Biology subjects

Ye, J.

Publications and source records attributed to Ye, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer

Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) cancer type. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low levels of the ASCL1 transcription factor die from ferroptosis upon Cys depletion. In contrast, ASCL1-high cells die from apoptosis but are ferroptosis resistant. This resistance to ferroptosis is driven by the direct upregulation of the gene coding for the GCH1 enzyme by ASCL1, which results in higher levels of the BH4/BH2 antioxidants. Accordingly, combining cysteine depletion with BH4/BH2 synthesis inhibition effectively reduces tumor growth in patient-derived xenografts. This work elucidates distinct metabolic states in SCLC and suggests new approaches to induce cell death in this lethal form of cancer.

cancer biology↗

bioRxiv2026

A Wnt-responsive fibrocartilage progenitor system coordinates postnatal mandibular condylar cartilage growth

Postnatal growth of the mandibular condyle requires coordinated expansion of fibrocartilage and production of chondrocytes, yet the cellular populations that organize this process remain incompletely defined. Here we identify a Wnt-responsive fibrocartilage progenitor population that contributes to postnatal mandibular condylar cartilage growth. Using a direct Wnt activity reporter (R26-WntVis), inducible genetic lineage tracing (Axin2CreERT2), and single-cell transcriptomics, we define a Wnt-enriched progenitor-like cluster localized predominantly within the fibrocartilage zone. Lineage tracing demonstrates that Axin2-lineage cells expand laterally within fibrocartilage and generate vertically aligned chondrocytes in the chondrocartilage compartment, indicating bidirectional growth contribution in vivo. Conditional ablation of {beta}-catenin in Axin2-lineage cells results in depletion of the fibrocartilage compartment and premature activation of chondrogenic differentiation programs, whereas constitutive {beta}-catenin activation disrupts compartmental organization without enhancing proliferation. Mechanistically, we identify Foxm1 as a Wnt-associated proliferative mediator enriched in fibrocartilage, and genetic reduction of Foxm1 cooperates with {beta}-catenin deficiency to impair condylar growth. In parallel, {beta}-catenin loss derepresses TGF-{beta}-Smad signaling and enhances chondrogenic differentiation, indicating that canonical Wnt activity coordinates proliferative maintenance while restraining lineage commitment within the same cellular compartment. Together, these findings identify a Wnt-responsive fibrocartilage progenitor system that regulates postnatal mandibular condylar cartilage growth by coupling Foxm1-associated proliferative maintenance with suppression of TGF-{beta}-dependent chondrogenic differentiation during temporomandibular joint development. Graphical abstractWnt-responsive fibrocartilage progenitors coordinate postnatal mandibular condylar cartilage growth through Foxm1-dependent proliferative maintenance and suppression of TGF-{beta}-driven chondrogenic differentiation.

developmental biology↗

bioRxiv2026

In vivo multiomic Perturb-seq with enhanced nuclear gRNA capture

In vivo CRISPR screening with joint transcriptomic and chromatin readouts has been limited by inefficient recovery of gRNAs from nuclei. Here, we developed in vivo multiomic Perturb-seq, an effective platform combining nuclear transcript anchoring with gRNA-specific capture and amplification to enable high-fidelity, high-recovery gRNA assignment and scalable perturbation-resolved single-nucleus multiomics. Applying this platform to interrogate neurodevelopmental disorder risk genes in the developing cortex reveals cell-type-specific transcriptomic and epigenomic perturbation phenotypes.

genomics↗

bioRxiv2026

Automated extraction and optimization of protein purification protocols using multi-agent large language models

Recent advances in Large Language Models (LLMs) present new opportunities for automating critical bottlenecks in scientific workflows such as literature reviews or protocol design. One such bottleneck is the purification of recombinant proteins, a vital aspect of biomedical research that frequently fails. To improve success rates, researchers must manually define optimal large-scale purification conditions and establish robust rescue protocols for proteins with low stability or solubility - a time-intensive process. To address this gap, we introduce a multi-agent LLM system that automates the creation and optimization of protein purification protocols to facilitate the production of high-concentration, high-purity protein samples. Our application streamlines the labor-intensive manual process of sequence similarity searches, literature reviews, and protocol comparison. Operating in a tool-like constrained workflow, the system identifies analogous proteins, leverages specialized LLM agents to extract successful purification methodologies from primary source literature, and cross-references them against failed protocols to generate optimization recommendations. Evaluation on a select number of targets demonstrated high accuracy in protocol extraction and the generation of scientifically sound, expert-validated optimization recommendations. While this system reduces complex analysis time from hours to minutes, we identify the lack of programmatic open access to literature, specifically primary citations in the Protein Data Bank, as a fundamental limitation to LLM agent-based scientific workflows. Ultimately, this system demonstrates the feasibility of using LLM agents to streamline wet-lab workflows while preserving methodological transparency and reproducibility.

bioinformatics↗

bioRxiv2026

Hormone signaling and immune programs define differential endocrine responsiveness in high-risk breast tissue

Hormone therapies are frequently used to reduce breast cancer risk in individuals at increased risk for primary or subsequent disease; however, tissue-level responses to these therapies are heterogeneous and incompletely understood. Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) provides a non-invasive radiologic readout of breast tissue features associated with endocrine responsiveness and cancer risk. Although BPE is associated with hormonal exposure, a subset of patients with BPE do not show a response to preventive endocrine therapy and therefore may remain at increased breast cancer risk. In this study, we integrated single-nucleus RNA sequencing and spatial transcriptomics to define the determinants of endocrine responsiveness in the setting of BPE. We identify hormone-driven epithelial cells with high levels of estrogen signaling and endocrine responsiveness, together with immune-associated epithelial programs characterized by diminished luminal identity and increased expression of immune-modulatory pathways, including major histocompatibility complex (MHC) class II and CD74. Functional organoid assays validate that these epithelial states exhibit differential sensitivity to tamoxifen and demonstrate that inflammatory signals can induce immune-modulatory epithelial programs. Together, our findings identify hormone signaling and immune programs as key determinants of endocrine responsiveness in breast tissue and provide a biological basis for interpreting radiologic markers relevant to cancer prevention.

cancer biology↗

bioRxiv2026

NRF2 pathway activation and SPP1⁺TREM2⁺ macrophages drive chemoradiotherapy resistance in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive cancers, with low rates of durable response to chemoradiotherapy and limited therapeutic options for relapsed disease. To uncover mechanisms of treatment resistance and relapse, we performed comprehensive multi-omics profiling of >100 pre-treatment and post-relapse ESCC tumors from a prospective clinical trial (NCT04694391), integrating whole-exome/genome sequencing, bulk RNA-sequencing, single-cell RNA sequencing, and spatial transcriptomics. We identify somatic alterations in NFE2L2/KEAP1 in nearly 40% of relapsed patients, which are associated with upregulation of NRF2 signaling targets in resistant tumors and cell line models. At single-cell and spatial resolution, relapsed tumors are enriched for NRF2-activated epithelial cells that physically co-localize with immunosuppressive SPP1TREM2 macrophages. This co-localization suggests a synergistic interaction between NRF2-driven tumor programs and macrophage-mediated immune suppression that promotes relapse after chemoradiotherapy. Our findings nominate NFE2L2/KEAP1 mutations as predictive biomarkers for patient stratification and highlight therapeutic targeting of NRF2 signaling and SPP1TREM2 macrophages as rational strategies to overcome resistance in ESCC.

cancer biology↗

bioRxiv2026

Immunopeptidomics reveals peptide antigens preferentially presented in psoriasis lesional skin of HLA-C*06:02 carriers

BackgroundHuman leukocyte antigen (HLA)-C*06:02 is a major genetic risk factor for psoriasis and understanding the HLA-C*06:02-presented peptide antigen repertoire (immunopeptidome) in the skin of patients is crucial for identifying autoantigens. Yet, no skin immunopeptidome data from patients stratified by their HLA-C*06:02 status exists. ObjectiveWe analysed biopsies from lesional and non-lesional skin of patients with psoriasis vulgaris (n=12), guttate psoriasis (n=8), or from skin of healthy controls (n=16). MethodsHLA class I and class II peptide complexes were isolated by serial immunoprecipitation and HLA-bound peptides identified by liquid chromatography-tandem mass spectrometry. HLA-C*06:02 genotyping was performed by polymerase chain reaction. ResultsOver 99,000 non-redundant peptide ligands were identified across all samples. Substantially more HLA class I and class II peptides were detected in lesional psoriatic skin compared to matched non-lesional and healthy skin. Three peptides predicted to bind HLA-C*06:02, including MRASSFLIV from the known psoriasis marker peptidase inhibitor 3 (PI3), were identified in all lesions of HLA-C*06:02-positive patients but were rarely detected or absent in HLA-C*06:02-negative patient lesional skin and not detected at all in unaffected skin. Keratinocyte differentiation-associated protein (KRTDAP) was a notable source of lesion-specific HLA class II ligands contributing three out of six peptides detected in more than half of the lesional samples. ConclusionActive psoriatic lesions display an altered and expanded immunopeptidome compared to unaffected skin. We have identified numerous unreported, lesion-specific HLA-bound peptides and their source proteins. These findings offer insights into the pathobiology of psoriasis and provide a resource for future functional studies. CAPSULE SUMMARYA selection of immunopeptides is presented exclusively in lesional skin of HLA-C*06:02+ patients with psoriasis that may represent antigenic drivers of disease.

immunology↗

bioRxiv2026

A reconfigurable DNA memory architecture for hierarchical data management via programmable phase transitions

DNA has emerged as a promising medium for the post-silicon era of information storage due to its ultrahigh density and longevity. However, current systems are bifurcated, with solid-state systems providing robust cold archival but lacking accessibility, while fluidic molecular computing systems offer dynamic processing but suffer from low density and instability. This mutual exclusivity has hindered the development of hierarchical memory, a standard in modern computing, within molecular storage systems. Here, we bridge this gap by engineering a reconfigurable DNA memory architecture driven by programmable liquid-liquid phase separation (LLPS). Our system leverages sequence-based encoding to achieve an ultrahigh storage density of 7x1010 GB/g, approaching the theoretical limits of DNA accessibility. In its fluidic hot state, DNA droplets enable rapid data loading ([~]83.8% in 5 min) and function as an in-memory editing platform supporting versatile, addressable bit-level operations including selective erasure ([~]65.1%) and high-efficiency rewriting and replacement (>99%) via programmable strand displacement. Importantly, to resolve the stability trade-off, we engineered a programmable phase transition whereby the triggered assembly of a rigid tetrahedral DNA framework (TDF) armor transforms liquid condensates into robust armored droplets. This cold state confers exceptional resistance to enzymatic and physical degradation, projecting multi-millennial data stability. By enabling reversible transitions between a editable, high-density computing mode and a stabilized archival mode, this work establishes the architectural foundation for scalable molecular information storage capable of hierarchical data management.

synthetic biology↗

bioRxiv2026

Enabling Skilled Human-Computer Interaction After Paralysis via a Wearable sEMG Interface

Most individuals with tetraplegia retain some myoelectric function in their forearms, which offers the possibility of using surface electromyographic (sEMG) control for human-computer interaction (HCI). We demonstrate the potential of this approach by showing that people with motor-complete (n=5) and motor-incomplete (n=2) tetraplegia can accurately control myoelectric activity in their forearm to perform discrete button-click and continuous positioning tasks. These control inputs were mapped to the firing rate of motor units detected by a wireless wristband sensor designed for everyday use. Participants completed four testing sessions to assess their speed and accuracy. Motor units that displayed a wide dynamic range in their firing rate performed best during tasks requiring continuous, single-axis control. Interestingly, the level of impairment did not affect performance on the clicking and 1D cursor control tasks. However, those with motor-incomplete injuries showed greater independent control over two motor units than participants with motor-complete injuries, who exhibited stronger coupling between units. Participants also confirmed the practical utility of the device, successfully placing and removing the sEMG wristband on their own and consistently rating it as comfortable and easy to manage. These findings are significant because they offer the first demonstration of motor unit-based control in individuals with cervical spinal cord injury (SCI) using a fully wearable wristband interface, highlighting the feasibility of moving these systems out of the lab and into daily life. One-Sentence SummaryPeople with tetraplegia used a wristband sensor to detect forearm motor unit firing and perform human-computer interaction tasks.

bioengineering↗

bioRxiv2025

Stemness factor Mex3a times translation and protein trafficking to ensure robust differentiation of olfactory sensory neurons

During the switch from progenitor to differentiated cell, cellular physiology must change to accommodate increased translation and trafficking of membrane-bound proteins. We identify RNA-binding and E3 ubiquitin ligase Mex3a as a key driver of proper neuronal differentiation by regulating mRNA translation and trafficking of cell surface proteins in the context of Unfolded Protein Response (UPR) signaling. Loss of Mex3a in immature olfactory sensory neurons (OSNs) leads to defects in cilia structure, cell surface protein expression, and planar cell polarity in mature OSNs. Proteomics reveal a Mex3a-dependent decrease in proteins related to vesicle transport, lipid metabolism, and ribosome biogenesis. We identify RNA and ubiquitin targets of Mex3a and provide evidence that Mex3a may confer K27 ubiquitin linkage on substrates. Finally, modulating cellular levels of Mex3a changes the recruitment of translation factors Serbp1 and p-eEF2 to ribosomes with possible effects on translation. Our data reveal how a stemness factor regulates development post-transcriptionally and post-translationally to ensure robust differentiation. HighlightsLoss of stemness factor Mex3a in immature olfactory neurons leads to defects in mature olfactory neurons. Translation/Trafficking of cell surface proteins, cilia structure, and planar cell polarity are compromised in the absence of Mex3a. Mex3a may confer K27 ubiquitination on stress granule protein Serbp1 and ribosome protein Rps7. Mex3a levels are associated with Serbp1 and p-eEF2 recruitment to ribosomes.

genetics↗

bioRxiv2025

Single-cell transcriptomic dynamics exposes hidden survival trajectory under antibiotic treatment

Heterogeneity plays a major role in bacterial resistance to antibiotic treatment while the mechanism at single-cell level is largely unknown. Here, we employed a robust integration of bulk and bacterial single-cell RNA-seq (scRNA-seq) to uncover how individual cells of Acinetobacter baumannii reorganise the heterogenous transcriptome in response to antibiotic. Using polymyxin as a representative, bulk RNA-seq showed canonical envelope- and efflux-centred responses but obscured underlying heterogeneity. Single-cell profiling resolved these averages into discrete subpopulations whose abundances shifted with concentration and time. Specifically, in early time an envelope-stress programme predominated survival at the low concentration, whereas an outer-membrane repair/efflux programme dominated survival at the high concentration. These patterns revealed structured and time-resolved heterogeneity, highlighting an ingenious bacterial stress responsive strategy. Through trajectory inference, we further revealed a concentration-dependent bifurcation of cell fates: low-concentration treated cells detoured through a transient stress state and rejoined growth, whereas high-concentration treated survivors diverted into a slow-growing, tolerant branch. Perturbing marker genes from these programmes altered fitness eventually and rapidly increased permeability, depolarisation and reactive-oxygen burden, linking state to survival capability. Collectively, we map a dynamic, concentration-structured landscape of antibiotic responses at the single-cell level, revealing diverse survival trajectories that are obscured in conventional population-averaged analyses. Our developed single-cell based framework revealed tolerant bacterial cells with rewiring of the transcriptional landscape, causing emergence of antibiotic resistance. Importantly, these findings urge precision antimicrobial therapy in patients to minimise emergence of antibiotic resistance.

microbiology↗

bioRxiv2025

Flexible brain state engagement predicts cognitive control transdiagnostically

Cognitive control supports adaptive responses in an ever-changing world. While alterations in cognitive control have been consistently observed in a range of psychiatric disorders, the neural mechanisms giving rise to this behavioral variation remain elusive. Here, we tested whether the ability to flexibly recruit recurring brain activation patterns (i.e., brain states) may serve as an intermediate phenotype supporting cognitive control in individuals with a spectrum of clinical symptoms. We leveraged machine learning and external validation to explore this question in three independent, transdiagnostic datasets (N>600), including participants with anxiety disorders, schizophrenia, mood disorders, substance use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, and neurodevelopmental disorders. To capture cognitive controls multifaceted nature, we assessed two of its components--inhibition and shift-- using both task-based and questionnaire data. Flexible brain state engagement predicted all cognitive control metrics in previously unseen individuals transdiagnostically, regardless of which dataset was used for model training. Connectome-based predictive modeling also revealed that shared brain networks underpinned flexible brain state engagement in a transdiagnostic manner. Leveraging brain network dynamics, we further observed that moments of more flexible brain state engagement aligned with moments of network connectivity related to better cognitive control within the same individual. This temporal alignment was replicated in all three datasets with heterogeneous samples. Altogether, this study suggests flexible engagement of brain states may support both inter- and intra-individual differences in cognitive control across individuals with diverse mental health profiles. Funding sourcesThis work was supported by F31AA032179 and R01MH121095. Data were provided in part by the Consortium for Neuropsychiatric Phenomics (NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410) and the Transdiagnostic Connectome Project (TCP) dataset. Datasets were accessed through OpenNeuro (https://openneuro.org/datasets/ds005237 and https://openneuro.org/datasets/ds000030/versions/00016).

neuroscience↗

bioRxiv2025

Molecular mechanism decipher of Alzheimer's disease based on single-cell RNA-seq information

BackgroundAlzheimers disease (AD) is a most common age-related neurodegenerative disease with no effective treatments, is one of the leading contributions to global disease burden. AD is represented by complicated biological mechanisms and complexity of brain tissues, often manifested histologically by the parenchymal deposition of amyloid-beta (A{beta}) plaques, the formation of neurofibrillary tangles and neuroinflammation. The etiology of AD is likely due to complex interactions among different brain cell types leading to interconnected cellular pathologies. Single-cell RNA sequencing (RNA-seq) technologies enable unbiased characterization of cell types and states, transitions from normal to disease and responses to therapies, providing an effective tool to systematically resolve cellular heterogeneity in AD. MethodsIn this study, to investigate the molecular mechanisms of AD, we collected single cell RNA-seq data of disease and control samples and designed an precise computational analysis pipeline for the dataset. We further proposed a consensus non-negative matrix factorization model to extract disease cellular gene expression programs. ResultsAccording to the computational pipeline, we get the most disease-related sub-clusters, cellular process gene expression programs, and disease-related gene programs. We further investigated the enrichment pathways of disease gene programs. DiscussionThis research might provide a cell type specific gene program targets therapeutic approach to combat the disease. HighlightsO_LIWe designed a consensus non-negative matrix factorization method, which could extract cellular process gene expression programs, and disease-related gene programs. C_LIO_LIWe further investigated the enrichment pathways of the most disease-related sub-clusters. C_LIO_LIWe provide a cellular foundation for a new perspective on AD molecular mechanism that informs personalized therapeutic development, targeting the disease-related gene program. C_LI

bioinformatics↗

bioRxiv2025

Cooperative short- and long-range interactions enable robust symmetry breaking and axis formation

Establishing the anterior-posterior (A-P) axis is a key symmetry-breaking event in mammalian development. Gastruloids, aggregates of embryonic stem cells, undergo a similar process, forming a single posterior pole from an initially spherical aggregate. This requires the aggregate to convert an inside-outside difference in cell state into one A-P axis. We asked what cell-cell interactions can make this transition robust. We built an agent-based coarse-grained model with an outer cell population and an inner cell population. Cells interacted through short-range adhesion and, in some simulations, through an effective long-range attraction. Adhesion alone rarely produced a single stable axis, often leaving weakly separated or unstable clusters. Adding long-range attraction between outer cells changed this behavior. The outer cells collected into one pole, the inner cells remained in the opposite domain, and most cells stayed in one aggregate. This occurred across a broad range of adhesion strengths. The model also made a simple prediction. If two polarized gastruloids merge in opposite orientations, the two posterior poles should move around the fused aggregate and join into one pole. Human gastruloid merging experiments showed this behavior. Same-orientation pairs fused rapidly. Opposite-orientation pairs fused more slowly as their posterior poles moved around the aggregate and converged. Finally, we built a minimal gene-regulatory model that generated inner and outer states and turned on the same mechanical interactions. In this model, an initially uniform cell population formed one polarized axis. Together, these results suggest that short-range adhesion and long-range attraction can work together to convert radial patterning into one body axis. They also suggest a design principle for synthetic developmental biology: adhesion can sort cells locally, but building one reproducible axis may require interactions that act beyond direct cell-cell contact.

systems biology↗

bioRxiv2025

A neural circuit for female-specific defensive homeostasis in risk assessment

HighlightsSC CB1R+ neurons encode visual survival threats and initiate risk assessment in both sexes CB1R+ SC-LHb GABAergic circuit maintains defensive homeostasis in risk assessment in females eCBs gate this circuit by disinhibiting presynaptic GABA release exclusively in females Disruption of this mechanism female-specifically impairs risk assessment and stress coping In BriefLiu et al. identify a female-specific subcortical circuit in which eCB signaling, via CB1R on GABAergic terminals in the SC, suppresses transmission to the LHb to maintain precise defensive homeostasis in risk assessment. These findings uncover the circuit and neuronal mechanisms that contribute to the sexually dimorphic maintenance of defensive homeostasis. Risk assessment in defensive behavior is an adaptive mechanism shaped by natural selection, enabling individuals to evaluate potential threats and thereby maintain defensive homeostasis. However, it remains unknown whether specific neural circuits maintain their behavioral homeostasis in a sex-specific manner. To address this, we investigated its neural basis by hierarchical behavior analysis framework with neural circuit dissection. In mice of both sexes, visual survival threats activated cannabinoid 1 receptor (CB1R)-expressing neurons in the superior colliculus (SC) to initiate consistent risk assessment. Deletion of CB1R in SC GABAergic neurons female-specifically impairs risk assessment by disinhibiting GABA release in SC-lateral habenula (LHb) projections, resulting in shortened risk assessment. This disruption furthermore increases the occurrence of abnormal spontaneous behavior following chronic stress exclusively in females. We identified a female-specific SC-LHb GABAergic circuit gated by CB1R maintains defensive homeostasis in risk assessment. Our findings reveal how a conserved neuromodulatory system sex-specifically gates a subcortical circuit to orchestrate distinct survival strategies.

neuroscience↗

bioRxiv2025

Myofibroblastic CAFs arising from bone-resident osteoblast precursors retain an osteolineage signature and support breast cancer progression via Osterix-mediated signaling.

Cancer-associated fibroblasts (CAFs) are a major component of the breast cancer (BC) microenvironment, involved in tumor progression and resistance to therapy. Despite the recent identification of multiple CAF subtypes with unique functions, it remains unclear whether each subtype arises from a distinct precursor or a shared common progenitor. Here, we identified a unique subpopulation of myofibroblast CAFs (myCAFs) arising from committed Osterix (Osx)+ osteoblast progenitors in the bone, recruited to primary tumors in both murine BC models and BC patients. Osx+myCAFs exhibit strong protumorigenic features and retain osteoblastic gene expression, which distinguishes them from OsxnegCAF subsets. Osx drives the expression of extracellular matrix remodeling genes and promotes tumor growth via the secretion of MMP13, a key Osx target gene. Finally, we find that increased Osx+myCAFs and a stromal osteolineage gene signature correlate with poor therapeutic response and reduced BC patient survival.

cancer biology↗

bioRxiv2025

ACAD10 encodes two orphan enzymes in the ether lipid biosynthetic and salvage pathways

Ether lipids play critical roles in membrane dynamics, antioxidant defense, and signaling. They comprise ~20% of mammalian phospholipids, and disruptions in their metabolism cause severe genetic disorders and are associated with neurodegenerative and metabolic diseases. Ether lipids are synthesized de novo from glycolytic intermediates or salvaged from the diet. While the products of these pathways are known, several key enzymes remain unidentified, including the 1-O-alkylglycerol kinase and the 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate phosphatase. Here, we show that acyl-CoA dehydrogenase member 10 (ACAD10) catalyzes the phosphorylation of 1-O-alkylglycerols and the dephosphorylation of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate. Worms and mice lacking ACAD10 have reduced ether lipid levels and cannot salvage dietary alkylglycerols. Furthermore, individuals from the Akimel O'odham (Pima) tribe carrying ACAD10 polymorphisms also show decreased plasma ether lipid levels. Collectively, our findings resolve two long-standing gaps in ether lipid biochemistry and reveal a mechanistic link between ether lipid metabolism and a population-associated risk factor for type 2 diabetes.

biochemistry↗

bioRxiv2025

Fine needle aspiration biopsy of breast specimens effectively harvests cells for patient-derived organoids modeling breast ductal carcinoma in situ

BackgroundPatient-derived organoids (PDOs) generated from benign breast tissue and breast carcinomas have successfully recapitulated their respective in vivo counterparts. PDOs model tumorigenesis and allow for screening of novel therapeutics personalized to individual patients. However, acquiring cells to generate PDOs is cumbersome. We demonstrate the feasibility of fine needle aspiration biopsy (FNAB) for harvesting cells for PDOs modeling ductal carcinoma in situ (DCIS). MethodsSurgical specimens from patients with biopsy-proven DCIS were used for this study. Core needle biopsy (CNB) was performed on fresh specimens in the operating room, and tissue was mechanically dissociated before culture in basement membrane extract (BME) and organoid medium to generate PDOs. FNAB was performed in the gross room on fresh specimens, and the remaining aspirate was similarly submitted for PDO culture. ResultsPDOs were successfully generated in 15/18 specimens obtained by CNB and 7/11 specimens obtained by FNAB. The average time to initial organoid growth was 4 days for FNAB specimens compared to 19.3 days for CNB specimens. Tumor cells were seen on 7/11 FNAB smears and 16/18 CNB touch preps. Immunofluorescence staining confirmed the presence of both luminal and myoepithelial cells in derived PDOs. ConclusionsFNAB effectively obtains cells for PDOs modeling DCIS. CNB after mincing yielded PDOs with a high success rate, but they were slow to establish. Notably, the time to organoid growth was significantly shorter for FNAB specimens. Thus, FNAB offers an efficient alternative for breast PDO culture and can reduce the time and resources spent on generating PDO cultures.

cell biology↗