Biology subjects

Feng, Y.

Publications and source records attributed to Feng, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

A 5'-end based Molecular Marker Enables Identification and Deployment of a Functional Rpi-vnt1.1 Allele for Durable Late Blight Resistance in Potato

Potato (Solanum tuberosum) is a globally important food crop, yet its production is severely threatened by late blight, caused by Phytophthora infestans. Deploying resistance (R) genes in breeding programs offers a sustainable approach for disease management. Rpi-vnt1.1 is a broad-spectrum R gene cloned from wild Solanum species Solanum venturii. Here, we developed a PCR marker targeting the 5'-end extension of Rpi-vnt1.1, which enables efficient and specific detection of the resistant alleles. Screening of advanced breeding lines from the International Potato Center (CIP) identified line C1848, which carries a functional Rpi-vnt1.1 allele. Inoculation assays confirmed C1848 confers strong resistance to P. infestans. Subsequent functional assays, including RNAi-mediated silencing in C1848 and heterologous expression in Nicotiana benthamiana, demonstrated that this resistance is specifically mediated by the Rpi-vnt1.1 allele. This specific marker provides a rapid, low-cost tool for marker-assisted breeding, facilitating the deployment of potato cultivars carrying Rpi-vnt1.1.

plant biology↗

bioRxiv2025

Cross-competition shapes CD8+ T cell hierarchies and differentiation after RNA vaccination

Short SummaryImmunodominance is a universal feature of adaptive immunity that constrains T cell expansion, clonal diversity and breadth resulting in a narrowly focused T cell response. While observed across diverse priming settings and vaccine platforms, the influence of immunodominance on T cell phenotype remains unclear. Using an mRNA lipoplex vaccine encoding multiple antigens to study how immunodominance influences CD8+ T cell fate, we found that dominant CD8+ T cell responses alter the magnitude and phenotype of subdominant responses through peptide-MHC-I stability-mediated T cell cross-competition. Dominant CD8+ T cell responses preferentially acquired markers associated with terminal differentiation and cytotoxic function, while sub-dominant responses adopted memory-precursor and stem-like features. Removal of dominant responses allowed increased expansion of sub-dominant T cell responses and adoption of terminally differentiated effector phenotypes. These findings reveal that immunodominance dynamically shapes the magnitude, breadth and differentiation of CD8+ T cell responses and highlights opportunities to fine-tune T cell responses for therapeutic vaccination.

immunology↗

bioRxiv2025

A blueprint for mutation-defined hallmark vulnerabilities across human cancers

Hallmark gene mutations shape cancer cell vulnerabilities and inform drug discovery1-3. A systematic map of hallmark gene mutation-defined cancer dependencies and therapeutic responses is essential to uncover novel targets and refine therapeutic strategies. Here, we present the first pan-cancer blueprint of hallmark vulnerabilities, systematically linking hallmark gene mutation markers to cancer cell dependencies and drug sensitivities across 22 cancer cohorts. We integrated multi-omics data from patient tumours with large-scale CRISPR-Cas9 screens and pharmacologic profiling of over a thousand cancer cell lines. Our analysis revealed the cancer type-specific nature of hallmark gene expression programs, uncovered previously unrecognised mutation-target gene dependencies, and highlighted metabolic programs as a dominant class of functional vulnerabilities. Notably, we identified oxidative phosphorylation (OXPHOS) addiction in CDKN2A-loss lung squamous cell carcinoma (LUSC) and experimentally validated this dependency. Our validation highlights the greater selectivity of CDKN2A-loss LUSC cells to metformin, an FDA-approved antidiabetic drug known for its OXPHOS inhibitory activity. Proteogenomic integration further prioritised targets overexpressed in mutant tumours, constituting therapeutic windows. Pharmacologic profiling identified both oncology and non-oncology agents with selective activity in mutation-defined subgroups, revealing opportunities for drug repurposing. Our machine learning framework, Comet-X, for the first time fully leveraged gene mutation combinations to predict these target dependencies and drug responses. The resulting pan-cancer mutation-dependency map provides a comprehensive resource of hallmark gene targets and candidate therapeutics, stratified by mutation markers, to pave the way for drug development, clinical trial design and discovery research.

cancer biology↗

bioRxiv2025

GRASP: Gene-Relation Adaptive Soft Prompt for Universal Gene Network Inference

Gene networks (GNs) encode diverse molecular relationships and are central to interpreting cellular function and disease. The heterogeneity of interaction types has led to computational methods specialized for particular network contexts. Large language models (LLMs) offer a unified, language-based formulation of GN inference by leveraging biological knowledge from large-scale text corpora, yet their effectiveness remains sensitive to prompt design. Here, we introduce Gene-Relation Adaptive Soft Prompt (GRASP), a parameter-efficient and trainable framework that conditions inference on each gene pair through only three virtual tokens. Using factorized gene-specific and relation-aware components, GRASP learns to map each pairs biological context into compact soft prompts that combine pair-specific signals with shared interaction patterns. Across diverse GN inference tasks, GRASP consistently outperforms alternative prompting strategies. It also shows a stronger ability to recover unannotated interactions from synthetic negative sets, suggesting its capacity to identify biologically meaningful relationships beyond existing databases. Together, these results establish GRASP as a scalable and generalizable prompting framework for LLM-based GN inference.

bioinformatics↗

bioRxiv2025

Molecular mechanism of the key dormancy regulator DosR-dependent transcription activation in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is the etiological agent responsible for the worldwide disease Tuberculosis. DosR is recognized as the key dormancy regulator of Mtb due to its global transcriptional regulation in intracellular adaptation and long-term persistence prevailing in latent infection. However, the molecular mechanism regarding DosR-dependent transcription activation remains inadequately defined. Here, we successfully determined the cryo-EM structure of an intact DosR-dependent transcriptional activation complex (DosR-TAC), comprising Mtb RNA polymerase (RNAP), DosR, and the hypoxic promoter DNA. In DosR-TAC, two DosR monomers symmetrically dimerize through their N-terminal receiver domains (DosR_RECs) and the distinct 10 helices of the C-terminal DNA-binding domains (DosR_DBDs). Unlike its inhibitory configuration, the DosR dimer undergoes significant conformational changes within the original linker, isomerizing DosR_REC into a canonical ({beta})5 fold. This extended linker affords the DosR_DBDs and DosRI_REC to contact promoter DNA, while concurrently interacting with the conserved domains of RNAP ({sigma}AR4, CTD, and NTD). Additionally, RT-qPCR and growth curve assays of the wild-type and DosR mutant strains, also unravel the physiological importance of this divergent linker. These findings, together with prior hypotheses regarding DosR, support an allosteric activation-recruitment model for DosR. Altogether, these results highlight the molecular mechanism of DosR-dependent transcription activation critical for dormancy survival of Mtb, and offer potential targets for developing anti-dormancy strategies against persistent tuberculosis.

microbiology↗

bioRxiv2025

TRPM2 is a direct pain transducer

Chronic pain results from maladaptive interaction between the immune and nervous systems. TRPM2 channels in immune cells (immune TRPM2) are believed to facilitate chronic pain by indirectly promoting immune-inflammatory responses. Whereas TRPM2 in sensory neurons (neuronal TRPM2) acts as a warmth sensor critical to sense innocuous warm temperatures. However, neuronal TRPM2 mediates the warmth sensitivity of less than 3.5% of sensory neurons. The functions of the vast majority (42%) of TRPM2+ neurons are unknown. Here we show that neuronal TRPM2 functions as a pain sensor responsible for directly transducing acute and chronic pain independently of immune TRPM2. Both chronic arthritis pain and neuropathic pain were markedly reduced in TRPM2-knockout mice, and the pain deficit was recapitulated by sole deletion of neuronal TRPM2. However, immune and inflammatory responses were largely similar between wild-type and neuronal TRPM2-deficient mice. Moreover, antagonizing joint TRPM2 rapidly reversed chronic arthritis pain without affecting joint inflammation. Mechanistically, TRPM2 is activated by PGE2 and IgG immune complex (IgG-IC) through GoA and Fc{gamma}RI coupling, respectively, independently of conventional signalling messengers. Consistently, acute pain induced by PGE2 and IgG-IC was abolished in TRPM2 mutant mice. We conclude that neuronal TRPM2 is a convergent direct pain transducer independently of inflammation, representing an appealing target for alleviating chronic pain.

neuroscience↗

bioRxiv2025

A deep learning and co-conservation framework enable discovery of non-canonical Cas proteins

CRISPR-Cas systems are central to prokaryotic adaptive immunity, widely harnessed for biotechnology. Yet, their vast and uncharacterized diversity, especially non-canonical variants, impedes full exploitation. Here we present BioPrinCRISPR, a class-agnostic computational framework leveraging gene co-conservation, protein domain co-occurrence, and embedding similarity to identify and characterize CRISPR-Cas systems across prokaryotic genomes. Applying BioPrinCRISPR to over one million bacterial genomes, we uncovered extensive canonical and uncharacterized systems, revealing a rich landscape of atypical Cas proteins and novel domain architectures. Notably, we identified recurrent fusion proteins with unique enzymatic combinations, suggesting roles in regulatory control or nucleic acid remodeling. Experimental validation of two divergent Cas13an-like effectors demonstrated RNA knockdown capacity in human cells, confirming our frameworks predictive power. These findings expand the functional repertoire of CRISPR-associated proteins and highlight unexplored modes of microbial immunity. BioPrinCRISPR thus stands as a powerful tool for comprehensively mapping CRISPR-Cas diversity, offering new insights into prokaryotic defense and facilitating discovery of novel candidates for next-generation genome engineering. An accompanying interactive web platform was also developed to facilitate data exploration.

synthetic biology↗

bioRxiv2025

Programmable Aptamer-Embedded Circular RNAs for Targeted Antigen-Presenting Cells Immunotherapy

The targeted delivery of mRNA to specific cell types in vivo remains a major unmet need in mRNA-based therapeutics. Conventional strategies rely on nanocarriers engineered with various modifications. However, these exogenous materials could cause adverse reactions, and their complex manufacturing processes often hinder clinical application. By leveraging the innate programmability of RNA sequences, we herein report a carrier-free, scalable, and programmable aptamer-embedded circular RNAs (Apt-circRNAs) design that confers targeting capability through the strategic incorporation of different aptamers at varying densities, while retaining circular RNA stability and protein production capability. Experimental results show that antigen-loaded Apt-circRNAs enable targeted delivery to antigen-presenting cells (APCs), drive endogenous antigen expression, activate antigen-specific T cells, and elicit potent immune responses that mediate clearance of both early-and late-stage tumors in mouse models. In humanized models of colorectal cancer, the combination of Apt-circRNA and PD-1 blockade produced synergistic antitumor effects and significantly reshaped the tumor microenvironment. In a first-in-human (FIH) clinical trial, Apt-circRNA vaccine encoding KRAS G12D/G12V neoantigens exhibited a favorable safety profile and induced robust immune activation, T cell mobilization, and neoantigen-specific immune responses. With this study, we have established a new paradigm in carrier-free, APC-targeted RNA vaccine design, offering a safe and effective platform for next-generation cancer immunotherapy.

bioengineering↗

bioRxiv2025

Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes

RationaleThe discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. ObjectivesEvaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. Methods16S rRNA gene sequencing, cell counts and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. Measurements and Main ResultsLower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, {gamma}8T cells, PD-1+ T lymphocytes as well as higher NET levels. ConclusionsOur analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

immunology↗

bioRxiv2025

Body temperature drives azole tolerance in Candida albicans by hindering the autophagic degradation of Erg11

Human body temperature has been shown to limit the antifungal efficacy of azoles; however, the precise mechanisms underlying this limitation remain insufficiently understood. In this study, we observed that short-term exposure (24 h) to human body temperature (37{square}{degrees}C), in contrast to 30{square}{degrees}C, significantly enhances the tolerance of Candida albicans to azoles without inducing resistance. Our findings suggest that this increased tolerance is due to a reduction in the degradation of C. albicans Erg11 at 37{square}{degrees}C compared to 30{square}{degrees}C, thereby promoting azole tolerance. This phenomenon occurs because Erg11 degradation is mediated by autophagy, which is inhibited in C. albicans at 37{square}{degrees}C. The suppression of autophagy at this temperature may be associated with elevated mitochondrial production of reactive oxygen species, leading to mitochondrial dysfunction. In response to heat stress-induced mitochondrial dysfunction, autophagy-related proteins such as Atg8 accumulate around the mitochondria, while their levels in the endoplasmic reticulum decrease, consequently inhibiting autophagy in C. albicans. These findings suggest that promoting the degradation of Erg11 in C. albicans may serve as a viable strategy to augment the fungicidal efficacy of azoles in the human host.

microbiology↗

bioRxiv2025

GPR97/ADGRG3 is activated by its tethered peptide agonist and not by steroids to induce neutrophil polarization and migration

Most adhesion G protein coupled receptors (AGPCRs) are activated by intramolecular binding of a tethered-peptide agonist (TA). Shear force-induced dissociation of the AGPCR N-terminal fragment (NTF) and C-terminal fragment (CTF) exposes the TA. The decrypted TA binds rapidly to its orthosteric site within the CTF to stabilize the active state of the AGPCR. Corticosteroids were previously proposed to be agonists for GPR97/ADGRG3. Later, other steroids and androgens were purported to be selective agonists of additional AGPCRs. Here, we demonstrate that GPR97/ADGRG3 is activated by dissociation of its NTF/CTF and follows the TA mechanism. TA peptidomimetics and the ADGRG subfamily partial agonist 3-acetoxydihydrodeoxygeduin (3--DOG), but not corticoids, stimulated GPR97/ADGRG3 in cell-based luciferase reporter assays and receptor/G protein reconstitution assays. GPR97 was defined as a promiscuous AGPCR that couples to G13, Gs and Gi, but not Gq. GPR97 is highly expressed in human polymorphonuclear neutrophils (hPMNs). Neutrophils undergo actin polymerization-induced cell shape changes and polarization and migrate upon activation. We found that GPR97 activation via TA peptidomimetics or 3--DOG robustly stimulated hPMN and mouse bone-marrow neutrophil (mBMN) polarization. Furthermore, GPR97 TA peptidomimetics and 3--DOG, but not beclomethasone, induced hPMN and mBMN chemotaxis. Together, our results demonstrate that GPR97/ADGRG3 utilizes a tethered agonist mechanism to activate G protein signaling and induce neutrophil polarization and migration. One Sentence SummaryGPR97/ADGRG3 tethered agonism regulates G protein signaling in neutrophils.

pharmacology and toxicology↗

bioRxiv2025

Assembly of the complete horse genome reveals variants associated with reproduction and temperamental traits

A high-quality horse genome assembly is crucial for genetic analysis of equine. Benefiting from long-read sequencing techniques and trio-binning strategy, we assembled a complete telomere-to-telomere horse genome (T2T-horse 1.0) with a size of 2.80 Gb and a base accuracy of more than 99.9999%, comprising a 34.11-Mb entire Y chromosome. T2T-horse 1.0 filled the gaps and corrected errors in previous assemblies, and added 180.30 Mb of previously unresolved regions and 77 new genes compared with the previous reference genome TB-T2T. We identified five types of centromeric satellites and revealed the features of the horse centromeric regions. We characterized the structure of the Y chromosome, and determined the borders of PAR transposed region, and annotated 59 novel genes on Y chromosome of T2T-horse 1.0. Using SNPs in the X-degenerate region of the Y chromosome of T2T-horse 1.0, we performed selection signatures analysis between indigenous horses and horses from intensively selected breeds, and detected the selected genes ARSF and NLGN4Y, which are closely associated with reproduction and temperamental traits, respectively.

genomics↗

bioRxiv2025

PGRP-LA regulates peritrophic matrix synthesis and influences trypanosome infection outcomes in tsetse flies

Peptidoglycan Recognition Proteins (PGRPs) are conserved pattern-recognition receptors that detect microbe-associated molecular patterns (MAMPs) and activate host immune responses. Compared to other dipterans, the tsetse fly (Glossina morsitans morsitans) genome encodes only five PGRPs-PGRP-LA, -LB, -LC, -SA, and -SB - far fewer than most dipterans, likely reflecting its sterile blood diet and streamlined microbiota. Here, we identify PGRP-LA as a critical regulator of peritrophic matrix (PM) integrity in the cardia (proventriculus), the tissue responsible for PM production. The PM is a chitinous sleeve-like barrier that separates the midgut epithelium from the ingested bloodmeal, supporting digestive homeostasis and infection resistance. We show that pgrp-la is prominently expressed in the cardia, transiently induced after a bloodmeal in newly eclosed flies, and reinduced following subsequent feedings, likely in response to blood-constituents or mechanical stretch. This induction is sustained during microbial exposure and prolonged in trypanosome-infected flies. RNAi-mediated reduction of pgrp-la significantly increased the prevalence of midgut trypanosome infections, indicating a protective role during early infection. PGRP-LA did not mediate infection resistance via canonical IMD pathway signaling, as its silencing did not affect antimicrobial peptide expression. Instead, PGRP-LA modulated the expression of PM-associated genes and gut barrier integrity. Silencing pgrp-la reduced PM structure, increased midgut weights and enhanced fly survival following oral challenge with entomopathogen Serratia marcescens, likely due to earlier epithelial immune responses through a compromised PM. Similar phenotypes were observed when flies were fed anti-PGRP-LA antibodies, supporting a structural role for PGRP-LA. In addition, soluble variant surface glycoproteins (sVSGs) from trypanosomes and knockdown of microRNA-275 (miR-275), also decreased pgrp-la expression, suggesting that PGRP-LA is part of a broader regulatory network, including the miR-275/Wingless signaling. Collectively, our results identify PGRP-LA as novel regulator of PM biogenesis and vector competence in tsetse, expanding the functional repertoire of PGRPs in insect gut barrier maintenance beyond canonical immune signaling pathways. Author SummaryInsect vectors such as tsetse flies can be infected with pathogens that cause devastating disease in mammals. To protect themselves insect vectors rely on pattern recognition receptors (PRRs) that detect pathogens and activate the production of antimicrobial peptides (AMPs). Physical barriers in the gut also play an important role in limiting infections. One such barrier is the peritrophic matrix (PM), a sleeve-like structure that lines the insect gut and separates the blood meal and its contents from the underlying cells. For trypanosome parasites, which cause sleeping sickness in humans, the PM is the first barrier they must traverse to colonize the tsetses gut. In this study, we identified a PRR, PGRP-LA, that, unlike related proteins in other insects that activate AMPs, regulates the integrity of the tsetses protective PM barrier. When PGRP-LA was disrupted, the gut barrier weakened, and flies became more susceptible to trypanosome infection. Our work highlights a previously unrecognized role for PGRP-LA in maintaining gut barrier integrity and suggest that targeting this pathway could be a strategy to help reduce parasite transmission.

immunology↗

bioRxiv2025

Interneuron theta phase locking controls seizure susceptibility

The timing of neuronal activity is highly precise and often organized by brain-wide oscillations. Many neurons modulate their firing rates at specific phases of theta (known as theta phase locking), creating discrete windows for information processing. Disrupted theta phase locking has been found across several neurological and psychiatric disorders (e.g., epilepsy), but gaps in technology have prevented its causal influence from being tested. Here, we developed PhaSER, a closed-loop optogenetic system designed to control the phase locking of specific interneurons, and demonstrate a causal role for inhibitory phase locking in seizure susceptibility. We first found that parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the dentate gyrus (DG) show distinct theta phase locking profiles and are differentially impacted in a mouse model of chronic temporal lobe epilepsy. In healthy mice, PV+ interneurons have extremely consistent phase-locked firing near the trough of CA1 theta, aligned with excitatory inputs to DG. However, in epileptic mice, PV+ interneuron activity is dispersed across the theta cycle, suggesting that altered inhibitory phase locking could be a causal mediator of seizure susceptibility in epilepsy. To test this hypothesis, we applied PhaSER to directly control the phase locking of DG interneurons during an acute test of seizure susceptibility. In epileptic mice, re-aligning DG PV+ interneuron theta phase locking reduced seizure susceptibility, while in healthy mice, disrupting normal phase locking of PV+ interneurons increased seizure susceptibility. Together, this provides the first causal evidence that inhibitory theta phase locking can directly control network function by shifting seizure susceptibility in the healthy and epileptic brain.

neuroscience↗

bioRxiv2025

Structural and mechanistic insights into bacterial hydrazine biosynthesis

Nitrogen-nitrogen (N-N) bond-containing motifs are prevalent in both clinical drugs and natural products. Bacterial hydrazine synthetases catalyze N-N bond formation by coupling an amino acid and a hydroxylamine via a distinctive O-aminoacyl-hydroxylamine intermediate. Despite its wide occurrence, the structural and mechanistic basis of this process has remained elusive. Here, we report the first crystal structures of the O-aminoacyl-hydroxylamine synthetase component of a bacterial hydrazine synthetase, captured in binary and ternary complexes with substrates and catalytic intermediates. These structures reveal the molecular determinants of substrate recognition and, together with biochemical and computational analyses, establish a detailed mechanistic framework for the hydrazine synthetase family. Leveraging these insights, we expanded hydrazine biosynthesis through the targeted discovery of novel hydrazine synthetases and implemented a chemoenzymatic synthesis strategy. This work provides fundamental insights into hydrazine synthetases and lays the groundwork for their rational engineering as versatile biocatalysts.

microbiology↗

bioRxiv2025

Streamline Density Normalization: A Robust Approach to Mitigate Bundle Variability in Multi-Site Diffusion MRI

Tractometry enables quantitative analysis of tissue microstructure is sensitive to variability introduced during tractography and bundle segmentation. Differences in processing parameters and bundle geometry can lead to inconsistent streamline reconstructions and sampling, ultimately affecting the reproducibility of tractometry analysis. In this study, we introduce Streamline Density Normalization (SDNorm), a supervised two-step method designed to reduce variability in bundle reconstructions. SDNorm first computes streamline weights using linear regression to match a subjects bundle to a template streamline density map, then iteratively prunes streamlines to achieve a target density using a novel metric called effective Streamline Point Density (eSPD). We evaluate SDNorm across multiple bundles and acquisition protocols in dMRI data from a subset of subjects from Alzheimers Disease Neuroimaging Initiative and demonstrate that it can significantly reduce variability in streamline density, improve consistency in along-tract microstructure profiles, and provide useful metrics for automated bundle quality control. These results suggest that SDNorm can help enhance the reproducibility and robustness of bundle reconstruction across heterogeneous image acquisition protocols and tractography settings, making it well-suited for large-scale and multi-site neuroimaging studies.

neuroscience↗

bioRxiv2025

White Matter Tract Vulnerability to Amyloid Pathology on the Alzheimer's Disease Continuum

Alzheimers disease (AD) is marked by progressive cognitive decline and memory loss, due to the abnormal accumulation of amyloid-beta (A{beta}) plaques, which facilitate the spread of tau pathology, and a gradually spreading pattern of neuronal loss. Understanding how amyloid positivity affects the brains neural pathways is critical for understanding how the brain changes with AD pathology. Tractometry offers a powerful approach for the in vivo, 3D quantitative assessment of white matter tracts, enabling the localization of microstructural abnormalities in diseased populations and those at risk. In this study, we applied BUAN (Bundle Analytics) tractometry to multi-cohort diffusion MRI data from a total of 1,908 participants: 606 participants in ADNI3 (Alzheimers Disease Neuroimaging Initiative Phase 3) and 1,302 participants from the HABS-HD (Health and Aging Brain Study-Health Disparities). Using BUAN and along-tract statistical analysis, we assessed the localized effects of amyloid positivity on white-matter pathways, which may be further influenced by downstream tau accumulation. Amyloid positivity was quantified via amyloid-sensitive positron emission tomography (PET). BUAN enables tract-specific quantification of white matter microstructure and supports statistical testing along the full length of fiber bundles to detect subtle, spatially localized associations. We present 3D visualizations of tractwise amyloid associations, highlighting distinct patterns of white matter degeneration in AD.

neuroscience↗

bioRxiv2025

Deterministic versus Probabilistic Tractography: Impact on White Matter Bundle Shape

In diffusion MRI-based tractography, deterministic and probabilistic algorithms reconstruct white matter using distinct strategies, yet their impact on bundle morphology remains uncertain. Using bundle shape similarity analysis, we compared both methods for the left arcuate fasciculus (AF_L) (The left arcuate fasciculus is a critical white matter tract that connects language comprehension and production areas in the human brain, enabling fluent language processing) across four datasets: Alzheimers Disease Neuroimaging Initiative (ADNI), Human Connectome Project-Aging (HCP-A), National Institute of Mental Health and Neurosciences (NIMHANS), and Pediatric Imaging, Neurocognition, and Genetics (PING). Probabilistic tractography consistently produced higher inter-subject shape similarity, by capturing broader anatomical trajectories and enhancing reproducibility. However, this extensive coverage may obscure subtle pathological variations critical for clinical detection. Bundle shape similarity analysis with atlas corroborated these findings, showing stronger alignment for probabilistic tracking and highlighting its utility in quantitative quality control. These results emphasize the need to balance morphological consistency with sensitivity to neuroanatomical variation when selecting tractography methods for research and clinical applications.

neuroscience↗