sorafenib resistance remains enigmatic. The expression of XPO1 in HCC tumor tissues and sorafenib-resistant (SR) cells were analyzed by bioinformatics analysis, immunohistochemistry (IHC) and Western blotting. The interaction mechanism between XPO1 and Nucleophosmin (NPM1) was investigated by immunoprecipitation (IP), Mass-spectrometric (MS) analysis, immunofluorescence colocalization, CRISPR/CAS9 technology and RNA-seq. Analyses were also conducted on KPT-8602 and sorafenib's combined therapeutic effect. Our findings unraveled that the XPO1 overexpression was observed in HCC, and correlated with poorer survival. Knockdown of XPO1 inhibited the migration and proliferation of HCC cells, and also reduced the resistance of HCC cells to sorafenib. Mechanistically, XPO1 interacted with the C-terminus of NPM1 and mediated the acetylation of NPM1 at lysine 54 to maintain sorafenib resistance. XPO1 was bound to Vimentin, resulting in the epithelial-mesenchymal transition (EMT) progression in sorafenib-resistant cells. KPT-8602 in combination with sorafenib suppressed the tumor growth. These results highlighted the therapeutic value of targeting XPO1 in overcoming sorafenib resistance. The combinational treatment of KPT-8602 and sorafenib might be an improved therapeutic option.

TGF-ß-p-STAT1-LAIR2 axis has a "self-rescue" role for exhausted CD8+ T cells in hepatocellular carcinoma.

BACKGROUND: TGF-ß is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-ß affecting the function of CD8+ T cells in hepatocellular carcinoma (HCC) have not been clearly resolved. METHODS: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-ß on HCC infiltrating CD8+ T cells. RESULTS: Here, we demonstrated that the overall effect of TGF-ß on CD8+ T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-ß upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-ß-p-STAT1-LAIR2 axis relieved CD8+ T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-ß stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8+ T cells was improved by using TAK-981 to amplify "self-rescue" signal. CONCLUSION: Our study describes a "self-rescue" mechanism of CD8+ T cells in HCC against exhaustion and the good effects from amplifying this signal.

2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis.

BACKGROUND: 2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear. METHODS: In this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora. RESULTS: We found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis. CONCLUSIONS: Our study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now.

Targeted inhibition of RBPJ transcription complex alleviates the exhaustion of CD8+ T cells in hepatocellular carcinoma.

Impaired function of CD8+ T cells in hepatocellular carcinoma (HCC) is an important reason for acquired resistance. Compared with single-target inhibitors, small-molecule compounds that could both inhibit tumor cells and alleviate T cell exhaustion are more promising to reduce resistance. In this study, we screened immunosuppressive targets in HCC by combining cancer-immunity cycle score with weighted gene co-expression network and system analysis. Through in vitro and in vivo validation experiments, we found that one of the screened molecules, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), was negatively correlated with CD8+ T cell mediated killing function. More importantly, its transcription complex inhibitor RIN1 not only inhibited the malignant biological behaviors of HCC cells by inhibiting mTOR pathway, but also reduced the expression of PD-L1 and L-kynurenine synthesis in HCC cells, thus alleviating T cell exhaustion. Meanwhile, the combination of RIN1 and anti-PD-1/PD-L1 antibodies could further activate CD8+ T cells. In short, RBPJ is an important factor regulating the function of T cells. Target inhibition of RBPJ transcription complex by small molecule compound may be a new strategy for immunotherapy of HCC.

SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma.

PURPOSE: High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research. METHODS: SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF). RESULTS: We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models. CONCLUSIONS: This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.

SUMOylated IL-33 in the nucleus stabilizes the transcription factor IRF1 in hepatocellular carcinoma cells to promote immune escape.

Interleukin-33 (IL-33) functions both as a secreted cytokine and as a nuclear factor, with pleiotropic roles in cancer and immunity. Here, we explored its role in hepatocellular carcinoma (HCC) and identified that a posttranslational modification altered its nuclear activity and promoted immune escape for HCC. IL-33 abundance was overall decreased but more frequently localized to the nucleus in patient HCC tissues than in normal liver tissues. In human and mouse HCC cells in culture and in vivo, IL-33 overexpression inhibited proliferation and repressed the abundance of programmed death ligand 1 (PD-L1) at the transcriptional level by promoting the ubiquitin-dependent degradation of interferon regulatory factor 1 (IRF1). However, this interaction was disrupted by SUMOylation of IL-33 at Lys54 mediated by the E3 ligase RanBP2. IL-33 SUMOylation correlated with its nuclear localization in HCC cells and tumors. An increase in SUMOylated IL-33 in HCC cells in cocultures and in vivo stabilized IRF1 and increased PD-L1 abundance and chemokine IL-8 secretion, which prevented the activation of cytotoxic T cells and promoted the M2 polarization of macrophages, respectively. Mutating the SUMOylation site in IL-33 reversed these effects and suppressed tumor growth. These findings indicate that SUMOylation of nuclear IL-33 in HCC cells impairs antitumor immunity.

Identifying and expression analysis of WD40 transcription factors in walnut.

Walnut (Juglans regia L.) is an important woody oil plant and will be affected by abiotic and biological stress during its growth and development. The WD-repeat (WD40) protein is widely involved in plant growth, development, metabolism, and abiotic stress response. To explore the stress response mechanism of walnut, based on the complete sequencing results of the walnut genome, this study identified and analyzed the physiological, biochemical, genetic structure, and conservative protein motifs of 42 JrWD40 genes, whose expression to abnormal temperature were tested to predict the potential biological function. The results showed that the open reading frame (ORF) of theseWD40 genes were 807-2,460 bp, encoding peptides were 29,610.55-90,387.98 Da covering 268-819 amino acids, as well as 12-112 phosphorylation sites. JrWD40 proteins were highly conserved with four to five WD40 domains and shared certain similarity to WD40 proteins from Arabidopsis thaliana (L.) Heynh. JrWD40 genes can be induced to varying degrees by low and high temperature treatments. JrWD40-32, JrWD40-27, JrWD40-35, and JrWD40-21 are affected by high temperature more seriously and their expression levels are higher; while JrWD40-37, JrWD40-26, JrWD40-20, JrWD40-24, and other genes are inhibited under low temperature stress. JrWD40-40, JrWD40-28, and JrWD40-18 were first suppressed with low expression, while as the treatment time prolonging, the expression level was increased under cold condition. JrWD40-14, JrWD40-18, JrWD40-34, and JrWD40-3 displayed strong transcriptions response to both heat and cold stress. These results indicated that JrWD40 genes can participate in walnut adaptation to adversity and can be used as important candidates for walnut resistance molecular breeding.

Interleukin 33 mediates hepatocyte autophagy and innate immune response in the early phase of acetaminophen-induced acute liver injury.

Despite interleukin 33 (IL-33) functions as an "alarmin" released from hepatic dead cells in response to tissue damages, the interrelationship between IL-33-mediated hepatocyte autophagy and innate immune response in the acetaminophen (APAP)-induced liver injury (AILI) process remains obscure. This study aimed to explore the regulation of IL-33 on hepatocyte autophagy and macrophage polarization after APAP challenge in vivo and vitro. We found IL-33 released from hepatic necrosis was elevated in the AILI mouse model. Blockage of IL-33 exacerbated liver injury by consuming liver-resident macrophages cells (Kupffer cells, KCs) and promoting hepatic inflammatory factors secretion, such as TNF-α, IL-6 and IL-1ß in the early phase of liver injury. Interestingly, IL-33 deficiency further activated hepatocyte autophagy and disrupted M2 macrophage polarization post-APAP challenge in vivo and vitro, which can be reversed by recombinant IL-33 treatment. Mechanistically, administration of IL-33 can directly enhance M2 polarization via PI3K/Akt signaling pathway and activate protective hepatocyte autophagy via AMPKα/mTOR signaling pathway in the AILI process. In conclusion, our data firstly demonstrates that IL-33 exerts protective effects on hepatocytes through the activation of autophagy and functions as an innate immunity regulator mediating macrophage polarization in the early phase of AILI.

A Scale-Free, Fully Connected Global Transition Network Underlies Known Microbiome Diversity.

Microbiomes are inherently linked by their structural similarity, yet the global features of such similarity are not clear. Here, we propose as a solution a search-based microbiome transition network. By traversing a composition-similarity-based network of 177,022 microbiomes, we show that although the compositions are distinct by habitat, each microbiome is on-average only seven neighbors from any other microbiome on Earth, indicating the inherent homology of microbiomes at the global scale. This network is scale-free, suggesting a high degree of stability and robustness in microbiome transition. By tracking the minimum spanning tree in this network, a global roadmap of microbiome dispersal was derived that tracks the potential paths of formulating and propagating microbiome diversity. Such search-based global microbiome networks, reconstructed within hours on just one computing node, provide a readily expanded reference for tracing the origin and evolution of existing or new microbiomes. IMPORTANCE It remains unclear whether and how compositional changes at the "community to community" level among microbiomes are linked to the origin and evolution of global microbiome diversity. Here we propose a microbiome transition model and a network-based analysis framework to describe and simulate the variation and dispersal of the global microbial beta-diversity across multiple habitats. The traversal of a transition network with 177,022 samples shows the inherent homology of microbiome at the global scale. Then a global roadmap of microbiome dispersal derived from the network tracks the potential paths of formulating and propagating microbiome diversity. Such search-based microbiome network provides a readily expanded reference for tracing the origin and evolution of existing or new microbiomes at the global scale.

Microbiome Search Engine 2: a Platform for Taxonomic and Functional Search of Global Microbiomes on the Whole-Microbiome Level.

Metagenomic data sets from diverse environments have been growing rapidly. To ensure accessibility and reusability, tools that quickly and informatively correlate new microbiomes with existing ones are in demand. Here, we introduce Microbiome Search Engine 2 (MSE 2), a microbiome database platform for searching query microbiomes in the global metagenome data space based on the taxonomic or functional similarity of a whole microbiome to those in the database. MSE 2 consists of (i) a well-organized and regularly updated microbiome database that currently contains over 250,000 metagenomic shotgun and 16S rRNA gene amplicon samples associated with unified metadata collected from 798 studies, (ii) an enhanced search engine that enables real-time and fast (<0.5 s per query) searches against the entire database for best-matched microbiomes using overall taxonomic or functional profiles, and (iii) a Web-based graphical user interface for user-friendly searching, data browsing, and tutoring. MSE 2 is freely accessible via http://mse.ac.cn For standalone searches of customized microbiome databases, the kernel of the MSE 2 search engine is provided at GitHub (https://github.com/qibebt-bioinfo/meta-storms).IMPORTANCE A search-based strategy is useful for large-scale mining of microbiome data sets, such as a bird's-eye view of the microbiome data space and disease diagnosis via microbiome big data. Here, we introduce Microbiome Search Engine 2 (MSE 2), a microbiome database platform for searching query microbiomes against the existing microbiome data sets on the basis of their similarity in taxonomic structure or functional profile. Key improvements include database extension, data compatibility, a search engine kernel, and a user interface. The new ability to search the microbiome space via functional similarity greatly expands the scope of search-based mining of the microbiome big data.

Noncloggingly Sieving Sub-6 nm Nanoparticles of Noble Metals into Conductive Mesoporous Foams with Biological Nanofibrils.

Porous metal foams have been one of the most sought-after materials owing to their combination of bulk metallic characteristics (e.g., thermal/electrical conductivity and ductility) and nanometric size-effect properties (e.g., catalytic reactivity, plasmonic behavior, and high surface area). Traditional sol-gel approaches, though one of the most frequently used method to produce mesoporous metal foams, were hindered for scalable production and wide applications because of its tedious multistep procedure, time-consuming gelation time, and polydisperse pore sizes. Herein, by depositing biological nanofibrils (chitin, cellulose, and silk) on commercial filtration membranes, we report a facile approach to sieve and recycle sub-6 nm nanoparticles of noble metals (Au and Pt) via nonclogging filtration into three-dimensional (3D) networks with interconnected mesopores. The porous networks could withstand air-drying, in contrast to freezing/supercritical drying conventionally used for mesoporous foams preparation. This approach was also applicable to both mesoporous monometallic (Au, Pt) and bimetallic (Au-Pt) foams. Moreover, the resultant mesoporous metallic foams show high porosity up to 90%, homogeneous mesoporous structure, and metallic conductivity up to 104 S/cm. Thus, this rapid and scalable sieving procedure not only offers a possibility of sieving noncloggingly for efficient recovery of metal nanoparticles but also starts a pathway to produce conductive and flexible mesoporous foams applicable in broad fields such as continuous flow catalysis and smart actuating.