Biology subjects

Fan, L.

Publications and source records attributed to Fan, L..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Horizontal Transfer and Evolution of the Biosynthetic Gene Cluster for Benzoxazinoid

Benzoxazinoids are a class of protective and allelopathic plant secondary metabolites, first identified in maize (Zea mays) and subsequently shown to be encoded by a biosynthetic gene cluster (BGC), the Bx cluster. Data mining of mining 40 high-quality grass genomes identified complete Bx clusters (containing genes Bx1 to Bx5 and Bx8) in three genera (Zea, Echinochloa and Dichanthelium) in the Panicoideae and partial clusters in the Triticeae. The Bx cluster originated from gene duplication of native analogues of Bx genes and chromosomal translocation. An ancient Bx cluster including additional Bx genes (e.g., Bx6) is found in ancestral Panicoideae. The ancient Bx cluster was gained by the Triticeae ancestor via a horizontal transfer (HT) event from the ancestral Panicoideae and later separated into three parts on different chromosomes. Bx6 appears to have been under less constrained selection during evolution of the Panicoideae as evidenced by the fact that was translocated [~]1.31-Mb away from the Bx cluster in Z. mays, moved to other chromosomes in Echinochloa, and even lost in Dichanthelium. Further investigation indicated that intense selection and polyploidization shaped the evolutionary trajectory of the Bx cluster in the grass family. This study provides the first case of HT of BGCs among plants and sheds new insights on the evolution of BGCs. SignificanceBiosynthetic gene clustering and horizontal gene transfer are two evolutionary inventions for rapid adaption by organisms. Horizontal transfer of a gene cluster has been reported in fungi and bacteria, but not in plants up to now. By mining the genomes of 40 monocot species, we deciphered the organization of Bx gene cluster, a biosynthetic gene cluster for benzoxazinoids in grasses. We found that the Bx cluster was formed by gene duplication of native analogues of individual Bx genes and directional translocation. More importantly, the Bx cluster in Triticeae was inherited from the Panicoideae via horizontal transfer. Compared with the native analogues, Bx clusters in grasses show constrained purifying selection underscoring their significance in environmental adaption.

evolutionary biology↗

bioRxiv2021

Regnase-1 deficiency restrains Klebsiella pneumoniae infection by regulation of a Type I interferon response

Excessive inflammatory responses can cause collateral tissue damage or autoimmune inflammation, sometimes with severe morbidity or mortality. During host defense responses, numerous negative feedback mechanisms are established to prevent excessive unchecked inflammation. However, this restraint can sometimes come at the cost of suboptimal infection control, and we do not fully understand how this balance is maintained during different infection settings. The endoribonuclease Regnase-1 (Reg1, Zc3h12a, MCPIP1) is an RNA binding protein (RBP) that binds and degrades many target mRNA transcripts. Reg1 is a potent feedback regulator of IL-17 and LPS signal transduction, among other stimuli. Consequently, Reg1 deficiency exacerbates autoimmune inflammation in multiple mouse models, but on the other hand, reduced Reg1 improves immunity to fungal infection. To date, the role of Reg1 in bacterial immunity is poorly defined. Here, we show that mice deficient in Reg1 are more resistant to pulmonary Klebsiella pneumoniae (KP) infection. Unexpectedly, effects of Reg1 deficiency were not due to accelerated eradication of bacteria or increased pro-inflammatory cytokine expression. Rather, alveolar macrophages from Reg1-deficient mice showed enrichment of Type I IFN-related genes upon KP infection, accompanied by increased Ifnb1 expression. Surprisingly, the stability of Ifnb1 mRNA was not altered by Reg1-deficiency; rather, mRNA encoding its upstream regulator IRF7 appeared to be a more prominent target. Blockade of IFNR during KP infection reversed disease improvement. Thus, impaired Reg1 induces Type I IFN and enhances resistance to KP, raising the possibility that Reg1 could be a potential clinical target in acute bacterial infections. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/469389v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@8c3235org.highwire.dtl.DTLVardef@345086org.highwire.dtl.DTLVardef@92bec2org.highwire.dtl.DTLVardef@29b7fa_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

A Developmentally Prometastatic Niche to Hepatoblastoma in Neonatal Liver mediated by the Cxcl1/Cxcr2 Axis

Background and RationaleHepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development. MethodsHB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. ResultsWe found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers. ConclusionWe demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.

cancer biology↗

bioRxiv2021

Integrative Analysis of Spatial Transcriptome with Single-cell Transcriptome and Single-cell Epigenome in Mouse Lungs after Immunization

Immunological memory is key to productive adaptive immunity. An unbiased, high throughput gene expression profiling of tissue-resident memory T cells at their precise anatomical locations within the lung is fundamental to understanding lung immunity, but such spatial information has yet to be characterized. In this study, using a well-established Klebsiella pneumoniae infection model, we performed an integrative analysis of spatial transcriptome with single-cell RNA-seq and single-cell ATAC-seq on lung cells from mice after immunization using the 10x Genomics Chromium and Visium platform. We employed several deconvolution algorithms and established an optimized deconvolution pipeline to accurately decipher specific cell-type composition by anatomic location. We identified and located 12 major cell types by scRNA-seq and spatial transcriptomic analysis. Integrating scATAC-seq data from the same cells processed in parallel with scRNA-seq, we found epigenomic profiles provide more robust cell type identification, especially for lineage-specific T helper cells. When combining all three data modalities, we observed a dynamic change in the location of T helper cells as well as their corresponding chemokines for chemotaxis. Furthermore, cell-cell communication analysis of spatial transcriptome provided evidence of lineage-specific T helper cells receiving designated cytokine signaling. In summary, our first-in-class study demonstrated the power of multi-omics analysis to uncover intrinsic spatial- and cell-type-dependent molecular mechanisms of lung immunity. Our data provides a rich research resource of single cell multi-omics data as a reference for understanding spatial dynamics of lung immunization.

bioinformatics↗

bioRxiv2021

Isolation, identification and molecular characterization of Aeromonas spp. from farmed loach (Misgurnus anguillicaudatus)

Gram-negative Aeromonas bacteria is known to contaminate aquaculture products and retains the ability to infect wide range of host including fishes, shrimps and humans. This study is designed to evaluate the presence of Aeromonas in healthy loaches (Misgurnus anguillicaudatus) collected from the markets in Hainan and Guangdong provinces of China. Based on the molecular sequencing and phylogenetic analysis with single 16S rRNA and concatenated genes (gyrA and ropD), 104 isolates were identified as Aeromonas species followed by further classification to A. veronii (83.65%), A. jandaei (9.62%), A. hydrophila (3.85%) and A. allosaccharophila (2.88%). More than half of the isolates displayed hemolytic activity of 87.5% and were able to form moderate biofilm (78.26%). Fourteen antibiotics from ten representative classes were screened that demonstrated complete resistance to ampicillin, 89.4% and 68.3% to lincomycin and nalidixic acid. Moreover, a notable detection and prevalence was found in screening of ten virulence-related and nine resistance genes. To our knowledge, it is the first report of its kind demonstrating potential threat of the commercial loaches carrying Aeromonas to human health. These findings will assist professionals working in clinical settings to optimize their prescription accordingly and researchers to access the impacts of Aeromonas resistance on human health. ImportanceThis study demonstrates high infection rate of loaches by Aeromonas spp. in Hainan and Guangdong provinces of China. The most prevalent species was Aeromonas veronii. Most of the isolates displayed hemolytic activity and formed moderate biofilm. Multiple virulence genes, resistance genes and multi-antibiotic resistance were detected. Aeromonads risks should be considered in loach industry.

microbiology↗

bioRxiv2021

The exosomes derived from urine of premature infants target MAPK8 via miR-30a-5p to protect cisplatin-induced acute kidney injury in mice

AimAcute kidney injury (AKI), a global public health issue, not only causes millions of deaths every year, but is also a susceptible factor for chronic kidney disease (CKD). Nephrotoxic drugs are an important cause of AKI. There is still a lack of effective and satisfactory prevention method in clinical practice. This study investigated the protective effect of the exosomes derived from urine of premature infants on cisplatin-induced acute kidney injury. MethodsIsolation of exosomes from fresh urine of premature infants: The characteristics of exosomes were determined by flow cytometry, transmission electron microscopy and Western blotting. A C57BL/6 mice model of cisplatin-induced acute kidney injury was established. The mice in the experimental group were given 100ug exosomes dissolved in 200ul solution. The mice in the control group were given normal saline (200ul). These treatments were performed 24 hours after AKI was induced by intraperitoneal injection of cisplatin. To evaluate renal function, blood was drawn 24 hours after AKI model was established and serum creatinine (sCr) was measured. The mice were euthanized 72 hours after exosome treatment. The kidneys were collected for pathological examination, RNA and protein extraction, and the evaluation of renal tubular damage and apoptosis. In the in-vitro experiment, human renal cortex/proximal tubular cells (HK2) was induced by cisplatin to assess the protective ability of the exosomes derived from urine of premature infants. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blotting were used to evaluate the effect of exosomes treatment on the apoptosis of HK2 cells induced by cisplatin. Exosome microRNA sequencing technology and bioinformatics analysis method were applied to investigate the miRNAs enriched in exosomes and their target genes. The dual luciferase gene reporter system was used to detect the interaction of target genes. ResultsTreatment of exosomes derived from urine of premature infants could decrease the level of serum creatinine and the apoptosis of renal tubular cell, inhibit the infiltration of inflammatory cell, protect mice from acute kidney injury induced by cisplatin and reduce mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes derived from urine of premature infants. It protected HK2 cells from cisplatin-induced apoptosis by targeting and down-regulating the 3UTR of mitogen-activated protein kinases (MAPK8) mRNA. ConclusionsAccording to our results, the exosomes derived from urine of premature infants alleviated cisplatin-induced acute kidney injury in mice and inhibited the apoptosis of human proximal tubular cells (HK2) induced by cisplatin in vitro. MiR-30a-5p in exosomes inhibited cisplatin-induced MAPK activation, ameliorated apoptosis, and protected renal function. The exosomes derived from urine of premature infants provided a promising acellular therapy for AKI.

molecular biology↗

bioRxiv2021

Spermidine dampens inflammation by directly inhibiting Th17 cytokine production through a PRDX1 associated antioxidant pathway

The activation of IL-17 signaling has been linked to the pathogenesis of many chronic, inflammatory lung diseases including Cystic Fibrosis (CF). Through unbiased single-cell RNAseq screening, we found that IL-17+ T cells highly express Srm and Smox, which encode two key enzymes for spermidine synthesis. Spermidine has been shown to reduce inflammation by regulating macrophage activation and balancing Th17/Treg differentiation, but its direct effects on Th17 cytokine production has not been carefully investigated. Here, using already differentiated Th17 cells from cultured mouse splenocytes, we found that exogenous spermidine directly inhibits IL-1{beta}/IL-23 induced IL-17 production. Blockade of endogenous spermidine synthesis enhanced IL-17 production above native levels, further supporting that spermidine is a direct regulator of cytokine secretion independent of differentiation. In vivo, spermidine alleviates lung inflammation in both PA infection and LPS induced acute lung injury models. Further RNA-seq analysis suggests spermidine suppression of Th17 cytokine production is mediated through its PRDX1 dependent antioxidant activity. Our data establishes that spermidine is a direct regulator of Type-17 T cell cytokine production and has potent anti-inflammatory effects against lung inflammation.

immunology↗

bioRxiv2021

The genome sequence of Sorbus pohuashanensis provides insights into population evolution and leaf sunburn response

Sorbus pohuashanensis is a potential horticulture and medicinal plant, but its genomic and genetic background remains unknown. Here, we de novo sequenced and assembled the S. pohuashanensis (Hance) Hedl. reference genome using PacBio long reads. Based on the new reference genome, we resequenced a core collection of 22 Sorbus spp. samples, which were divided into two groups (G1 and G2) based on phylogenetic and PCA analysis. These phylogenetic clusters were highly in accordance with the classification based on leaf shape. Natural hybridization between the G1 and G2 groups was evidenced by a sample (R21) with a highly heterozygous genotype. Nucleotide diversity ({pi}) analysis showed that G1 has a higher diversity than G2, and that G2 originated from G1. During the evolution process, the gene families involved in photosynthesis pathways expanded and gene families involved in energy consumption contracted. Comparative genome analysis showed that S. pohuashanensis has a high level of chromosomal synteny with Malus domestica and Pyrus communis. RNA-seq data suggested that flavonol biosynthesis and heat-shock protein (HSP)-heat-shock factor (HSF) pathways play important roles in protection against sunburn. This research provides new insight into the evolution of Sorbus spp. genomes. In addition, the genomic resources and the identified genetic variations, especially those genes related to stress resistance, will help future efforts to introduce and breed Sorbus spp.

genomics↗

bioRxiv2021

Enhanced soil quality after forest conversion to vegetable cropland and tea plantation has contrasting effects on soil microbial structure and functions

Land-use changes could potentially exert a strong influence on soil quality and soil microbial communities. Moreover, microbial taxa are also important drivers of soil ecological functions. However, the linkage between soil quality and soil microbial communities is in need of deeper understanding. In this study, we examined the effects of soil quality on microbial community structure and functions after forest conversion to vegetable cropland and tea plantations. Soil quality index was significantly increased after natural forest conversion to vegetable cropland and tea plantations. Soil bacterial beta diversity significantly correlated to soil quality, but the sensitivity of individual microbial groups varied in response to changes in soil quality. Higher soil quality promoted bacterial diversity in vegetable cropland but decreased it in tea plantations, which implied soil quality was a structural factor in bacterial community composition but had contrasting effects for croplands versus plantations. Agricultural management played a negative role in maintaining microbial interactions, as identified by the network analysis, and furthermore the analysis revealed key functions of the microbial communities. After land-use change, the abundance (e.g., level, intensity) of microbial N-cycling function increased in tea plantations but decreased in vegetable cropland. The abundance of C-cycling function featured an opposite trend. Higher level of N-fixation in tea plantations but the higher abundance of N-oxidation in vegetable cropland was demonstrated. Higher abundance of ammonia-oxidizing bacteria and ammonia-oxidizing archaea as identified by qPCR in vegetable cropland corroborated the FAPROTAX function prediction. Therefore, the key taxa of soil microbial communities and microbial functions were largely dependent on changes in soil quality and determined responses to specific agricultural management.

ecology↗

bioRxiv2021

BAI-Net: Individualized Human Cerebral Cartography using Graph Convolutional Network

Brain atlas is an important tool in the diagnosis and treatment of neurological disorders. However, due to large variations in the organizational principles of individual brains, many challenges remain in clinical applications. Brain atlas individualization network (BAI-Net) is an algorithm that subdivides individual cerebral cortex into segregated areas using brain morphology and connectomes. BAI-Net integrates topological priors derived from a group atlas, adjusts the areal probability using the connectivity context derived from diffusion tractography, and provides reliable and explainable individualized brain parcels across multiple sessions and scanners. We demonstrate that BAI-Net outperforms the conventional iterative clustering approach by capturing significantly heritable topographic variations in individualized cartographies. The topographic variability of BAI-Net cartographies shows strong associations with individual variability in brain morphology, connectivity fingerprints and cognitive behaviors. This study provides a new framework for individualized brain cartography and paves the way of atlas-based precision medicine in clinical practice.

neuroscience↗

bioRxiv2021

Uncovering the Genetic Profiles Underlying the Intrinsic Organization of the Human Cerebellum

The functional diversity of the human cerebellum is largely believed to be derived more from its extensive connections rather than being limited to its mostly invariant architecture. However, whether and how the determination of cerebellar connections in its intrinsic organization interact with microscale gene expression is still unknown. Here we decode the genetic profiles of the cerebellar functional organization by investigating the genetic substrates simultaneously linking cerebellar functional heterogeneity and its drivers, i.e., the connections. We not only identified 443 network-specific genes but also discovered that their co-expression pattern correlated strongly with intra-cerebellar functional connectivity (FC). Ninety of these genes were also linked to the FC of cortico-cerebellar cognitive-limbic networks. To further discover the biological functions of these genes, we performed a "virtual gene knock-out" by observing the change in the coupling between gene co-expression and FC and divided the genes into two subsets, i.e., a positive gene contribution indicator (GCI+) involved in cerebellar neurodevelopment and a negative gene set (GCI-) related to neurotransmission. A more interesting finding is that GCI- is significantly linked with the cerebellar connectivity-behavior association and many recognized brain diseases that are closely linked with the cerebellar functional abnormalities. Our results could collectively help to rethink the genetic substrates underlying the cerebellar functional organization and offer possible micro-macro interacted mechanistic interpretations of the cerebellum-involved high order functions and dysfunctions in neuropsychiatric disorders.

neuroscience↗

bioRxiv2021

Microtubules Promote the Non-cell Autonomy of MicroRNAs by Inhibiting their Cytoplasmic Loading into ARGONAUTE1 in Arabidopsis

Mobile microRNAs (miRNAs) serve as local and long-distance signals in developmental patterning and stress responses in plants. However, mechanisms governing the non-cell autonomous activities of miRNAs remain elusive. Here, we show that mutations that disrupt microtubule dynamics are specifically defective for the non-cell autonomous actions of mobile miRNAs, including miR165/6 that is produced in the endodermis and moves to the vasculature to pattern xylem cell fates in Arabidopsis roots. We show that KTN1, a subunit of a microtubule-severing enzyme, is required in source and intermediary cells to inhibit the loading of miR165/6 into ARGONUATE1 (AGO1), which is cell-autonomous, to enable the miRNA"s cell exit. Microtubule disruption enhances the association of miR165/6 with AGO1 in the cytosol. These findings suggest that, while cell-autonomous miRNAs load into AGO1 in the nucleus, cytoplasmic AGO1 loading of mobile miRNAs is a key step regulated by microtubules to promote the range of miRNA"s cell-to-cell movement.

plant biology↗

bioRxiv2021

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

BackgroundBone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. MethodsUsing C57BL/6 mice as a model, we employed the bone-protected PPAR{gamma} constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a CT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers. ResultsWe have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPAR{gamma} acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/{beta}- catenin signaling. ConclusionsAdipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. FundingThis work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).

molecular biology↗

bioRxiv2021

HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

Huntingtons disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 [A] cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass-spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The polyglutamine tract containing N-terminal exon 1 region of HTT is dynamic, but shows greater conformational variety in the mutant than wildtype exon 1. By providing novel insight into the structural consequences of HTT polyglutamine expansion, our data provide a foundation for future functional and drug discovery studies targeting Huntingtons disease.

biochemistry↗

bioRxiv2021

Genotyping-by-sequencing-based identification of Arabidopsis pattern recognition receptor RLP32 recognizing proteobacterial translation initiation factor IF1

Pattern-triggered immunity (PTI) is a central component of plant immunity. Activation of PTI relies on the recognition of microbe-derived structures, termed patterns, through plant encoded surface-resident pattern recognition receptors (PRRs). We have identified proteobacterial translation initiation factor 1 (IF1) as an immunogenic pattern that triggers PTI in Arabidopsis thaliana and some related Brassicaceae species. Unlike most other immunogenic patterns identified, IF1 elicitor activity cannot be assigned to a small peptide epitope, suggesting that tertiary fold features are required for IF1 receptor activation. We have deployed natural variation in IF1 sensitivity to identify leucine-rich repeat (LRR) receptor-like protein 32 (RLP32) as the corresponding Arabidopsis receptor using a restriction site-associated DNA sequencing (RAD-seq) approach. Transgenic expression of RLP32 confers IF1 sensitivity to rlp32 mutants, IF1-insensitive Arabidopsis accessions and IF1-insensitive Nicotiana benthamiana. RLP32 binds IF1 specifically and forms complexes with LRR receptor kinases SOBIR1 and BAK1 to mediate signaling. Similar to previously identified PRRs RLP32 confers resistance to Pseudomonas syringae infection, highlighting an unexpectedly complex array of bacterial pattern sensors within a single plant species.

plant biology↗

bioRxiv2021

Recovery of high-qualitied Genomes from a deep-inland Salt Lake Using BASALT

Metagenomic binning enables the in-depth characterization of microorganisms. To improve the resolution and efficiency of metagenomic binning, BASALT (Binning Across a Series of AssembLies Toolkit), a novel binning toolkit was present in this study, which recovers, compares and optimizes metagenomic assembled genomes (MAGs) across a series of assemblies from short-read, long-read or hybrid strategies. BASALT incorporates self-designed algorithms which automates the separation of redundant bins, elongate and refine best bins and improve contiguity. Evaluation using mock communities revealed that BASALT auto-binning obtained up to 51% more number of MAGs with up to 10 times better MAG quality from microbial community at low (132 genomes) and medium (596 genomes) complexity, compared to other binners such as DASTool, VAMB and metaWRAP. Using BASALT, a case-study analysis of a Salt Lake sediment microbial community from northwest arid region of China was performed, resulting in 426 non-redundant MAGs, including 352 and 69 bacterial and archaeal MAGs which could not be assigned to any known species from GTDB (ANI < 95%), respectively. In addition, two Lokiarchaeotal MAGs that belong to superphylum Asgardarchaeota were observed from Salt Lake sediment samples. This is the first time that candidate species from phylum Lokiarchaeota was found in the arid and deep-inland environment, filling the current knowledge gap of earth microbiome. Overall, BASALT is proven to be a robust toolkit for metagenomic binning, and more importantly, expand the Tree of Life.

bioinformatics↗

bioRxiv2021

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy

Activation of microglia, the brains innate immune cells, is a prominent pathological feature in tauopathies, including Alzheimers disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-{kappa}B exacerbated, while inactivation diminished, tau seeding and spreading in PS19 mice, consistent with the observation that NF-{kappa}B activation accelerates processing of internalized tau fibrils in primary microglia. Remarkably, inhibition of microglial NF-{kappa}B specifically also rescued tau-mediated learning and memory deficits, and restored overall transcriptomic changes while increasing tau inclusions. On a single cell level, we discovered that tau-associated disease states in microglia were diminished by NF-{kappa}B inactivation and further transformed by constitutive NF-{kappa}B activation. Our study establishes a central role for microglial NF-{kappa}B signaling in mediating tau toxicity in tauopathy.

neuroscience↗

bioRxiv2021

Paradoxical Roles of Peritumoral Hepatic Stellate Cells in Liver Tumorigenesis in Mice: Retarding Tumor Growth and Promoting Tumor Dissemination

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on cancer-associated fibroblast residing within iCCA tumor mass, little is known about the fibrotic response from the tumor-surrounding liver and its role in iCCA development. In this study, we find a significant accumulation of peritumoral myofibroblasts (pMFs) in both patient iCCA and tumors from an iCCA orthotopic allograft mouse model. Using tumor and liver spheroid coculture we show that iCCA-liver interaction induces rapid pMF accumulation at the interface. We find pMFs placed around iCCA spheroids exert a strong suppressive effect on tumor cells growth, in contrast to the pro-proliferative effect of MFs mixed within tumor spheroids. However, prolonged iCCA-pMF interaction elicits tumor cell dissemination in vitro. We find an upregulation of Vcam1 in tumor cells in the early phase of iCCA-pMF interaction both in vitro and in vivo which is downregulated when tumor cells disseminate. Blocking Vcam1 activity in iCCA allograft mouse models slows primary tumor growth but lead to increased tumor metastasis. Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA, with the ability to suppress tumor growth but elicit tumor cell dissemination.

cancer biology↗