Biology subjects

Zhuang, M.

Publications and source records attributed to Zhuang, M..

14 recordsLinked to original sources

bioRxiv2026

Brain Structure Shapes Function through higher-order Functional Interactions

Brain function is deeply embedded within multiscale structural architecture. Conventional studies predominantly utilize pairwise connectivity networks to investigate structure-function relationships. However, this low-dimensional perspective overlooks multi-region collaborations for complex cognition. Consequently, whether and how anatomy constrains such higher-order functional networks remains unresolved. To address this pivotal question, we utilize an information-theoretic O-information approach to characterize higher-order functional interactions (HOIs). By reconstructing individual-level HOIs from multimodal structural networks, we directly validate the structural constraint on HOIs. The resulting reconstruction coefficients are defined as structural-functional constraint strength (SFCS), serving as a quantitative vehicle to decipher how anatomy shapes these higher-order networks. SFCS uncovers a highly heterogeneous structural constraint landscape across data modalities, spatial regions, and informational interaction modes. Crucially, individualized SFCS robustly predicts multi-domain cognitive phenotypes, showing higher sensitivity for informant-reported than patient-reported assessments. Finally, we show that this landscape undergoes pathological, mode-specific reorganization in Alzheimers disease. Cross-scale alignment with spatial transcriptomics further demonstrates that this macroscale network remodeling is coupled with microscale metabolic and regulatory gene pathways. Collectively, our findings not only validate the structural constraint on higher-order functional networks but also decipher its precise underlying mechanisms. This constraint paradigm plays a pivotal role in shaping diverse cognitive capabilities, while its pathological disruption in Alzheimers disease highlights the potential of SFCS as a biomarker for tracking neurodegenerative network impairments.

neuroscience↗

bioRxiv2025

A family of endonucleases that block nanotube-mediated plasmid dissemination

Small non-conjugative plasmids constitute a substantial portion of the bacterial mobile genome, driving the dissemination of beneficial genes, with their transfer primarily attributed to transformation, transduction, or co-mobilization with conjugative elements1-3. Here we explore an understudied plasmid spread route among bacteria, mediated by intercellular membranous nanotube conduits4. We reveal that, unlike traditional donor-to-recipient delivery, Nanotube-dependent Plasmid exchange (NPex) operates bidirectionally, enabling both plasmid donation and, to a lesser extent, plasmid acquisition. By identifying a Bacillus subtilis natural isolate deficient in NPex, we discovered a prophage-encoded factor, YokF, that blocks plasmid transmission, chiefly acting within the donor cell to inhibit plasmid donation. YokF is a nuclease that localizes to the membrane, where it interacts with a nanotube component to selectively impede plasmid transfer through degradation. Importantly, YokF homologs from various bacterial species were found to exhibit anti-NPex activity. Given their prevalence in Gram-positive bacteria, we propose that YokF homologs represent a conserved family of NPex gatekeepers that restrict plasmid flow within bacterial communities.

microbiology↗

bioRxiv2025

Sulcal landmarks reveal lineage-specific trajectories and multi-scale specialization of the mammalian cortex

An important topic of evolutionary neuroscience is to understand how brain function and structure across evolutionary time. In the absence of functional data for ancestral species, studies often rely on structural features such as cortical volume or surface area. However, atlas-based metrics derived from human or a few model organisms lack biological interpretability across species with divergent cortical architectures. Here, we investigate sulcal pits--the locally deepest points of cortical folds--as conserved, atlas-independent landmarks that provide a robust basis for cross-species comparison. Using cortical surface reconstructions from 90 mammalian species, we show that sulcal pit distribution patterns partly recapitulate phylogenetic relationships, independent of overall brain size (volume and surface area), and vary systematically with ecology and lifestyle. By tracing pit-based evolutionary trajectories from 80 million years ago to the present, we found pronounced differences across ecological and behavioral categories, indicating that cortical folding has diversified in close association with species habitats, lifestyles, and social structures. Using sulcal pits, we identified Homo sapiens-specific regions and species-shared regions. The Homo-specific areas were functionally associated with higher cognitive and emotional processes, distinguished by unique histological features, enriched for gene sets related to neural regulation, and exhibited markedly different cell-type abundance profiles compared to shared regions. Together, these results establish sulcal pits as a robust, evolutionarily informative feature for cross-species cortical alignment, offering new insights into the structural innovations underlying brain evolution study.

evolutionary biology↗

bioRxiv2025

Molecular and cellular dynamics of measurable residual disease progression in myelodysplastic syndromes

Cancer relapse after treatment invariably proceeds from the persistence and progression of measurable residual disease (MRD), an ultrasmall malignant population. Despite the poor prognostic impact established by increasingly sensitive MRD detection methods, the molecular pathways defining MRD remain unknown. To identify the unique features of MRD and the molecular forces shaping its progression, we performed single-cell multi-omic profiling on DNA, RNA and protein layers for a longitudinal patient cohort with relapsed myelodysplastic syndromes (MDS) after stem cell transplantation (SCT), the only curative modality for MDS. We provide a comprehensive molecular portrait of MRD cells with novel markers, shared across genetically heterogeneous patients. MDS relapse after SCT manifested universally with marked phenotypic evolution. Genotype and phenotype analyses revealed MRD progression as a dynamic, evolutionary process rather than a static expansionary one, driven by both subclonal sweeping and cell state transitions. Malignant cells adapted to infiltrating T cells by rewiring IFN-{gamma} responses to activate a key immunoevasive pathway. Our study demonstrates the power of longitudinal, single-cell multi-omic analysis for identifying, tracking, and understanding MRD cells, opening new avenues to target MRD persistence and progression.

cancer biology↗

bioRxiv2024

CRISPR screens reveal ZBTB17/MIZ1 as a peroxisome regulator

Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes in humans, with defects often linked to diseases. The functions of peroxisomes are regulated at transcriptional, translational, and post-translational levels. In this study, we employed the CRISPR/Cas9-based genetic screening of a ubiquitin ligase library to identify regulators of human peroxisomes. We discovered that ZBTB17 (also referred as MIZ1) plays a role in regulating the import of proteins into peroxisomes. Independent of its ubiquitin ligase activity, ZBTB17/MIZ1 operates as a transcription factor to directly modulate the expression of key importer PEX13, thereby influencing the localization of peroxisomal enzymes. Furthermore, metabolomic profiling reveals that the knockdown of ZBTB17 or PEX13 results in similar metabolic alterations, characterized by downregulated purine synthesis, suggesting that ZBTB17s role in metabolic regulation likely operates through peroxisomes. Collectively, we identify ZBTB17 as a key regulator of peroxisomal protein import, thereby affecting peroxisomal function and nucleotide metabolism. Our findings provide insights into the multifaceted regulation of peroxisomes in complex human cells and shed light on the molecular mechanisms underlying ZBTB17s role as a transcriptional regulator.

cell biology↗

bioRxiv2023

Ubiquitin Ligase MARCH5 Regulates the Formation of Mitochondria Derived Pre-peroxisomes

Peroxisome biogenesis involves two pathways: growth and division from pre-existing mature peroxisomes and de novo biogenesis from the endoplasmic reticulum, with a contribution from mitochondria, particularly in peroxisome deficient cells. However, the key components that regulate peroxisome de novo biogenesis are largely unknown. Dual organelle localized ubiquitin ligase MARCH5 functions on peroxisomes to regulate pexophagy. Here, we show that mitochondria localized MARCH5 is essential for the formation of vesicles in the de novo biogenesis of peroxisomes from mitochondria. Loss of MARCH5 specifically impedes the budding of PEX3-containing vesicles from mitochondria, thereby blocking the formation of pre-peroxisomes. Overall, our study highlights a novel function of MARCH5 for mitochondria derived pre-peroxisomes, emphasizing MARCH5 as one key regulator to maintain peroxisome homeostasis.

cell biology↗

bioRxiv2022

YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory

N6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of granule cells in DG. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.

neuroscience↗

bioRxiv2022

Phenethylamine-producing gut bacteria induces diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis

Despite the strong association between gut microbial dysbiosis, serotonin (5-HT) dysregulation and diarrhea-predominant irritable bowel syndrome (IBS-D), the mechanism by which changes in the gut microbiota contribute to the pathogenesis of IBS-D, particularly the role of dysregulated 5-HT production, remains unclear. The present study identified Ruminococcus gnavus in the human gut microbiota as a key risk factor of IBS-D. R. gnavus was significantly enriched in IBS-D patients and exhibited positive correlation with serum 5- HT level and severity of diarrhea symptoms. We showed that R. gnavus induced diarrhea-like symptoms in mice by promoting microbial shunting of essential aromatic amino acids to aromatic trace amines including phenethylamine and tryptamine, thereby stimulating the biosynthesis of peripheral 5-HT, a potent stimulator for gastrointestinal transit. This study identify gut-microbial metabolism of dietary amino acids as a cause of IBS-D and lays a foundation for developing novel therapeutic target for the treatment of IBS-D. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/483096v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@48400aorg.highwire.dtl.DTLVardef@1645aedorg.highwire.dtl.DTLVardef@18d878dorg.highwire.dtl.DTLVardef@be4b30_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Gut microbiota-derived tryptamine impairs insulin sensitivity

Gut-microbiota plays a pivotal role in development of type 2 diabetes (T2D), yet the molecular mechanism remains elusive. Here, we show that tryptamine, a microbial metabolite of tryptophan, impairs glucose tolerance and insulin sensitivity. Tryptamine presents a higher level in monkeys with spontaneous diabetes and human with T2D and positively correlated with the glucose tolerance. In parallel, tryptamine level was suppressed by dietary fibers intervention in T2D subjects and negatively correlated with improvement of glucose tolerance. The inhibitory effect of tryptamine on insulin signaling as shown was dependent on a trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Monoassociation of T2D-associated tryptamine-producing bacteria Ruminococcus gnavus impairs insulin sensitivity in pseudo germ-free mice. Our findings indicate gut microbiota-derived tryptamine contributes to the development of insulin resistance in T2D and may serve as a new target for intervention. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2021

THEMIS is a priming substrate of non-receptor tyrosine phosphatase PTPN6/SHP1 and plays dual roles during T cell development

THEMIS plays an indispensable role in T cells, but its mechanism of action is highly controversial. Using the systematic proximity labeling methodology PEPSI, we identified THEMIS as an uncharacterized substrate for the phosphatase SHP1. Saturated mutagenesis analysis revealed that THEMIS phosphorylation at the evolutionally conserved Tyr34 residue was oppositely regulated by SHP1 and the kinase LCK. Like THEMIS-/- mice, THEMISY34F/Y34F knock-in mice showed a significant decrease in CD4 thymocytes and mature CD4 T cells, but a normal thymic development and peripheral homeostasis of CD8 T cells. Mechanistically, phosphorylated THEMIS induced by TCR activation acts as a "priming substrate" to bind SHP1 and convert its phosphatase activity from basal level to nearly fully activated level, ensuring an appropriate negative regulation of TCR signaling. However, cytokine signaling in CD8 T cells failed to elicit THEMIS Y34 phosphorylation, revealing both phosphorylation-dependent and -independent roles of THEMIS in controlling T cell maturation and expansion.

cell biology↗

bioRxiv2021

The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells

The precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here we find that the m6A reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes. Impact statementThe m6A reader YTHDF2 negatively regulates RGC dendrite branching through destabilizing its m6A-modified target mRNAs encoding proteins controlling dendrite development and maintenance. Ythdf2 cKO improves visual acuity and alleviates acute ocular hypertension-induced glaucoma in mice.

neuroscience↗

bioRxiv2021

Cbln1 regulates axon growth and guidance in multiple neural regions

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon guidance have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS). Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system. Impact statementDespite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.

neuroscience↗

bioRxiv2020

Discordant transcriptional signatures of mitochondrial genes in Parkinson's disease human myeloid cells

An increasing number of identified Parkinsons disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their potential role in pathological mechanisms is not obvious. We have generated transcriptomic profiles of CD14+ monocytes from 230 individuals with sporadic PD and age-matched healthy subjects. We identified dysregulation of genes involved in mitochondrial and proteasomal function. We also generated transcriptomic profiles of primary microglia from autopsied brains of 55 PD and control subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified PD susceptibility genes, whose expression, relative to each risk allele, is altered in monocytes. These findings reveal that transcriptomic mitochondrial alterations are detectable in PD monocytes and are distinct from brain microglia, and facilitates efforts to understand the roles of myeloid cells in PD.

neuroscience↗

bioRxiv2020

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time and space dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer. Knockdown of the kinase attenuates metastatic phenotypes in tumor cells. Here we employed mass spectrometry and biochemical approaches to identify IRS4 as a novel substrate of FER. Using a proximity-based tagging system, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85{beta}, the regulatory subunit of PI-3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4, delayed tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate regulatory mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

molecular biology↗