Biology subjects

Liang, X.

Publications and source records attributed to Liang, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

DNA sensor ABCF1 phase separates with cccDNA to inhibit HBV replication

Objectives: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence. However, it is still less known how the host immune system responds to cccDNA and suppresses HBV replication. Therefore, it is essential to explore host proteins that interact with cccDNA and efficiently suppress HBV replication. Design: The interaction of cccDNA and ABCF1 was assessed by ChIP and pull-down assay. HBV replication was assessed in different cell models, including cccDNA surrogate-transfected and HBV-infected hepatocytes models. Phase separation of recombinant ABCF1 fusion proteins with cccDNA was observed by fluorescence microscopy. Results: Our data found that ABCF1 interacts with cccDNA to form phase-separated condensates via the poly-glutamine (PolyQ) of N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. Conclusions: Taken together, our study showed that ABCF1 acts as an antiviral restriction factor of HBV cccDNA by phase-separation-driven innate immune signaling and transcription inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.

microbiology↗

bioRxiv2023

Dendritic cell-derived lncRNA in patients with acute coronary syndrome

BackgroundLong non-coding RNA (lncRNA) and dendritic cells (DC) play an important role in the occurrence and development of acute coronary syndrome (ACS). However, the role and mechanism of DC-derived lncRNA in patients with ACS still remains understudied. ObjectiveTo investigate the expression difference and role of lncRNA in monocyte-derived DC(moDC) in patients with acute coronary syndrome(ACS). Methods and ResultsThe subjects were divided into 4 groups: (1) healthy control group (CON), (2) unstable angina group (UA), (3) non-ST elevation myocardial infarction group (NSEMI or NST) and (4) ST elevation myocardial infarction group (STEMI or ST). Peripheral blood was extracted and isolated to obtain mononuclear cells (PBMC). After induction into moDC, morphology was observed by electron microscope and identified by flow cytometry (FCM) (CD80, CD86, CD11c, CD14, HLA-DR), and morphological and functional differences were compared. The differentially expressed lncRNA were screened by gene sequencing, and the biological functions of which were predicted by GO and KEGG and the correlation between candidate lncRNA and target genes was analyzed. The expression levels of markers, signaling pathways, inflammatory factors and target gene were performed by FCM, RT-PCR, WB and ELISA after the candidate lncRNA were over-expressed or silenced. Electron microscope showed that the cells were suspended cells of dendritic pseudopodia. FCM showed that the expression levels of DC markers CD11c (99.02{+/-}0.12%) and HLA-DR (99.32{+/-}0.08%) were high, while the expression levels of CD80 (24.27{+/-}0.99%) and CD86 (32.38{+/-}0.59%) were low. The number of differentially expressed lncRNA screened by gene sequencing was as follows: CON vs UA, 3; CON vs. NST, 49; CON vs ST, 35; UA vs. NST, 115; UA vs ST, 113; ST vs NST, 4. The results of FCM, RT-PCR, WB and ELISA showed that the expression levels of markers (CD80, CD86, HLA-DR), signaling pathways (p-PI3K, p-AKT), inflammatory factors (IL-6 and IL-12p70) and target gene (CCL14) were increased after over-expression of CCL15-CCL14; On the contrary, its expression level was decreased. ConclusionsThere are differences in moDC morphology and function and lncRNA expression in different types of ACS patients, and the differentially expressed lncRNA (CCL15-CCL14) regulates the function of moDC.

immunology↗

bioRxiv2023

FASlpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate dosage effects of FASlpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (sle1homo.lprhet) and compared it with B6.Faslpr/lpr(lprhomo), B6.Sle1/Sle1 (sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, sle1homo.lprhet mice exhibited significantly elevated serum anti-dsDNA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1, IL-2, and IL-27. Taken together, sle1homo.lprhet mice emerge as a more faithful model of human SLE, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing.

immunology↗

bioRxiv2023

Recognition of the Nucleotide-Dependent Feature Facilitates the Microtubule End-Binding of MCAK

The growing plus-end is a key regulatory site for microtubule dynamics. MCAK (mitotic centromere-associated kinesin), a microtubule depolymerizing kinesin, is an end-binding regulator of catastrophe frequency. It is intriguing how MCAK specifically binds to growing microtubule ends. Here, we measure the end-binding kinetics of MCAK using single-molecule imaging, and reveal that MCAK binds to the entire GTP cap, including the region where EB1 preferentially binds and the distalmost tip. Further analysis shows that MCAK strongly binds to GTP{gamma}S microtubules, and this binding preference is dependent on the nucleotide state of MCAK. This finding suggests that MCAK recognizes the nucleotide-dependent feature of microtubules. Moreover, we show that although MCAK and XMAP215 partly share binding regions at the distalmost ends, their regulatory effects can be additive, highlighting a simple rule of how the end-binding regulators coordinate their activities. Overall, our findings provide new insights into how MCAK regulates microtubule end dynamics.

biochemistry↗

bioRxiv2023

SACNet: A Multiscale Diffeomorphic Convolutional Registration Network with Prior Neuroanatomical Constraints for Flexible Susceptibility Artifact Correction in Echo Planar Imaging

Susceptibility artifacts (SAs), inevitable in brain diffusion MR (dMRI) scans acquired using single-shot echo planar imaging (EPI), severely compromise the accurate detection of human brain structure. Existing SA correction (SAC) methods offer inadequate correction quality and limited applicability across diverse datasets with varied acquisition protocols. To address these challenges, we proposed SACNet, a SAC framework based on unsupervised registration convolutional networks, featuring: i) a novel diffeomorphism regularization function to avoid unnatural SAC warps, modified from a potential well function; ii) an integration with prior neuroanatomical constraints and coarse-to-fine processing strategy to enables multi-scale geometric and intensity recoveries in severe distorted areas; iii) a unified registration framework that incorporates multiple phase-encoding (PE) EPI images and structural images, ensuring compatibility with both single- and inverse-PE protocols, with or without field maps. Utilizing simulated dMRI images and over 2000 brain scans from neonatal, child, adult and traveling participants, our method consistently demonstrates state-of-the-art correction performance. Notably, SACNet effectively reduces SAs-related multicenter effects compared to existing methods. We have developed user-friendly tools using containerization techniques, hope to facilitate SAC correction quality across extensive neuroimaging studies.

neuroscience↗

bioRxiv2023

Functional connectome through the human life span

The lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimers disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

An extracellular vesicle delivery platform based on the PTTG1IP protein

Extracellular vesicles (EVs) hold great promise as therapeutic delivery vehicles, although their potential is limited by a lack of efficient EV engineering strategies to enhance loading and functional delivery of therapeutic cargo. Here, we identified N-glycosylation as a putative EV- sorting feature using a novel bioinformatics analysis strategy. We exploited this finding to develop a platform for EV-mediated delivery of macromolecular cargoes based on PTTG1IP, a small N- glycosylated, single spanning transmembrane protein. We demonstrate that PTTG1IP EV enrichment is dependent on its N-glycosylation at two sites, and that PTTG1IP is a suitable scaffold for EV loading of therapeutic cargoes. To achieve functional delivery, cargoes were fused to PTTG1IP, separated by various self-cleaving sequences intended to promote cargo release from the scaffold after EV loading. In addition, the fusogenic VSVG protein was co-expressed to enhance endosomal escape. This PTTG1IP-based strategy enabled highly efficient functional delivery of Cre protein to recipient cells and mouse xenograft tumors, as well as Cas9 and Cas9/sgRNA complex delivery to reporter cells. Importantly, PTTG1IP exhibited improved protein delivery potential relative to a scaffold based on CD63 (a common EV marker). Moreover, we developed various PTTG1IP variants with improved properties, demonstrating the versatility of PTTG1IP as an EV scaffold. The EV-loading platform described in this study offers significant advantages over other strategies, such as favourable membrane topology, the potential for further engineering, and functional delivery capability, which will enable the development of improved EV-based therapeutics.

molecular biology↗

bioRxiv2023

Molecular mechanism of acid stress response of A. acidoterrestris DSM 3922T under sublethal pH environment

Acid-responsive proteome expression profiles of Alicyclobacillus acidoterrestris (A. acidoterrestris) were analysed using label-free quantitative mass spectrometry to investigate its acid resistance mechanism at sublethal pH. Totally, 325 differential expression proteins were identified during acid stress at pH2.5 condition for 15 min, of which the expressions of 83 proteins were up-regulated and the other 242 proteins expressions were down-regulated. Differentially expressed proteins were mainly involved in organic nitrogen compounds metabolism, small molecule metabolism, organic acid metabolism and signal transduction. Overall, they were mapped into 97 metabolic pathways. Combination of KEGG pathway analysis and protein functional analysis suggested that the pH homeostasis system, changes in metabolic pathways, cell membrane permeability and DNA repair are the main acid resistance mechanisms of A. acidoterrestris at sublethal pH conditions. It is speculated that A. acidoterrestris may sense and transmit pH signals from the external environment through the nhaB protein which holds histidine-dependent acid resistance system, initiating a series of acid tolerance reactions. Our study demonstrated global physiological response of A. acidoterrestris to sublethal pH, which provided a better understanding of acid adaption mechanism of A. acidoterrestris.

microbiology↗

bioRxiv2023

Identification of Novel Scaffold Proteins for Improved Endogenous Engineering of Extracellular Vesicles

Extracellular vesicles (EVs) are gaining ground as next-generation drug delivery modalities. Genetic fusion of the protein of interest to a scaffold protein with high EV-sorting ability represents a robust cargo loading strategy. To address the paucity of such scaffold proteins we conducted a large-scale comparative study involving 244 candidate proteins. Their EV-sorting potential was evaluated using a simple but reliable assay that can distinguish intravesicular cargo proteins from surface and non-vesicular proteins. Notably, 24 proteins with conserved EV-sorting abilities across five types of producer cells were identified. Most of these are first to be reported including TSPAN2 and TSPAN3, which emerged as lead candidates, outperforming the well-known CD63 scaffold. Importantly, these engineered EVs show promise as delivery vehicles as demonstrated by in vitro and in vivo internalization studies with luminal cargo proteins as well as surface display of functional domains. The discovery of these novel scaffolds provides a new platform for EV-based engineering.

synthetic biology↗

bioRxiv2023

Multimodal engineering of extracellular vesicles for efficient intracellular protein delivery

Extracellular vesicles (EVs) are promising tools to transfer macromolecular therapeutic molecules to recipient cells, however, efficient functional intracellular protein delivery by EVs remains challenging. Here, we have developed novel and versatile systems that leverage selected molecular tools to engineer EVs for robust cytosolic protein delivery both in vitro and in vivo. These systems, termed VSV-G plus EV-sorting Domain-Intein-Cargo (VEDIC) and VSV-G-Foldon-Intein-Cargo (VFIC), exploit an engineered mini-intein (intein) protein with self-cleavage activity to link cargo to an EV-sorting domain and release it from the EV membrane inside the EV lumen. In addition, we utilize the fusogenic protein VSV-G to facilitate endosomal escape and cargo release from the endosomal system to the cytosol of recipient cells. Importantly, we demonstrate that the combination of the self-cleavage intein, fusogenic protein and EV-sorting domain are indispensable for efficient functional intracellular delivery of cargo proteins by engineered EVs. As such, nearly 100% recombination and close to 80% genome editing efficiency in reporter cells were observed by EV-transferred Cre recombinase and Cas9/sgRNA RNPs, respectively. Moreover, EV-mediated Cre delivery by VEDIC or VFIC engineered EVs resulted in significant in vivo recombination in Cre-LoxP R26-LSL-tdTomato reporter mice following both local and systemic injections. Finally, we applied these systems for improved treatment of LPS-induced systemic inflammation by delivering a super-repressor of NF-B activity. Altogether, this study describes a platform by which EVs can be utilized as a vehicle for the efficient intracellular delivery of macromolecular therapeutics for treatments of disease. Graphic summary: Development of VEDIC and VFIC systems for high-efficiency intracellular protein delivery in vitro and in vivo.Intein in tripartite fusion protein (EV-sorting Domain-Intein-Cargo) performs C-terminal cleavage during the process of EV-biogenesis, resulting in enriched free cargo proteins inside of vesicles. Together with fusogenic protein, VSV-G, these engineered EVs achieve high-efficiency intracellular delivery of cargo protein (Cre and super repressor of NF-B) or protein complex (Cas9/sgRNA RNPs) both in reporter cells and in mice models. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/535834v4_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@d0da37org.highwire.dtl.DTLVardef@1a6514corg.highwire.dtl.DTLVardef@235c9aorg.highwire.dtl.DTLVardef@194bbfa_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings

Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibition is neither efficacious nor an option. TPD is mediated through harnessing E3 ligases and redirecting them to ubiquitinate de novo target proteins for subsequent proteasomal degradation. Until recently, E3 ligase chemical matter available for mediating TPD has been limited to a relatively low number of ligases, considering that over 600 E3 ligases are encoded by the human genome. In addition, the most utilized ligase for TPD approaches, CRBN, has been observed to be downregulated in settings of acquired resistance to immunomodulatory inhibitory drugs (IMiDs). IMiDs are molecular glues that target IKZF transcription factors to CRBN for degradation. Resistance is potentially accelerated by non-essentiality of CRBN for cell viability. Here we investigated if the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a potent, non-covalent DCAF1 binder. We show that this binder, selective for the CRL4DCAF1 E3 ligase complex, can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirm specific degradation via the CRL4DCAF1 E3 ligase. We further highlight the versatility of DCAF1 for TPD by developing a DCAF1-dasatininb PROTAC targeting multiple cytosolic and membrane bound tyrosine kinases. We expand these findings towards Brutons tyrosine kinase (BTK) selective PROTACs and through extensive optimization and characterization efforts share key observations that led to a potent and selective DCAF1-BTK PROTAC (DBt-10). Finally, with this PROTAC DBt-10, we show rescue of BTK degradation in a BTK-dependent, CRBN-degradation-resistant cell line and provide a rationale for E3 ligase swap to overcome CRBN mediated resistance.

biochemistry↗

bioRxiv2023

Novel endogenous engineering platform for robust loading and delivery of functional mRNA by extracellular vesicles

Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, Extracellular Vesicles (EVs), is established by expressing a highly specific RNA-binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, VSVg, enables functional mRNA delivery in vivo at doses substantially lower than currently used clinically with synthetic lipid-based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV-based nucleic acid delivery systems and is a leap forward to clinical EV applications. Graphical Abstract(Figure created using BioRender) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/533081v3_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@140058eorg.highwire.dtl.DTLVardef@2ceaccorg.highwire.dtl.DTLVardef@eafd52org.highwire.dtl.DTLVardef@19d4019_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies

In most cell types, nuclear {beta}-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of {beta}-catenin but critically depended on GSK3{beta} for effective {beta}-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that {beta}-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, {beta}-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive {beta}-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3{beta} small molecule inhibitors to subvert {beta}-catenin degradation. Clinically approved GSK3{beta}-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of {beta}-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3{beta}-inhibitors for targeted engagement of lymphoid-specific {beta}-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTSO_LIUnlike other cell lineages, B-cells express nuclear {beta}-catenin protein at low baseline levels and depend on GSK3{beta} for its degradation. C_LIO_LIIn B-cells, {beta}-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. C_LIO_LICRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed {beta}-catenin-dependent Myc repression and induction of cell death. C_LIO_LIThe discovery of GSK3{beta}-dependent degradation of {beta}-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3{beta}-inhibitors for the treatment of refractory B-cell malignancies. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/532152v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1b70e4dorg.highwire.dtl.DTLVardef@10bfcc8org.highwire.dtl.DTLVardef@b10eorg.highwire.dtl.DTLVardef@1683a3e_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIAbundant nuclear {beta}-catenin C_LIO_LI{beta}-catenin pairs with TCF7 factors for transcriptional activation of MYC C_LIO_LIB-cells rely on efficient degradation of {beta}-catenin by GSK3{beta} C_LIO_LIB-cell-specific expression of Ikaros factors C_LI Unique vulnerability in B-cell tumors: O_LIGSK3{beta}-inhibitors induce nuclear accumulation of {beta}-catenin. C_LIO_LI{beta}-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC C_LI

cancer biology↗

bioRxiv2022

Structural connectome architecture shapes the maturation of cortical morphology from childhood to adolescence

Cortical thinning is an important hallmark of the maturation of brain morphology during childhood and adolescence. However, the connectome-based wiring mechanism that underlies cortical maturation remains unclear. Using neuroimaging, connectome, transcriptome, and computational modeling, we mapped cortical thinning patterns primarily located in lateral frontal and parietal heteromodal nodes during childhood and adolescence, which is structurally constrained by white matter network architecture and is particularly represented using a network-based diffusion model. Furthermore, connectome-based constraints are regionally heterogeneous, with the largest constraints residing in frontoparietal nodes, and are associated with gene expression signatures of microstructural neurodevelopmental events. These results are highly reproducible while using another independent dataset. Our findings advance our understanding of network-level mechanisms and the associated genetic basis that underlies the maturational process of cortical morphology during childhood and adolescence.

neuroscience↗

bioRxiv2022

Neurons Alter Endoplasmic Reticulum Exit Sites to accommodate Dendritic Arbor Size

Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not well understood. Endoplasmic reticulum exit sites (ERESs) are essential for maintaining secretory flux, and are required for normal dendrite development, but how neurons of different size regulate secretory capacity remains unknown. In C. elegans, we find that the ERES number is strongly correlated with the size of a neurons dendritic arbor. The elaborately branched sensory neuron, PVD, has especially high ERES numbers. Asymmetric cell division provides PVD with a large initial cell size critical for rapid establishment of PVDs high ERES number before neurite outgrowth, and these ERESs are maintained throughout development. Maintenance of ERES number requires the cell fate transcription factor MEC-3, C. elegans TOR (ceTOR/let-363), and nutrient availability, with mec-3 and ceTOR/let-363 mutant PVDs both displaying reductions in ERES number, soma size, and dendrite size. Notably, mec-3 mutant animals exhibit reduced expression of a ceTOR/let-363 reporter in PVD, and starvation reduces ERES number and somato-dendritic size in a manner genetically redundant with ceTOR/let-363 perturbation. Our data suggest that both asymmetric cell division and nutrient sensing pathways regulate secretory capacities to support elaborate dendritic arbors.

cell biology↗

bioRxiv2022

Curvature Sensing and Membrane Remodeling of the VPS37A N-terminal Domain during Autophagy

VPS37A, a component of ESCRT-I, is essential for recruiting a subset of ESCRT proteins that seal the phagophore during autophagosome biogenesis. In this study, we uncover two hydrophobic motifs in the VPS37A N-terminal 148 amino acids (VPS37A1-148) that selectively interact with highly curved membranes. Mutations in these motifs nearly abolish VPS37A membrane binding in vitro and compromise its localization to the phagophore and autophagic flux in vivo. We also determined the solution structure of residues 21 to 131 and demonstrated that it is the UEVL (ubiquitin E2 variant-like) domain. Intriguingly, this domain remodels highly curved liposomes to high-order structures. We suggest that the specific interactions between VPS37A1-148 and the curved membrane may facilitate the recruitment of VPS37A to the phagophore and its subsequent closure. Our results support the premise that the distinct membrane architecture of the cup-like phagophore spatiotemporally regulates autophagosome biogenesis.

biochemistry↗

bioRxiv2022

Ratio-based quantitative multiomics profiling using universal reference materials empowers data integration

Multiomics profiling is a powerful tool to characterize the same samples with complementary features orchestrating the genome, epigenome, transcriptome, proteome, and metabolome. However, the lack of ground truth hampers the objective assessment of and subsequent choice from a plethora of measurement and computational methods aiming to integrate diverse and often enigmatically incomparable omics datasets. Here we establish and characterize the first suites of publicly available multiomics reference materials of matched DNA, RNA, proteins, and metabolites derived from immortalized cell lines from a family quartet of parents and monozygotic twin daughters, providing built-in truth defined by family relationship and the central dogma. We demonstrate that the "ratio"-based omics profiling data, i.e., by scaling the absolute feature values of a study sample relative to those of a concurrently measured universal reference sample, were inherently much more reproducible and comparable across batches, labs, platforms, and omics types, thus empower the horizontal (within-omics) and vertical (cross-omics) data integration in multiomics studies. Our study identifies "absolute" feature quantitation as the root cause of irreproducibility in multiomics measurement and data integration, and urges a paradigm shift from "absolute" to "ratio"-based multiomics profiling with universal reference materials.

systems biology↗

bioRxiv2022

Not just with the natives, but phylogenetic relationship between stages of the invasion process determines invasion success of alien plant species

Darwin proposed two alternate hypotheses on the invasion success of alien plant species based on their close or distant phylogenetic relationship with the natives. Here we tested these hypotheses along the invasion process at large spatio-temporal scale. Using two abundance-based phylogenetic metrics for the native and alien flora of China, our study showed that invasion success of alien plant species is influenced by the phylogenetic relationship with native and alien species of different invasion stages. Phylogenetic similarity with the native species helps the alien ones to introduce and naturalize, but phylogenetic dissimilarity with the natives facilitates invasion success. The co-occurrence of invasive and naturalized aliens also formed more clustered assemblages, showed specialized responses to environmental stress, and provided temporal stability to the phylogenetic measures. The native-alien phylogenetic relationship is dynamic across spatial, environmental, and taxonomic scales. Therefore, assessing Darwins naturalization conundrum at different gradients of community assembly process is important.

ecology↗