Biology subjects

Feng, Y.

Publications and source records attributed to Feng, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

Characterization of a novel fatty acid-modifying pathway toward the biosynthesis of tambjamine BE-18591 in Streptomyces

Tambjamines are a class of bacterial bipyrrolic natural products with potent biological activity. Recently, the first Actinomycete biosynthetic gene cluster (BGC) responsible for the production of a tambjamine (BE-18591) was discovered in Streptomyces albus, and bioinformatic analysis suggested the alkylamine tail component is constructed using disparate biosynthetic logic than employed by Proteobacteria to assemble structurally similar tambjamines YP1 and MYP1. Here, we report the experimental characterization of four novel streptomycete proteins and demonstrate that these enable the unique, late-stage assembly of the alkylamine component of BE-18951. Specifically, a fatty acyl-carrier protein (TabQ) is loaded with a 12-carbon acyl chain, selected for, in part, through the action of an editing type II thioesterase (TabJ). The resulting C12-TabQ adduct is then processed to an aldehyde by a novel acyl-ACP reductase (TabE) that harbors none of the telltale amino acid signatures that typically identify these proteins. The resulting aldehyde is finally converted to the amine by an{omega} -transaminase (TabA) that demonstrates some degree of promiscuity. These four proteins encoded by the BE-18591 BGC in Streptomyces albus enable the assembly of the fatty amine that is ultimately incorporated into the tambjamine. Our findings highlight the disparate chemical logic employed by Proteo- and Actinobacteria for the biosynthesis of the alkylamine components of tambjamine natural products.

biochemistry↗

bioRxiv2025

A chimeric Ad5-Envp-VLP vaccine platform confers broad-spectrum immunity against emerging and re-emerging pathogens

Integrating complementary vaccine modalities is essential for combating emerging infectious threats. Here, we developed Ad5-Envp-VLP, a chimeric adenoviral platform synergizing adenoviral delivery efficiency with virus-like particle (VLP) structural mimicry. This system stably produces self-assembling VLPs in suspension HEK293 cultures, exhibiting enhanced immunogenicity over soluble antigens. Following intramuscular immunization, the platform induces early B cell expansion and sustains germinal center reactions, driven by the upregulation of B cell cycle-related genes (Cdc6, Cdc45, Cdc20, Cdc25C, Aurka, Aurkb, and Ccnb1/2) and robust T follicular helper (Tfh) cell differentiation, generating durable neutralizing antibodies against both influenza virus and rabies virus. These effects are conserved across mouse, canine, and feline models. Crucially, integrated flow cytometry and scRNA-seq demonstrate that intranasal delivery recruits and functionally reprograms lung innate immune cells (notably alveolar macrophages and dendritic cells), driving mucosal sIgA secretion and CTL responses. A single nasal dose confers lasting protection against homologous and heterologous influenza A strains. The platform also elicits cross-neutralizing antibodies against SARS-CoV-2 variants. Together, Ad5-Envp-VLP thus establishes a modular vaccine platform for antigenically plastic pathogens by combining in vivo self-assembly with dual pulmonary-muscular delivery. One Sentence SummaryNovel mucosal and systemic vaccine delivers self-assembling particles, triggering strong lung immunity and broad virus protection across species.

immunology↗

bioRxiv2025

Structure of Photosystem I with SOD reveals coupling between energy conversion and oxidative stress protection

In photosynthetic organisms, Photosystem I (PSI) not only converts energy into its chemical form but is also a major source of superoxide (O2-), which can damage cellular components. Its detoxification by superoxide dismutase (SOD) is essential for redox homeostasis. We report the structure of the PSI-SOD supercomplex from Chromera velia (C. velia), revealing a direct coupling between energy conversion and oxidative stress protection. The heterodimeric SOD comprises a catalytic SOD2 and a non-catalytic SOD1 anchoring it to the conserved stromal PSI surface near the ferredoxin-binding site with four contact areas. Structural comparison with plants and algae shows that SOD could occupy a similar position via interactions with PsaD. C. velia PSI displays several distinct features, including a split subunit PsaA linked by PsaV, a unique iso-fucoxanthin bound to PsaB, and an extended PsaF coordinating an extra chlorophyll in the membrane. The antenna includes five fucoxanthin-chlorophyll family proteins (FCPs) stabilized by adaptations unique to each antenna protein. These findings reveal the structural basis for the integration of a photoprotective mechanism with energy metabolism in photosynthetic membranes.

biochemistry↗

bioRxiv2025

The ZNF512B-NuRD complex co-ordinates a neural-specific gene expression program

The nucleosome remodelling and deacetylase complex (NuRD) plays a key role in chromatin regulation and a wide range of biological processes including development, haemopoiesis, immunity and neurogenesis. Its interaction with tissue-enriched and sequence-specific transcription factors (TFs) leads to distinct functional outputs in the given tissue by targeting a specific set of genes. However, how NuRD dynamically and specifically regulates gene expression in a tissue-specific manner is poorly understood. Here, we refine an N-terminal specific NuRD interaction motif which enables direct engagement with many transcriptional regulatory proteins. Using a series of structural modelling and biochemical techniques, we show that ZNF512B, a poorly characterised neuronal-expressed zinc finger protein, directly binds to the RBBP4 subunit of the NuRD complex. Subsequent knockdown of ZNF512B results in the downregulation of several neural-related molecular pathways suggesting that ZNF512B may play a regulatory role during neurogenesis. We also show that in NTERA-2 neural cells, the expression of ZNF512B is necessary for cell growth and survival, and is markedly enhanced during neural progenitor cell (NPC) differentiation. In summary, our data suggest that ZNF512B might regulate neural-specific transcriptional programs via engagement with the NuRD complex.

molecular biology↗

bioRxiv2025

Structural insights into type I and type II Lamassu anti-phage systems

Bacteria have developed a variety of immune systems to combat phage infections. The Lamassu system is a prokaryotic immune system with a core conserved Structural Maintenance of Chromosomes (SMC) superfamily protein LmuB and diverse effectors named LmuA, whose mechanism remains unclear. Here, we present a series of cryo-electron microscopy structures of type I Lamassu complex from Bacillus cellulasensis and type II Lamassu complex from Vibrio cholerae, both in apo- and dsDNA-bound states, which reveal an unexpected stoichiometry and topological architecture, distinct from canonical SMC complexes. Combined structural and biochemical analyses show how the nuclease effector LmuA is sequestered in an inactive monomeric form within the Lamassu complex, and upon sensing foreign DNA ends, dissociates and assembles into an active tetramer capable of DNA cleavage. Our findings elucidate the mechanism by which Lamassu systems detect viral replication and implement anti-phage defense, highlighting the unprecedented roles of SMC proteins in prokaryotic immunity.

microbiology↗

bioRxiv2025

Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons

Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived i3 cortical neurons, we demonstrate that both 24S-HC and 27-HC significantly impair neuronal calcium signalling by elevating resting calcium levels, reducing spike amplitude, and disrupting network synchrony. These functional deficits are accompanied by widespread organelle dysfunction. Both oxysterols induce mitochondrial fragmentation, decrease spare respiratory capacity, and impair lysosomal degradation. Notably, 27-HC uniquely triggers lysosomal swelling and membrane permeabilisation. Additional signs of cellular stress, including axonal swellings and elevated endoplasmic reticulum calcium levels, were also observed. Furthermore, both 24S-HC and 27-HC were found to directly interact with alpha-synuclein (aSyn), promoting its accumulation in cellular models. In contrast, cholesterol itself had minimal impact, highlighting the distinct toxicity of its hydroxylated metabolites. Together, these findings reveal a mechanistic link between oxysterol accumulation and neuronal dysfunction, supporting the hypothesis that elevated levels of 24S-HC and 27-HC, commonly observed in Parkinsons and Alzheimers disease, may actively drive neurodegenerative processes. Targeting oxysterol metabolism may therefore represent a promising therapeutic avenue for intervention in neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Systemic organellar genome reconfiguration along the parasitic continuum in the Broomrape family (Orobanchaceae)

The transition from autotrophy to heterotrophy in parasitic plants disrupts organellar coordination and presents a unique opportunity to examine the coevolution of cellular genomes. Using the Broomrape family (Orobanchaceae) as a model, we analyzed mitochondrial and plastid genome evolution across 30 species representing the full spectrum of parasitic lifestyles. We show that plastid genome reduction is correlated with mitogenomic expansion, revealing a striking inverse relationship between genome compaction and inflation. Mitogenome enlargement in parasitic taxa is driven by the accumulation of horizontally and intracellularly transferred DNA, proliferation of short repeats, and integration of unique sequences with no detectable homology. Notably, foreign DNA insertions converge toward native mitochondrial GC content and often retain structural functionality, suggesting selective maintenance. Relaxed selection in ATP synthase and ribosomal genes contrasts with intensified selection on components of electron transport and cytochrome c maturation, reflecting functional reconfiguration of mitochondrial respiration in parasitic plants. RNA editing, intron loss, and frameshift insertions further reshape gene structure, particularly in obligate parasites. Together, our findings suggest that parasitism initiates a systemic genomic feedback loop in which relaxed selection and disrupted maintenance mechanisms affect even distant genomic compartments. This study provides the first comprehensive evolutionary framework for multi-compartment genome remodeling in parasitic plants and highlights the dynamic interplay between lifestyle specialization and organelle genome evolution.

evolutionary biology↗

bioRxiv2025

High-dimensional neuronal activity from low-dimensional latent dynamics: a solvable model

Computation in recurrent networks of neurons has been hypothesized to occur at the level of low-dimensional latent dynamics, both in artificial systems and in the brain. This hypothesis seems at odds with evidence from large-scale neuronal recordings in mice showing that neuronal population activity is high-dimensional. To demonstrate that low-dimensional latent dynamics and high-dimensional activity can be two sides of the same coin, we present an analytically solvable recurrent neural network (RNN) model whose dynamics can be exactly reduced to a low-dimensional dynamical system, but generates an activity manifold that has a high linear embedding dimension. This raises the question: Do low-dimensional latents explain the high-dimensional activity observed in mouse visual cortex? Spectral theory tells us that the covariance eigenspectrum alone does not allow us to recover the dimensionality of the latents, which can be low or high, when neurons are nonlinear. To address this indeterminacy, we develop Neural Cross-Encoder (NCE), an interpretable, nonlinear latent variable modeling method for neuronal recordings, and find that high-dimensional neuronal responses to drifting gratings and spontaneous activity in visual cortex can be reduced to low-dimensional latents, while the responses to natural images cannot. We conclude that the high-dimensional activity measured in certain conditions, such as in the absence of a stimulus, is explained by low-dimensional latents that are nonlinearly processed by individual neurons.

neuroscience↗

bioRxiv2025

A flexible end-to-end automated sample preparation workflow enables reproducible large-scale bottom-up proteomics

Bottom-up proteomics holds significant promise for clinical applications due to its high sensitivity and precision, but is limited by labor-intensive, low-throughput sample preparation methods. Advanced automation is essential to enhance throughput, reproducibility, and accuracy and to allow standardization to make bottom-up proteomics amenable for large-scale studies. We developed a fully integrated, automated sample preparation platform that covers the entire process from biological sample input to mass spectrometry-ready peptide output and can be applied on a multitude of biological samples. With this end-to-end solution, we achieved high intra- and inter-plate reproducibility, as well as longitudinal consistency, resulting in precise and reproducible workflows. We showed that our automated workflow surpasses established manual and semi-automated workflows, while improving time efficiency. Finally, we demonstrated the suitability of our automated sample preparation platform for drug development by performing a high-content compound characterization for targeted protein degradation, where high throughput and quantitative accuracy are indispensable. For this, we coupled application-specific workflows to perform proteome profiling and confirm target degradation by precise protein quantification. Overall, our results highlight the selective degradation of specific proteins of interest for ten selected compounds across two cell lines. Thus, the automated sample preparation platform facilitates rapid adaptation to emerging developments in proteomics sample preparation, combining standardization, flexibility, and high-throughput capabilities to drive significant advancements in clinical assays and proteomics research.

biochemistry↗

bioRxiv2025

Mechanistic dissection of Candidatus Liberibacter Triggered Chronic Immune Disease

Immunity is generally considered critical for plant health against pathogen infection. Citrus Huanglongbing (HLB) caused by the phloem colonizing bacterial pathogen Candidatus Liberibacter asiaticus (CLas) was suggested to be a pathogen triggered chronic immune disease. However, the genetic evidence and mechanistic understanding for such a disease model is lacking. Here, we show CLas triggers phloem cell death, reactive oxygen species (ROS) production and callose deposition in photosynthesis tissues, but little or none in non-photosynthesis tissues of citrus. We further demonstrate that CLas triggers ROS production in chloroplasts. Overexpression of flavodoxin (Fld), an electron shuttle, in chloroplasts reduced ROS production, cell death and HLB symptoms, but not phloem callose deposition induced by CLas. Knockout, silencing, and overexpression of phloem callose synthase genes CsCalS7a, CsCalS7b, or CsCalS7c demonstrated that phloem callose deposition also caused phloem cell death. Trunk injection with 2-deoxy-d-glucose, a callose deposition inhibitor, reduced fruit drop and increased fruit yield of HLB symptomatic trees in field trials. Using tomato-Ca. L. psyllaurous (Lpsy) as a model, knockout of Eds1 and Pad4 but not RbohB, Bik1 and Sobir1 abolished ROS production, phloem callose deposition, cell death and disease damages caused by Lpsy. This study provides genetic evidence for Ca. Liberibacter-triggered immune disease and reveals that tuning plant immune responses converts Ca. Liberibacter into a benign endophyte, providing a promising strategy for precision breeding to enhance resistance/tolerance against HLB.

plant biology↗

bioRxiv2025

Structural insight into the transcription activation mechanism of the phage Mor/C family activators

Bacteriophage Mu, a temperate phage that infects E. coli K-12 and other enteric bacteria, precisely controls its replication cycle through hijacking host RNA polymerase (RNAP) by the middle operon regulator Mor and the late gene transcription activator C. Though a dimeric arrangement and significant conformational changes are proposed for the distinct Mor/C family activators, the underlying transcription activation mechanism remains unclear. In this study, we present two cryo-EM structures of the transcription activation complex (Mor-TAC and C-TAC) with phage Mu middle and late gene promoters, respectively. Remarkably, the Mor/C activators bind to promoter DNA as a centrosymmetric tetramer rather than as the proposed dimer, concurrently stabilizing by the N-terminal dimerization domains and C-termini. The C-terminal DNA binding domains and two anti-{beta}-strands simultaneously interact with two adjacent DNA major grooves. The activators also engage a variety of interactions with the conserved domains (CTD, {sigma}70R4, and {beta} FTH) of RNAP, providing evidences for a recruitment mechanism. In addition, single-molecule FRET assays show that C significantly enhances RPitc formation, suggesting a different multi-step activation mechanism for C. Collectively, these findings reveal the unique transcription activation mechanism of tetrameric Mor/C family activators, unraveling a novel mode of phage hijacking and bacterial transcription regulation.

biochemistry↗

bioRxiv2025

Sialin2 Senses Nitrate to Activate Endosomal PI3K-AKT-NOS Signaling

Nitrate functions as a signaling molecule beyond its metabolic intermediate role. Despite progress in plants, the mechanisms underlying mammalian nitrate sensing and signaling remain unclear. The accompanying study identifies Sialin2--a proteolytic fragment of nitrate transporter Sialin--as a mammalian nitrate sensor mediating cellular responses. Here, we demonstrate that nitrate triggers endocytosis, inducing Sialin proteolysis and Sialin2 generation. Nitrate-induced Sialin2 scaffolds Lyn kinase with epidermal growth factor receptor (EGFR) at endosomes, activating phosphatidylinositol 3-kinase (PI3K)-AKT-nitric oxide synthase (NOS) pathway to stimulate localized nitric oxide (NO) production, enhancing angiogenesis and cell survival. In hypertensive rats, nitrate supplementation restores endothelial function and reduces blood pressure through AKT/eNOS-dependent signaling. Unlike the classical nitrate-nitrite-NO pathway, the Sialin2-PI3K-AKT-NOS axis confines NO synthesis to endosomal microdomains, enabling spatiotemporally precise vasodilation. By establishing Sialin2 as a mammalian nitrate sensor, this study unveils a novel paradigm in nitrogen homeostasis and provides targeted therapeutic strategies for vascular disorders.

cell biology↗

bioRxiv2025

Sialin2 Functions as a Mammalian Nitrate Sensor to Sustain Mitochondrial Homeostasis

Nitrogen homeostasis is fundamental for cellular physiology, yet mammalian nitrate (NO3-) sensing mechanisms remain elusive. Here, we identify Sialin2--a proteolytic fragment of the nitrate transporter Sialin generated by cathepsin B (CTSB) cleavage-- as the first mammalian nitrate sensor. Microscale thermophoresis (MST) reveals Sialin2 as a high-affinity nitrate sensor, while Cryo-Electron Microscopy (Cryo-EM) uncovers its structural basis for signaling. We show that Sialin2 localizes to mitochondria and scaffolds liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) complexes to drive organelle-specific metabolic adaptation via spatiotemporally controlled AMPK activation, enhancing mitochondrial biogenesis, ATP production, and cell survival. Real-time tracking using the sCiSiNiS biosensor demonstrates nitrate signaling dynamics at physiological levels. This signaling axis redefines nitrate as a direct ligand activating receptor-like cascades, independent of classical nitric oxide synthesis. Our findings establish a paradigm of "inorganic salt signaling biology", wherein anions co-opt trafficking systems to achieve signaling specificity, offering therapeutic avenues for mitochondrial disorders.

cell biology↗

bioRxiv2025

One-carbon metabolism enzyme Ahcy is a redox sensor that modulates gene expression to protect against light stress-induced retinal degeneration

One-carbon metabolism influences gene expression by providing methyl units for DNA, RNA, and histone methylation. Robust methylation requires rapid hydrolysis of the methylation by-product S-adenosylhomocysteine (SAH) by S-adenosylhomocysteinase (Ahcy). Here, we show Ahcy is a redox-sensitive enzyme that is inhibited by oxidation of a conserved cysteine, C195, in vitro and in vivo. Transient oxidation of Ahcy is neuroprotective in a Drosophila light stress model where it results in rapid gene expression changes and protects against retinal degeneration. Thus, redox sensing by the one-carbon metabolic enzyme Ahcy enables rapid changes in gene expression in response to changes in redox homeostasis.

biochemistry↗

bioRxiv2025

MiT4SL: multi-omics triplet representation learning for cancer cell line-adapted prediction of synthetic lethality

Synthetic lethality (SL) offers a promising approach for targeted cancer therapies. Current SL prediction models heavily rely on extensive labeled data for specific cell lines to accurately identify SL pairs. However, a major limitation is the scarcity of SL labels across most cell lines, which makes it challenging to predict SL pairs for target cell lines with limited or even no available labels in real-world scenarios. Furthermore, gene interactions could be opposite between training and test cell lines, i.e. SL vs. non-SL, which further aggravates the challenge of generalization among cell lines. A promising strategy is to transfer knowledge learned from cell lines with relatively abundant SL labels to those with limited SL labels for the discovery of novel SL pairs, i.e., cell line-adapted SL prediction. Here, we propose MiT4SL, a multi-omics triplet representation learning model for cell line-adapted SL prediction. The core idea of MiT4SL is to model cell lineage information as embeddings, which are generated by combining a protein-protein interaction network representation tailored to each cell line with the corresponding protein sequence embeddings. We then combine these cell line embeddings with gene pair representations derived from a biomedical knowledge graph and protein sequences. This triplet representation learning strategy enables MiT4SL to capture both shared biological mechanisms across cell lines and those unique to each cell line, effectively mitigating distribution shift and improving generalization to target cell lines. Additionally, explicit cell line embeddings provide the necessary signals for MiT4SL to effectively differentiate between cell line contexts, enabling it to adjust predictions and mitigate possible label conflicts for the same gene pair across different cell lines. Experimental results across various cell line-adapted scenarios show that MiT4SL outperforms six state-of-the-art models. To the best of our knowledge, MiT4SL is the first deep learning model designed specifically for cancer cell line-adapted SL prediction. AvailabilityThe code of our work is available at https://github.com/JieZheng-ShanghaiTech/MiT4SL.

bioinformatics↗

bioRxiv2025

Development a computational framework for risk evaluation of emerging flu viruses based on genomic sequences and AI

The recent resurgence of highly pathogenic avian influenza H5N1 viruses in North America and Europe has heightened global concerns regarding potential influenza pandemics. Despite significant progress in the surveillance and prevention of emerging influenza viruses, effective tools for rapid and accurate risk assessment remain limited. Here, we present FluRisk, an innovative computational framework that integrates viral genomic data with artificial intelligence (AI) to enable rapid and comprehensive risk evaluation of emerging influenza strains. FluRisk incorporates a curated database of over 1,000 experimentally validated molecular markers linked to key viral phenotypes, including mammalian adaptation, mammalian virulence, mammalian transmission, human receptor-binding preference, and antiviral drug resistance. Leveraging these markers, we developed three state-of-the-art machine learning models to predict human adaptation, mammalian virulence, and human receptor-binding potential, all of which demonstrated superior performance compared to traditional approaches such as BLAST, prior models, and baseline classifiers. In addition, a reference-based method was implemented to provide preliminary estimates of human transmissibility and resistance to six commonly used antiviral drugs. To facilitate broad accessibility and practical application, we developed a user-friendly web server that integrates both the molecular marker atlas and predictive tools for influenza virus phenotyping (available at: http://www.computationalbiology.cn/FluRisk/#/). This computational platform offers a valuable resource for the timely risk assessment of emerging influenza viruses and supports global influenza surveillance efforts.

bioinformatics↗

bioRxiv2025

A gut-selective Axl Inhibitor Attenuates Intestinal Fibrosis in myofibroblast cell models and the Mouse S. Typhimurium Model in vivo

BackgroundIntestinal fibrosis leads to intestinal failure in Crohns disease (CD), but we have no effective antifibrotic medical therapies. Axl inhibitors have been studied in the treatment of fibrosis in liver and lung, but not in intestine. The objective of this study was to test whether CCG264341, a novel gut selective Axl inhibitor, can treat intestinal fibrosis in both in vitro and in vivo IBD fibrosis models. MethodsCCD-18Co human intestinal myofibroblasts were co-treated with 100 ng/mL Fas ligand (FASL) and a dose range of CCG264341 for 5 hours, or treated with TGF{beta} for 48 hours, followed by protein isolation and western blot analysis. Tissue PK experiments in mice were performed to select the CCG264341 dose for the in vivo model. For the in vivo model, intestinal fibrosis was induced in CBA/J mice by S. typhimurium infection, Mice were treated with CCG264341 daily during days 4-21 after S. typhimurium infection, followed by sac on day 22. Cecum and proximal colon (affected tissue) was analyzed by gross pathology, histological fibrosis scoring, qRT-PCR, western blot, and immunofluorescence staining. ResultsCCG264341 at doses of 0.1/0.3/1.0 {micro}M sensitizes CCD-18Co myofibroblasts to FasL-mediated apoptosis over FasL alone, and this effect was dose dependent, per cleaved Parp protein quantitation. With TGF{beta} treatment, Axl protein expression was increased, along with Col1a1, MYLK, SMA and FN1 protein upregulation. CCG264341 could reduce AXL protein and downstream signal p-Akt expression with dose dependence, along with reduced Col1a1, MYLK, SMA and FN1 protein expression after treatment with CCG264341 treatment. The highest CCG264341 concentrations were detected in the terminal ileum after 5 hours oral feeding in PK experiments, and much lower compound concentrations could still be detected in other organs. A dose of 25mg/kg daily was selected for the mouse intestinal fibrosis treatment model. In the murine S. typhimurium model, AXL protein and downstream signals p-Akt, p-Erk and P-Stat3 expression were all increased in colon and cecum, with the expression of the fibrosis related proteins upregulated. CCG264341 treatment significantly inhibited AXL expression, with downstream signals and fibrosis related protein downregulation. By blinded histopathology with H&E and trichrome staining, as well as immunofluorescence for fibrosis related proteins, colon fibrosis scores significantly decreased. ConclusionsCCG264341is a partially gut selective Axl inhibitor. This compound could play a therapeutic role in IBD fibrosis models. Further work to improve gut selectivity and anti-fibrotic efficacy are needed, but this is a promising pathway for future therapeutic intervention in Crohns disease.

immunology↗

bioRxiv2025

Mapping Along-Tract White Matter Microstructural Differences in Autism

Previous diffusion magnetic resonance imaging (dMRI) research has indicated altered white matter microstructure in autism, but the implicated regions are highly inconsistent across studies. Such prior work has largely used conventional dMRI analysis methods, including the traditional microstructure model, based on diffusion tensor imaging (DTI). However, these methods are limited in their ability to precisely map microstructural differences and accurately resolve complex fiber configurations. In our study, we investigated white matter microstructure alterations in autism using the refined along-tract analytic approach, BUndle ANalytics (BUAN), and an advanced microstructure model, the tensor distribution function (TDF). We analyzed dMRI data from 365 autistic and neurotypical participants (5-24 years; 34% female) from 10 cohorts to examine commissural and association tracts. Autism was associated with lower fractional anisotropy and higher diffusivity in localized portions of nearly every commissural and association tract examined; these tracts inter-connected a wide range of brain regions, including frontal, temporal, parietal, and occipital. Taken together, BUAN and TDF allow robust and spatially precise mapping of microstructural properties in autism. Our findings rigorously demonstrate that white matter microstructure alterations in autism may be greater within specific regions of individual tracts, and that the implicated tracts are distributed across the brain.

neuroscience↗