Biology subjects

Liu, Z.-L.

Publications and source records attributed to Liu, Z.-L..

9 recordsLinked to original sources

bioRxiv2025

TMEM41B Contributes to Atherosclerosis by Promoting Lipid Synthesis in Vascular Smooth Muscle Cells via Fatty Acid Synthase Stabilization

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. VSMCs specific silencing TMEM41B expression in apolipoprotein E-deficient (ApoE-/-) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs alters intracellular lipid profiles through stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acids synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B/FASN axis drives lipid synthesis, promotes intracellular lipid storage, and facilitates the release of pro-inflammatory cytokines. Further, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in AS. These findings redefine the paradigm of VSMC-derived foam cell formation and suggest that targeting the TMEM41B/FASN axis could offer a transformative therapeutic strategy for AS, particularly in patients with HSV infection.

molecular biology↗

bioRxiv2024

Bacterial defenses and their trade-off with growth are not ubiquitous but depend on ecological contexts

Bacteriophages, also known as bacterial viruses, significantly influence microbial ecosystems, driving bacteria to evolve diverse antiviral defense mechanisms. This study explores the intricate relationship between bacterial defenses and growth rates across diverse ecological contexts. Our investigation reveals that bacteria lacking defenses exhibit prolonged doubling times. Integrating phylogenetic eigenvectors into the ecological feature matrix, we employed a phylogenetic random forest model to identify key ecological features influencing defense presence and abundance. Further phylogenetic regressions unveil nuanced dependencies of bacterial defenses on specific environmental factors, challenging assumptions of a universal defense system distribution and underscoring reliance on subtle ecological cues. Notably, symbiotic and endosymbiotic bacteria often exhibit reduced defense systems and negative correlations between defense system abundance and the minimal doubling time. Conversely, free-living and motile bacteria show significant positive correlations between minimal doubling time and defense system abundance. Moreover, we highlight the pivotal role of ecological variables like habitat specificity and nutrient availability in shaping bacterial growth rates and defense mechanisms. Our findings underscore the complexity of microbial interactions and stress the need to consider ecological context in understanding defense strategies. We propose that trade-offs between growth and defense are ubiquitous due to sporadically inefficient optimization of limited resources, particularly in populations with small effective sizes, where both mechanisms may weaken concurrently due to genetic drift. This challenges traditional notions of trade-offs and underscores the impact of ecological context on microbial strategies.

microbiology↗

bioRxiv2023

Early life high fructose exposure disrupts microglia function and impedes neurodevelopment

Despite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1-7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous systems (CNS) resident professional phagocyte8-10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruning in vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination of in vivo and in vitro nuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.

immunology↗

bioRxiv2023

WNK1 enforces macrophage lineage fidelity

The appropriate development of macrophages, the bodys professional phagocyte, is essential for organismal development, especially in mammals. This dependence is exemplified by the observation that loss-of-function mutations in colony stimulating factor 1 receptor (CSF1R) results in multiple tissue abnormalities owing to an absence of macrophages. Despite this importance, little is known about the molecular and cell biological regulation of macrophage development. Here, we report the surprising finding that the chloride-sensing kinase With-no-lysine 1 (WNK1) is required for development of tissue-resident macrophages (TRMs). Myeloid-specific deletion of Wnk1 resulted in a dramatic loss of TRMs, disrupted organ development, systemic neutrophilia, and mortality between 3 and 4 weeks of age. Strikingly, we found that myeloid progenitors or precursors lacking WNK1 not only failed to differentiate into macrophages, but instead differentiated into neutrophils. Mechanistically, the cognate CSF1R cytokine macrophage-colony stimulating factor (M-CSF) stimulates macropinocytosis by both mouse and human myeloid progenitors and precursor cells. Macropinocytosis, in turn, induces chloride flux and WNK1 phosphorylation. Importantly, blocking macropinocytosis, perturbing chloride flux during macropinocytosis, and inhibiting WNK1 chloride-sensing activity each skewed myeloid progenitor differentiation from macrophages into neutrophils. Thus, we have elucidated a role for WNK1 during macropinocytosis and discovered a novel function of macropinocytosis in myeloid progenitors and precursor cells to ensure macrophage lineage fidelity. Highlights- Myeloid-specific WNK1 loss causes failed macrophage development and premature death - M-CSF-stimulated myeloid progenitors and precursors become neutrophils instead of macrophages - M-CSF induces macropinocytosis by myeloid progenitors, which depends on WNK1 - Macropinocytosis enforces macrophage lineage commitment

immunology↗

bioRxiv2022

Comparative Mucomic Analysis of Three Functionally Distinct Cornu aspersum Secretions

Every animal secretes mucus, placing them among the most diverse biological materials. Mucus hydrogels are complex mixtures of water, ions, carbohydrates, and proteins. Uncertainty surrounding their composition and how interactions between components contribute to mucus function complicates efforts to exploit their properties. There is substantial interest in commercializing mucus from the garden snail, Cornu aspersum, for skincare, drug delivery, tissue engineering, and composite materials. C. asperum secretes three mucus -- one shielding the animal from environmental threats, one adhesive mucus from the pedal surface of the foot, and another pedal mucus that is lubricating. It remains a mystery how compositional differences account for their substantially different properties. Here, we characterize mucus proteins, glycosylation, ion content, and mechanical properties to understand structure-function relationships through an integrative "mucomics" approach. We identify new macromolecular components of these hydrogels, including a novel protein class termed Conserved Anterior Mollusk Proteins (CAMPs). Revealing differences between C. aspersum mucus shows how considering structure at all levels can inform the design of mucus-inspired materials.

biochemistry↗

bioRxiv2022

A Positive Correlation between CRISPR-Cas Spacer Abundance and Cell Cycle Duration Across the Bacteria Domain

CRISPR-Cas systems provide adaptive immunity for prokaryotic cells by recognizing and eliminating the recurrent genetic invaders whose sequences had been captured in a prior infection and stored in the CRISPR arrays as spacers. However, the biological/environmental factors determining the efficiency of this immune system have yet to be fully characterized. Recent studies in cultured bacteria showed that slowing the growth rate of bacterial cells could promote their acquisition of novel spacers. This study examined the relationship between the CRISPR-Cas content and the minimal doubling time across the bacteria and the archaea domains. Every completely sequenced genome could be used to predict a minimal doubling time. With a large dataset of 4142 bacterial samples, we found that the predicted minimal doubling times are positively correlated with spacer number and other parameters of the CRISPR-Cas systems, like array number, Cas gene cluster number, and Cas gene number. Different datasets gave different results. Weak results were obtained in analyzing bacterial empirical minimal doubling times and the archaea domain. Still, the conclusion of more spacers in slowly-grown prokaryotes was supported. In addition, we found that the minimal doubling times are negatively correlated with the occurrence of prophages, and the spacer numbers per array are negatively associated with the number of prophages. These observations support the existence of an evolutionary trade-off between bacterial growth and adaptive defense against virulent phages.

evolutionary biology↗

bioRxiv2021

Bacterial CRISPR abundance jumps up at around 45°C

Although performing adaptive immunity, CRISPR-Cas systems are present in only 40% of bacterial genomes. Here, we observed an abrupt transition of bacterial CRISPR-Cas abundance at around 45{degrees}C. Phylogenetic comparative analyses confirmed that the abundance correlates with growth temperature only at the temperature range around 45{degrees}C. Meanwhile, we noticed that the diversities of cellular predators have a precipitous decline at this temperature range. The grazing risk faced by bacteria reduces substantially at around 45{degrees}C and almost disappears above 60{degrees}C. So viral lysis would become the dominating factor of bacterial mortality, and antivirus immunity has a higher priority. In temperature ranges where the abundance of cellular predators does not change with temperature, temperatures would have negligible effects on CRISPR-Cas abundance. The hypothesis predicts that bacteria should also be rich in CRISPR-Cas systems if they live in other extreme conditions inaccessible to grazing predators.

genomics↗

bioRxiv2021

Significant Correlation between Growth Temperature and Guanine-Cytosine Content in Bacteria

BackgroundGC pairs are generally more stable than AT pairs; GC-rich genomes were proposed to be more adapted to high temperatures than AT-rich genomes. Previous studies consistently showed positive correlations between growth temperature and the GC contents of structural RNA genes. However, for the whole genome sequences and the silent sites of the codons in protein-coding genes, the relationship between GC content and growth temperature is in a long-lasting debate. ResultsWith a dataset much larger than previous studies (681 bacteria and 155 archaea with completely assembled genomes), our phylogenetic comparative analyses showed positive correlations between optimal growth temperature (Topt) and GC content both in bacterial and archaeal structural RNA genes and in bacterial whole genome sequences, chromosomal sequences, plasmid sequences, core genes, and accessory genes. However, in the 155 archaea, we did not observe a significant positive correlation of Topt with whole-genome GC content (GCw) or GC content at four-fold degenerate sites. We randomly drew 155 samples from the 681 bacteria for 1000 rounds. In most cases (> 95%), the positive correlations between Topt and genomic GC contents became statistically nonsignificant (P > 0.05). This result suggested that the small sample sizes might account for the lack of positive correlations between growth temperature and genomic GC content in the 155 archaea and the bacterial samples of previous studies. Comparing the GC content among four categories (psychrophiles/psychrotrophiles, mesophiles, thermophiles, and hyperthermophiles) also revealed a positive correlation between GCw and growth temperature in bacteria. By including the GCw of incompletely assembled genomes, we expanded the sample size of archaea to 303. Positive correlations between GCw and Topt appear especially after excluding the halophilic archaea whose GC contents might be are strongly shaped by intense UV radiation. ConclusionsThis study explains the previous contradictory observations and ends a long debate. Prokaryotes growing in high temperatures have higher GC contents. Thermal adaptation is one possible explanation for the positive association. Meanwhile, we propose that the elevated efficiency of DNA repair in response to heat mutagenesis might have the by-product of increasing GC content like that happens in intracellular symbionts and marine bacterioplankton.

evolutionary biology↗

bioRxiv2018

Effect of Platelet-activating factor on barrier function of ARPE-19 cells

PURPOSETo examine the effects of platelet-activating factor (PAF) on tight junction permeability in cultured retinal pigment epithelial (RPE) cells.\n\nMETHODSA human RPE cell line (ARPE-19) cultured on microporous filter supports was used. PAF and WEB2086, which is a specific PAF-receptor (PAF-R) antagonist, were added to the culture medium. RPE monolayer permeability was measured using transepithelial electrical resistance (TER) and sodium fluorescein flux. The expression of the tight junction protein zonula occludens (ZO)-1 was assessed using immunohistochemistry. We also measured the vascular endothelial growth factor (VEGF) level in cultures treated with PAF, and RPE monolayer permeability was measured again in the presence of neutralizing antibodies to VEGF.\n\nRESULTSPAF significantly decreased the TER of the RPE monolayer and enhanced sodium fluorescein flux. ZO-1 expression was downregulated in PAF-supplemented medium. These effects were abolished with PAF-R blockage. PAF stimulation increased VEGF expression in RPE cells, and neutralization of VEGF with antibodies caused partial recovery of barrier properties.\n\nCONCLUSIONSThe tight junctions of ARPE-19 cells are altered by PAF, and these effects are partly mediated by the upregulation of VEGF expression in these cells. Our results contribute to growing evidence supporting the role of PAF in choroidal neovascularization, and our findings suggest that PAF is a novel therapeutic target for increased permeability of the RPE monolayer.

cell biology↗