Biology subjects

Liu, G.

Publications and source records attributed to Liu, G..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

The enhancement of electricity generation using cellulose based on ternary microbial consortium

Cooperation between microorganisms is crucial to design an efficient inoculum for enhancing the electricity-producing ability of carboxymethyl cellulose (CMC) fed bioreactors. In the present study, the influence of microbial mutualistic interactions and electricity generation capability were investigated by designing several co-culture and ternary culture systems. It was found that a ternary culture system of Cellulomonas Lsc-8, Bacillus subtilis C9 and Geobacter sulfurreducens PCA was used to efficiently convert cellulose into electricity. The maximum current density of 796 {+/-} 30 {micro}A{middle dot}cm-2 were achieved by the ternary culture, which were much higher than that Geobacter sulfurreducens PCA using acetate and co-culture systems to utilize CMC in bioreactors, respectively. In this consortium, Cellulomonas Lsc-8, and Bacillus subtilis C9 simultaneously digested CMC to produce acetate and secreted riboflavin as an electron shuttle; Geobacter sulfurreducens PCA utilized acetate to generate electricity. The introduction of Bacillus subtilis C9 further promoted the degradation of CMC and secreted more riboflavin to enhance electricity generation of the ternary culture. This work suggested that the synergistic interaction between interspecies in microbial consortia is emergent in designing specific community for achieving maximum power generation using CMC as substrate. This research shows new insight into the design of more efficient, stable, and robust microbial consortia applicable in waste treatment and power generation. IMPORTANCEMicrobial fuel cells (MFCs) may benefit from microbial consortia that efficiently convert carbon sources to electricity. A key challenge with this system is how to manage microbial community assembly to maximize electricity generation. Herein, we constructed and tested a three-species microbial consortium to enhance conversion of cellulose to electricity. Cellulomonas Lsc-8 and Bacillus subtilis C9 efficiently converted cellulose to acetate (electron donor) and riboflavin (electron shuttle), which enabled Geobacter sulfurreducens to generate electricity. This study laid the foundation for design of more efficient, stable, and robust microbial consortia for waste treatment and energy applications.

microbiology↗

bioRxiv2024

Plasticity and Dynamics of Hematopoietic Cells within Bone Marrow Microenvironment in Leukemia

Extensive research has been conducted on the plasticity of malignant cells and nonmalignant cells in solid tumor. However, the plasticity of bone marrow hematopoietic cells in leukemia have remained largely unexplored. In this study, we aimed to investigate cell changings in hematopoietic cells through lineage tracing across various types of leukemias. We had compiled a landscape of leukemia and constructed phylogenetic trees of hematopoietic cells through utilizing massively parallel scRNA-seq data, mtDNA mutation and SNP analysis. Based on the observed cell changings, we identified several types of cell changings, including transdifferentiation, dedifferentiation, and state transition, except for differentiation and expansion. In AML and CMML, GMPs and neutrophils showed a higher potential for transferring to other cell types. In BPDCN, pDCs were less prone to switching to other cell types, while T cells demonstrated high plasticity. In B-ALL and B-CLL, B-ALL blast cells and B-CLL blast cells emerged at the most dynamic state. The dynamics of hematopoietic cells in AML, BPDCN and ALL changed along with the clinical process. Extrinsic factors within the leukemia microenvironment may influence the cell changings. Regulons encountered an intermediate cell state during the process of transition to myeloid cells and erythroid cells. We also found a correlation between B-common blast cells and T cells, suggesting a potential transition from B lymphoblastic leukemia to T lymphoblastic leukemia. In conclusion, our study unveiled the distinct plasticity and dynamics of hematopoietic cells in various types of leukemia. This sheds light on the possibility of targeting cell changes as a new strategy for leukemia treatment and improving current immunotherapy.

bioinformatics↗

bioRxiv2024

HOIL1 mediates MDA5 activation through ubiquitination of LGP2

The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust antiviral immune response. We have shown previously that HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex (LUBAC), is essential for interferon (IFN) induction in response to viruses sensed by MDA5, but not for viruses sensed by RIG-I. LUBAC contains two unusual E3 ubiquitin ligases, HOIL1 and HOIP. HOIP generates methionine-1-linked polyubiquitin chains, whereas HOIL1 has recently been shown to conjugate ubiquitin onto serine and threonine residues. Here, we examined the differential requirement for HOIL1 and HOIP E3 ligase activities in RLR-mediated IFN induction. We determined that HOIL1 E3 ligase activity was critical for MDA5-dependent IFN induction, while HOIP E3 ligase activity played only a modest role in promoting IFN induction. HOIL1 E3 ligase promoted MDA5 oligomerization, its translocation to mitochondrial-associated membranes, and the formation of MAVS aggregates. We identified that HOIL1 can interact with and facilitate the ubiquitination of LGP2, a positive regulator of MDA5 oligomerization. In summary, our work identifies LGP2 ubiquitination by HOIL1 in facilitating the activation of MDA5 and the induction of a robust IFN response.

immunology↗

bioRxiv2024

Let-7i-5p regulates osteogenic differentiation of bone marrow mesenchymal stem cells induced by psoralen by targeting CKIP-1

AbstractPrevious studies have shown that psoralen can treat osteoporosis by inducing osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CKIP-1 is an inhibitor of bone formation and plays a negative regulatory role in the osteogenic differentiation of BMSCs. MicroRNA (miRNA) is a kind of small single-stranded non-coding RNA, which regulates the occurrence and development process of cell proliferation, apoptosis, differentiation and metabolism. Studies have shown that miRNA can affect the proliferation and differentiation of BMSCs by targeting and regulating the expression of related genes. However, whether microRNA can regulate psoralen-induced osteogenic differentiation and its specific mechanisms remain unclear. The aim of this study was to identify miRNA target genes regulating the osteogenic differentiation of BMSCs induced by psoralen and further analyze the mechanism.miRNA microarray was performed to screen the differentially expressed mirnas induced by psoralen, and bioinformatics analysis and luciferase reporter gene assay were used to determine the target sites of let-7i-5p. The mechanism of let-7i-5p in psoralen induced osteogenic differentiation of BMSCs was investigated using in vitro overexpression or inhibition approaches.The results showed that miRNA microarray analysis and reverse transcription quantitative PCR further confirmed that let-7i-5p was up-regulated during the process of psoralin-induced osteogenic differentiation of BMSCs.Bioinformatics analysis and luciferase reporter gene assay confirmed CKIP-1 as a potential target of let-7i-5p.Overexpression of CKIP-1 by transfection with CKIP-1 mimetic significantly inhibited the expression of BMP, Runx2, and Smad1, while CKIP-1 inhibitor promoted their expression.Overexpression of let-7i-5p partially relieved the inhibitory effect of CKIP-1 on osteogenic differentiation of BMSCs.Our results suggest that let-7i-5p regulates psoralen-induced osteogenic differentiation of BMSCs by targeting CKIP-1, which provides a new therapeutic target for osteoporosis.

genetics↗

bioRxiv2024

ERNIE-RNA: An RNA Language Model with Structure-enhanced Representations

With large amounts of unlabeled RNA sequences data produced by high-throughput sequencing technologies, pre-trained RNA language models have been developed to estimate semantic space of RNA molecules, which facilities the understanding of grammar of RNA language. However, existing RNA language models overlook the impact of structure when modeling the RNA semantic space, resulting in incomplete feature extraction and suboptimal performance across various downstream tasks. In this study, we developed a RNA pre-trained language model named ERNIE-RNA (Enhanced Representations with base-pairing restriction for RNA modeling) based on a modified BERT (Bidirectional Encoder Representations from Transformers) by incorporating base-pairing restriction with no MSA (Multiple Sequence Alignment) information. We found that the attention maps from ERNIE-RNA with no fine-tuning are able to capture RNA structure in the zero-shot experiment more precisely than conventional methods such as fine-tuned RNAfold and RNAstructure, suggesting that the ERNIE-RNA can provide comprehensive RNA structural representations. Furthermore, ERNIE-RNA achieved SOTA (state-of-the-art) performance after fine-tuning for various downstream tasks, including RNA structural and functional predictions. In summary, our ERNIE-RNA model provides general features which can be widely and effectively applied in various subsequent research tasks. Our results indicate that introducing key knowledge-based prior information in the BERT framework may be a useful strategy to enhance the performance of other language models.

bioinformatics↗

bioRxiv2024

Screening of functional maternal-specific chromatin regulators in early embryonic development

The early stages of embryonic development rely on maternal products for proper regulation. However, systematic screening for functional maternal-specific factors has been challenging due to the time- and labor-intensive nature of traditional approaches. Here, we combined a computational pipeline and F0 homozygous mutation technology to screen for functional maternal-specific chromatin regulators in zebrafish embryogenesis and identified Mcm3l, Mcm6l, and Npm2a as playing essential roles in DNA replication and cell division. Our results contribute to understanding the molecular mechanisms underlying early embryo development and highlight the importance of maternal-specific chromatin regulators in this critical stage.

developmental biology↗

bioRxiv2024

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and Gi1, as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.

biophysics↗

bioRxiv2024

Aerobic exercise promotes PDAC vascular normalization through S1PR1 signaling in tumor endothelial cells

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by high resistance to anti-cancer therapies. This resistance is caused in part by hypo-vascularization and dysfunctional vessels which inefficiently deliver chemotherapy. Here, we define the mechanism of aerobic exercise-induced tumor vascular remodeling and improved chemotherapy delivery and efficacy. We found that aerobic exercise was able to improve tumor vascular function and increase the number of lymphatic vessels, and these effects were associated with increased gemcitabine delivery to and efficacy against PDAC in mice. Further, exercise increased sphingosine-1-phosphate (S1P) in plasma and the activation of sphingosine-1-phosphate receptor 1 (S1PR1) in tumor endothelial cells. S1PR1 endothelial cell-specific deletion blunted the exercise-induced improvements in tumor vascular function, gemcitabine efficacy and drug concentration. Preclinical findings were validated in a patient cohort in which we found that exercise during neoadjuvant chemotherapy remodeled PDAC vasculature and improved tumor vascular function. These findings provide direct evidence that exercise increases chemotherapy delivery and efficacy by improving vascular function, defining S1PR1 as a necessary mediator of exercise-induced vascular remodeling.

cancer biology↗

bioRxiv2024

Granulosa cell-layer stiffening prevents the granulosa cells from escaping the post-ovulatory follicle

Ovulation is necessary for successful reproduction. After ovulation, cumulus cells and oocytes are released, while granulosa cells (GCs) remain trapped within the post-ovulatory follicle to form the corpus luteum. However, the mechanism underlying GC confinement has long been unclear. Here, we provide in vitro and in vivo evidence demonstrating that the stiffening of GC-layer as an evolutionarily conserved mechanism that hinders GCs from escaping the post-ovulatory follicles. Spatial transcriptome analysis reveals that the assembly of focal adhesions is primarily responsible for this stiffening. Disrupting focal adhesion assembly through RNA interference results in the release of GCs from the post-ovulatory follicle, leading to the formation of an aberrant corpus luteum with reduced cell density and cavities. We also uncover that the LH (hCG) -cAMP-PKA-CREB signaling axis stimulates focal adhesion assembly and induce GC-layer stiffening. Our findings introduce a novel concept of "GC-layer stiffening", which offers valuable insights into the factors that prevent GCs escape from the post-ovulatory follicle.

cell biology↗

bioRxiv2024

Mesenchymal stem cell-derived extracellular vesicles attenuate symptoms in dextran sodium sulfate-induced ulcerative colitis mouse model

Inflammatory bowel disease (IBD) refers to a group of multifactorial and chronic inflammation affecting intestinal tract. Based on the pathogenic mechanisms, IBD mainly comprised of two categories: ulcerative colitis (UC) and Crohns disease (CD). In this study, we established a dextran sulfate sodium (DSS)-induced colitis model to mimic UC. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as therapeutic vectors have shown regenerating effect of damaged tissues. Here, intravenous administration of MSC-EVs ameliorated IBD symptoms including gaining weight, reducing disease activity index and restoring colon length. In addition, the protective effect of MSC-EVs were demonstrated by repairing colon mucosa and reducing the infiltration of macrophages in submucosa. Collectively, MSC-EV shows a therapeutic potential for IBD.

physiology↗

bioRxiv2024

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+ HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

molecular biology↗

bioRxiv2024

Perinatal ampicillin administration modulates murine bile acid metabolism in vivo - an observational study

Antibiotics are an indispensable tool of modern medicine, yet their impact extends beyond eliminating harmful bacteria to perturbing the commensal bacteria constituting the gut microbiome. This collateral damage is particularly significant in early life when the gut microbiome is still developing. In humans, antibiotic administration during infancy and childhood is associated with various long-term negative health outcomes. However, existing research has predominantly focused on the direct administration of antibiotics to infants, leaving uncertainties about whether indirect antibiotic exposure produces similar effects. Here, we use mouse models to investigate how three distinct routes of exposure to the commonly prescribed broad-spectrum antibiotic ampicillin influences parent and infant metabolism. These methods simulate major modes of both direct and indirect antibiotic exposure: intravenous antibiotic administration to the mother immediately before birth mimicking intrapartum antibiotic prophylaxis, antibiotic use by the mother during lactation, and direct administration to infants mimicking empiric antibiotic treatment for neonatal sepsis. Through untargeted metabolomics of fecal samples from mouse dams and infants, we identified one class of compounds, bile acids and related cholane steroids, as particularly sensitive to ampicillin treatment. Bile acids, produced by the host and extensively modified by the gut microbiome, serve as important mediators in the cross-talk between the microbiota and the host. Here, we detail the coordinated changes in bile acid metabolism in response to a commonly prescribed antibiotic, focusing on dams treated both pre- and postpartum. Additionally, we identify unique bile acids associated with weight gain in infant mice. ImportanceAntibiotics are widely used perinatally, administered to both parents and infants before, during, and after birth. While they can play a life-saving role, antibiotics also result in collateral damage to the beneficial microbes constituting the gut microbiome. These microbes have many important functions, particularly in the metabolism of small molecules in the body. One such group of molecules, bile acids, undergo extensive modifications by bacteria and may act as a "language" through which microbes communicate with the host. This observational study investigates the impact of the commonly prescribed antibiotic ampicillin on the metabolism of these molecules during childbirth. Our results indicate that ampicillin administration pre- or post-partum significantly alters the mothers bile acid metabolism, but has a minimal influence on infant bile acid levels. However, in all cases, ampicillin administration significantly increased infant weight, even when the antibiotic was solely administered to the mother.

pharmacology and toxicology↗

bioRxiv2024

Identification and classification of the genomes of novel Microviruses in a poultry slaughterhouse

Microviridae is a family of phages with circular ssDNA genomes and they are widely found in various environments and organisms. In this study, Virome techniques were employed to explore potential members of Microviridae in poultry slaughterhouse, leading to the identification of 98 novel and complete microvirus genomes. Using a similarity clustering network classification approach, these viruses were found to belong to at least 6 new subfamilies within Microviridae and 3 higher-level taxonomic units. Analysis of their genomes found that the genome size, GC content and genome structure of these new taxa showed evident regularities, validating the rationality of our classification method. Compared with the 19 families classified by previous researchers for microviruses dataset, our method can divide microviruses into about 45 more detailed clusters, which may serve as a new standard for classifying Microviridae members. Furthermore, addressing the scarcity of host information for microviruses, this study significantly broadened their host range and discovered over 20 possible new hosts, including important pathogenic bacteria such as Helicobacter pylori and Vibrio cholerae, as well as different taxa demonstrated differential host specificity. The findings of this study effectively expand the diversity of the Microviridae, providing new insights for their classification and identification. Additionally, it offers a novel perspective for monitoring and controlling pathogenic microorganisms in poultry slaughterhouse environments.

microbiology↗

bioRxiv2024

Image processing tools for petabyte-scale light sheet microscopy data

Light sheet microscopy is a powerful technique for high-speed 3D imaging of subcellular dynamics and large biological specimens. However, it often generates datasets ranging from hundreds of gigabytes to petabytes in size for a single experiment. Conventional computational tools process such images far slower than the time to acquire them and often fail outright due to memory limitations. To address these challenges, we present PetaKit5D, a scalable software solution for efficient petabyte-scale light sheet image processing. This software incorporates a suite of commonly used processing tools that are memory and performance-optimized. Notable advancements include rapid image readers and writers, fast and memory-efficient geometric transformations, high-performance Richardson-Lucy deconvolution, and scalable Zarr-based stitching. These features outperform state-of-the-art methods by over one order of magnitude, enabling the processing of petabyte-scale image data at the full teravoxel rates of modern imaging cameras. The software opens new avenues for biological discoveries through large-scale imaging experiments.

bioinformatics↗

bioRxiv2023

PIEZO1-HaloTag hiPSCs: Bridging Molecular, Cellular and Tissue Imaging

PIEZO1 is critical to numerous physiological processes, transducing diverse mechanical stimuli into electrical and chemical signals. Recent studies underscore the importance of visualizing endogenous PIEZO1 activity and localization to understand its functional roles. To enable physiologically and clinically relevant studies on human PIEZO1, we genetically engineered human induced pluripotent stem cells (hiPSCs) to express a HaloTag fused to endogenous PIEZO1. Combined with advanced imaging, our chemogenetic platform allows precise visualization of PIEZO1 localization dynamics in various cell types. Furthermore, the PIEZO1-HaloTag hiPSC technology facilitates the non-invasive monitoring of channel activity across diverse cell types using Ca2+-sensitive HaloTag ligands, achieving temporal resolution approaching that of patch clamp electrophysiology. Finally, we used lightsheet imaging of hiPSC-derived neural organoids to achieve molecular scale imaging of PIEZO1 in three-dimensional tissue organoids. Our advances offer a novel platform for studying PIEZO1 mechanotransduction in human cells and tissues, with potential for elucidating disease mechanisms and targeted therapeutic development.

biophysics↗

bioRxiv2023

Torques within and outside the human spindle balance twist at anaphase

At each cell division, nanometer-scale motors and microtubules give rise to the micron-scale spindle. Many mitotic motors step helically around microtubules in vitro, and most are predicted to twist the spindle in a left-handed direction. However, the human spindle exhibits only slight global twist, raising the question of how these molecular torques are balanced. Here, using lattice light sheet microscopy, we find that anaphase spindles in the epithelial cell line MCF10A have a high baseline twist, and we identify factors that both increase and decrease this twist. The midzone motors KIF4A and MKLP1 are redundantly required for left-handed twist at anaphase, and we show that KIF4A generates left-handed torque in vitro. The actin cytoskeleton also contributes to left-handed twist, but dynein and its cortical recruitment factor LGN counteract it. Together, our work demonstrates that force generators regulate twist in opposite directions from both within and outside the spindle, preventing strong spindle twist during chromosome segregation.

cell biology↗

bioRxiv2023

LightRoseTTA: High-efficient and Accurate Protein Structure Prediction Using an Ultra-Lightweight Deep Graph Model

Accurately predicting protein structure, from amino acid sequences to three-dimensional structures, is of great significance in biological research. To tackle this issue, a representative deep big model, RoseTTAFold, has been proposed with promising success. Here, we report an ultra-lightweight deep graph network, named LightRoseTTA, to achieve accurate and high-efficient prediction for proteins. Notably, three highlights are possessed by our LightRoseTTA: (i) high-accurate structure prediction for proteins, being competitive with RoseTTAFold on multiple popular datasets including CASP14 and CAMEO; (ii) high-efficient training and inference with an ultra-lightweight model, costing only one week on one single general NVIDIA 3090 GPU for model-training (vs 30 days on 8 high-speed NVIDIA V100 GPUs for RoseTTAFold) and containing only 1.4M parameters (vs 130M in RoseTTAFold); (iii) low dependency on multi-sequence alignments (MSA, widely-used homologous information), achieving the best performance on three MSA-insufficient datasets: Orphan, De novo, and Orphan25. Besides, our LightRoseTTA is transferable from general proteins to antibody data, as verified in our experiments. We visualize some case studies to demonstrate the high-quality prediction, and provide some insights on how the structure predictions facilitate the understanding of biological functions. We further make a discussion on the time and resource costs of LightRoseTTA and RoseTTAFold, and demonstrate the feasibility of lightweight models for protein structure prediction, which may be crucial in the resource-limited research for universities and academy institutions. We release our code and model to speed biological research.

bioinformatics↗

bioRxiv2023

Conservation of heat stress acclimation by the inositol polyphosphate multikinase, IPMK responsible for 4/6-InsP7 production in land plants

Inositol pyrophosphates (PP-InsPs) are soluble cellular messengers that integrate environmental cues to induce adaptive responses in eukaryotes. In plants, the biological functions of various PP-InsP species are poorly understood, largely due to the absence of canonical enzymes present in other eukaryotes. The recent identification of a new PP-InsP isomer with yet unknown enantiomeric identity, 4/6-InsP7 in the eudicot Arabidopsis thaliana, further highlights the intricate PP-InsP signalling network employed by plants. The abundance of 4/6-InsP7 in land plants, the enzyme(s) responsible for its synthesis, and the physiological functions of this species are all currently unknown. In this study, we show that 4/6-InsP7 is the major PP-InsP species present across land plants. Our findings demonstrate that the Arabidopsis inositol polyphosphate multikinase (IPMK) homolog, AtIPK2 generates 4/6-InsP7 in vitro. Furthermore, the cellular level of 4/6-InsP7 is controlled by the two Arabidopsis IPMK isoforms, AtIPK2 and AtIPK2{beta}. Notably, the activity of these IPMK proteins is critical for heat stress acclimation in Arabidopsis. During heat stress, the expression of genes encoding various heat shock proteins controlled by the heat shock factors (HSFs) is affected in the AtIPK2-deficient plants. Furthermore, we show that the transcription activity of HSF is regulated by the AtIPK2 proteins. Our parallel investigations using the liverwort Marchantia polymorpha suggest that the InsP6 kinase activity of IPMK and the role of IPMK in regulating the heat stress response are evolutionarily conserved. Collectively, our study indicates that IPMK has played a critical role in transducing environmental cues for biological processes during land plant evolution.

plant biology↗