Biology subjects

Lu, J.

Publications and source records attributed to Lu, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2025

Neural hierarchy for coding articulatory dynamics in speech imagery and production

Mental imagery is a hallmark of human cognition, yet the neural mechanisms underlying these internal states remain poorly understood. Speech imagery--the internal simulation of speech without overt articulation--has been proposed to partially share neural substrates with actual speech articulation. However, the precise feature encoding and spatiotemporal dynamics of this neural architecture remain controversial, constraining the understanding of mental states and the development of reliable speech imagery decoders. Here, we leveraged high-resolution electrocorticography recordings to investigate the shared and modality-specific cortical coding of articulatory kinematic trajectories (AKTs) during speech imagery and articulation. Applying a linear model, we identified robust neural dynamics in frontoparietal cortex that encoded AKTs across both modalities. Shared neural populations across the middle premotor cortex, subcentral gyrus, and postcentral-supramarginal junction exhibited consistent spatiotemporal stability during the integrative articulatory planning. In contrast, modality-specific populations for speech imagery and articulation were somatotopically interleaved along the primary sensorimotor cortex, revealing a hierarchical spatiotemporal organization distinct from shared encoding regions. We further developed a generalized neural network to decode multi-population neural dynamics. The model achieved high syllable prediction accuracy for speech imagery (79% median accuracy), closely matching the performance of speech articulation (81%). This model robustly extrapolated AKT decoding to untrained syllables within each modality while demonstrating cross-modal generalization across shared populations. These findings uncover a somato-cognitive hierarchy linking high-level supramodal planning with modality-specific neural manifestation, revolutionizing an imagery-based brain-computer interface that directly decodes thoughts for synthetic telepathy.

neuroscience↗

bioRxiv2025

An Adipose mTORC1 Effector Links Nutrient-induced Ribosomal Protein Translation to Lifespan in Drosophila

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes critical for physiological homeostasis and organismal ageing1. While mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs that predominantly encode ribosomal proteins (RPs) via the translational repressor 4E-BP 2, this mTORC1 function is resistant to rapamycin inhibition 3. TOP mRNAs are exceptionally abundant, thus imposing a major translational burden on cells; yet how their translation is physiologically tuned and linked to longevity remain unexplored. Here we identify Lsp2, originally known as a storage protein 4, as an adipose effector of mTORC1 that modulates lifespan in Drosophila. Lsp2 is induced by essential amino acids (EAAs) via mTORC1. Genetic ablation of Lsp2 to blunt organismal response to protein diets drives robust lifespan extension without compromising key life-history traits such as reproduction. Translatomic profiling reveals that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan via a mechanism distinct from rapamycin inhibition that fails to reduce 4E-BP phosphorylation in vivo. Finally, Lsp2 adipokine promotes 4E-BP phosphorylation and acts systemically across tissues to shape the lifespan responses to dietary protein. Collectively, our findings establish Lsp2 as a novel translational regulator of TOP genes that mechanistically couples physiological ribosomal protein synthesis with organismal longevity.

physiology↗

bioRxiv2025

Investigating milk derived extracellular vesicles as mediators of maternal stress and environmental intervention

Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases lipid content, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the bioactive mediators in milk underlying resilience remain poorly understood. Milk-derived extracellular vesicles (MEVs) transport and deposit biologically active cargo, including microRNAs (miRNAs) that induce post-translational regulation of candidate mRNA in the nursing offsprings tissues and cells. Using a rat model, we show that lactational MIA alters MEV-miRNA cargo and the expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA changes in MEVs and the neonatal hippocampus were rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA. This was supported by the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV-miRNA as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.

neuroscience↗

bioRxiv2025

Too much sugar makes plants "pregnant": maternal sucrose signals fertilization in Arabidopsis seeds

Reproduction is deemed successful if it ensures the perpetuation of the species. Nonetheless, evolution has optimized reproductive efficiency across a diverse range of strategies. Animal vivipary, the process in which embryos develop inside the parents body, allows for larger offspring and better protection. This reproductive strategy relies on a fertilization signal sent to the maternal tissues to establish an embryo-supportive environment, a process known as "maternal recognition of pregnancy". Despite being a strictly animal-only term, plants independently evolved a conceptually similar strategy: the seed habit, wherein the embryo is nourished and protected by surrounding maternal tissues. We discovered that sucrose is sufficient to trigger a fertilization-independent response in the maternal tissues of Arabidopsis ovules. Upon fertilization, the release of Polycomb-mediated repression promotes the symplastic and apoplastic flow of sucrose into the seed by modulating auxin and trehalose 6-phosphate signaling. The sucrose signal is then perceived by the TARGET OF RAPAMYCIN kinase and transduced into a gibberellin response to initiate the differentiation of the seed maternal tissues. This work revealed a zygotic-maternal interplay of hormonal and sugar signaling that drives the plant "maternal recognition of fertilization", incorporating energetic cues into developmental pathways.

plant biology↗

bioRxiv2025

Prg4+ fibro-adipogenic progenitors in muscle are crucial for bone fracture repair

Clinically, compromised fracture healing often occurs at sites with less muscle coverage and muscle flaps can provide the necessary healing environment for appropriate healing in severe bone loss. However, the underlying mechanisms are largely unknown. Here, we established a mouse reporter model for studying muscle cell contribution to bone fracture repair. Analyzing skeletal muscle scRNA-seq datasets revealed that Prg4 marks a fibro-adipogenic progenitor (FAP) subpopulation. In mice, Prg4+ cells were specifically located in the skeletal muscle, but not at the periosteum or inside cortical bone. These cells expressed FAP markers, responded to muscle injury, and became periosteal cells under normal and muscle injury conditions. Fracture fragmented muscle fibers, rapidly expanded Prg4+ FAPs at the injury site and promoted their migration into the fracture site. Later, they gave rise to many chondrocytes, osteoblasts, and osteocytes in the outer periphery of callus next to muscle. In repaired bones, the descendants of Prg4+ FAPs were detected as mesenchymal progenitors in the periosteum and osteocytes at the prior fracture site. A second fracture activated those cells and stimulated them to become osteoblasts in the inner part of callus. Importantly, ablation of Prg4+ FAPs impaired fracture healing and functional repair. In an intramembranous bone injury model (drill-hole), Prg4+ FAPs became periosteal cells, but their contribution to bone defect repair was significantly less than in fractures. Taken together, we demonstrate the critical role of FAPs in endochondral bone repair and uncover a novel mechanism by which mesenchymal progenitors transform from muscle to cortical bone. Significance statementFracture healing is often impaired in areas with less muscle coverage, but the mechanisms behind this are poorly understood. In this work, we uncovered a critical role of specific muscle cells, known as Prg4+ fibro-adipogenic progenitors (FAPs), in bone regeneration. Using mouse models, we show that these muscle-resident mesenchymal progenitors expand after bone injury, migrate to the fracture site, transform into various bone cells in the fracture callus, and eventually become bone surface progenitors after the bone is healed. This finding highlights the importance of muscle cells in endochondral fracture repair and reveals a novel crosstalk mechanism between muscle and bone tissues. Future studies targeting these muscle progenitor cells could develop new treatments for delayed and nonunion fractures.

cell biology↗

bioRxiv2025

Neuromodulation of risk preferences encoded in human orbitofrontal cortex activity

Human behavior presents a natural range of variation beyond which extreme behavior appears, often as a hallmark of psychiatric conditions. for example, risk preferences, which naturally range from risk-seeking to risk-averse, are characteristically affected in multiple pathologies, e.g. increased risk-taking in gambling disorders. Despite its basic and translational importance, how underlying brain activity reflects and determines behavioral variation is mostly unknown, in part due to the difficulty of directly examining neural activity in decision-relevant brain areas from cohorts of subjects with varying preferences. To address this, we combined human intracranial recordings (n=15 patients) from the orbitofrontal cortex (OFC), a key brain region in economic decision-making, with risky decision-making tasks and computational modeling. We observed significant behavioral variation in risk preferences, which was strongly correlated with low-frequency (delta-theta) oscillatory coherence in OFC. Low-frequency oscillatory phase was coupled to high-frequency activity amplitude, providing a potential neurophysiological mechanism for integrating preferences with trial-by-trial risk computations. Finally, targeted OFC electrical stimulation caused significantly decreased risk-taking behavior and faster reaction times without impairing overall decision-making. These results show a neural correlate for inter-individual variation in decision-making preferences and provide proof-of-principle evidence for modulation of risk-taking behavior through OFC-targeted neurostimulation, paving the way for developing neuromodulatory interventions for pathologies characterized by heightened risk-seeking, such as addiction and gambling disorders. Significance statementWe leverage invasive electrophysiological recordings from human orbitofrontal cortex to demonstrate that low-frequency oscillatory coherence reflects stable inter-individual economic preferences, with targeted neurostimulation causing risk averse behavior. These results provide a neurobiological substrate for interindividual differences in economic decision-making and provide a potential therapeutical avenue for brain disorders characterized by risky behavior.

neuroscience↗

bioRxiv2025

Separable Spatial Single-cell Transcriptome Representation Learning via Graph Transformer and Hyperspherical Prototype Clustering

Spatial transcriptomics enables the exploration of cell types, spatial domain organization, and cell-cell communication at tissue scale, serving as a powerful link between tissue morphology and molecular function. However, existing methods still struggle with limited spatial resolution, poor robustness in multi-slice alignment, and suboptimal ligand-receptor (L-R) detection in complex tissues. To address these challenges, we propose S3RL (Separable Spatial Single-cell transcriptome Representation Learning via Graph Transformer and Hyperspherical Prototype Clustering), a unified framework that integrates gene expression, spatial coordinates, and histological image features via a graph neural network and hyperspherical prototype-based separable representation learning. In spatial clustering tasks, S3RL improves the average Adjusted Rand Index (ARI) by nearly 120% on the Nanostring lung cancer dataset and over 26% on the 10X DLPFC dataset compared to state-of-the-art methods. For multi-slice spatial alignment, S3RL achieves an average ARI improvement of over 65.4% in partial brain slices and over 48.3% in complete slices relative to GraphST, highlighting its superior robustness and alignment consistency across heterogeneous spatial inputs. Moreover, S3RL reveals more biologically meaningful ligand-receptor signaling relationships, enhancing the interpretability of cell-cell communication patterns. Together, these results demonstrate S3RLs effectiveness in enhancing spatial resolution, cell type identification, and biological insight across diverse spatial transcriptomics datasets.

bioinformatics↗

bioRxiv2025

Structural insight into the substrate binding of the AMT complex via an inhibitor-trapped state

N6-adenine (6mA) DNA methylation plays an important role in gene regulation and genome stability. The 6mA methylation in Tetrahymena thermophila is mainly mediated by the AMT complex, comprised of the AMT1, AMT7, AMTP1 and AMTP2 subunits. To date, how this complex assembles on the DNA substrate remains elusive. Here we report the structure of the AMT complex bound to the OCR protein from bacteriophage T7, mimicking the AMT-DNA encounter complex. The AMT1-AMT7 heterodimer approaches OCR from one side, while AMTP1 N-terminal domain, assuming a homeodomain fold, binds to OCR from the other side, resulting in a saddle-shaped architecture reminiscent of what was observed for prokaryotic 6mA writers. Mutation of the AMT1, AMT7 and AMTP1 residues on the OCR-contact points led to impaired DNA methylation activity to various extents, supporting a role for these residues in DNA binding. Furthermore, structural comparison of the AMT1-AMT7 subunits with the evolutionarily related METTL3-METTL14 and AMT1-AMT6 complexes reveal sequence conservation and divergence on the region corresponding to the OCR-binding site, shedding light onto the substrate binding of the latter two complexes. Together, this study suggests a substrate binding-induced open-to-closed conformational transition of the AMT complex, with implications in its substrate binding and processive 6mA methylation.

biochemistry↗

bioRxiv2025

CTHRC1 is a new therapeutic target and serum diagnostic biomarker for aortic dissection

Aortic dissection (AD) is a cardiovascular disease with rapid onset and extremely high short-term mortality, currently lacking specific peripheral blood-based biomarkers and effective treatments. Here, our analysis of AD samples from animal models and human patients revealed elevated blood levels of CTHRC1, a protein secreted by vascular fibroblasts. Furthermore, CTHRC1 regulates the phenotypic switch of vascular smooth muscle cells (VSMCs) during arterial remodeling by binding to ADAM9 on the VSMC membrane, activating the ERK1/2 signaling pathway, and promoting a contractile-to-synthetic transition. In Ang-II/BAPN induced mouse models, genetic ablation or antibody-mediated blockade of CTHRC1 effectively prevented AD development. These findings unveil CTHRC1 as a critical regulator of VSMC phenotype and aortic structural integrity via the ERK1/2 pathway, suggesting its potential as a novel serum diagnostic biomarker for AD diagnostic and a promising therapeutic target. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/649636v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@6a3f14org.highwire.dtl.DTLVardef@15353e7org.highwire.dtl.DTLVardef@1a9928forg.highwire.dtl.DTLVardef@1d4ef3d_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefCTHRC1 is aberrantly expressed in aortic adventitial fibroblasts from dissected aortas and function as an exocrine mediator that induces phenotypic switching of vascular smooth muscle cells. A monoclonal antibody targeting CTHRC1 demonstrates therapeutic potential in mouse models of aortic dissection. HighlightsO_LICTHRC1 is highly expressed in aortic adventitial fibroblasts from dissected aortas C_LIO_LICTHRC1 interacts with ADAM9 to induce phenotypic switching of VSMCs C_LIO_LIAn anti-CTHRC1 antibody inhibits aortic dissection formationinvivo C_LIO_LIElevated levels of serum CTHRC1 can be used to identify AD in patients presenting with chest pain C_LI

cell biology↗

bioRxiv2025

A Novel No-Wash (Homogenous) High-Throughput Toxicity Assay on Primary Cells

Mitochondrial membrane potential (MMP) is a critical marker of mitochondrial and, therefore, cellular function. However, current dyes used for MMP measurement possess significant limitations: nonspecific targeting, long incubation times, potential mitochondrial toxicity, poor water solubility, and numerous wash steps. Using a novel fluorescent dye--mitochondrial membrane potential indicator (m-MPI)--in combination with a masking dye, we overcame said limitations and successfully measured MMP changes on different cell lines, as well as four different human primary cells. This no-wash assay has been miniaturized into a 384-well format. It is robust with Z value > 0.5 on both HepG2 and HeLa cells and can be used for high throughput screening. The reagents in the m-MPI homogeneous assay kit are not toxic to cells, as was demonstrated on HepG2 and HeLa cell lines using Dexorgens EnerCount ATP assay. Using this assay, we conducted a mini screening on human hepatocytes against the Library of Pharmacologically Active Compounds (LOPAC) (Sigma). The resulting hits were then confirmed with follow-up studies.

cell biology↗

bioRxiv2025

Large-scale single-neuron recording using the uFINE array in human cortex

Monitoring neural population activity at single-cell resolution is essential for driving fundamental research and clinical innovations. However, translating advanced recording techniques from animal models to humans remains a significant challenge. Flexible neural electrodes have recently emerged as powerful tools for large-scale single-unit recordings due to their superior biocompatibility and high recording density. Here, we demonstrate reliable, high-density single-unit recordings during intraoperative procedures in human patients using ultra-Flexible Implantable Neural Electrode (uFINE) arrays. The uFINE array exhibited sufficient mechanical robustness to maintain structural integrity throughout surgical operations. We successfully recorded 616 single units from 10 patients, with up to 135 single units simultaneously recorded. The flexibility of uFINE array minimized signal disturbances from brain pulsations, enabling stable and continuous single-unit detection. Stimulus and response tuning were observed at the level of individual neurons in awake patients. This uFINE-based recording approach offers unique opportunities to investigate human-specific cognitive functions and develop next-generation brain-machine interfaces.

bioengineering↗

bioRxiv2025

Rare Subset of T Cells Form Heterotypic Clusters with Circulating Tumor Cells to Foster Cancer Metastasis

The immune ecosystem is central to maintaining effective defensive responses. However, how immune cells in the periphery blood interact with circulating tumor cells (CTCs) - seeds of metastasis - remains largely understudied. Here, our analysis of the blood specimens (N=1,529) from patients with advanced breast cancer revealed that over 75% of the CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs). Detection of CTC-WBC clusters correlates with breast cancer subtypes (triple negative and luminal B), racial groups (Black), and decreased survival rates. Flow cytometry and ImageStream analyses revealed diverse WBC composition of heterotypic CTC-WBC clusters, including overrepresented T cells and underrepresented neutrophils. Most strikingly, a rare subset of CD4 and CD8 double positive T (DPT) cells showed an up to 140-fold enrichment in the CTC clusters versus its frequency in WBCs. DPT cells shared part of the profiles with CD4+ T cells and others with CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression with higher expression of TIM-3 and PD-1. Single-cell RNA sequencing and genetic perturbation studies further pinpointed the integrin VLA4 (4{beta}1) in DPT cells and its ligand VCAM1 in tumor cells as essential mediators of heterotypic WBC-CTC clusters. Neoadjuvant administration of anti-4 (VLA4) neutralizing antibodies markedly blocked CTC-DPT cell clustering and inhibited metastasis for extended survival in preclinical mouse models in vivo. These findings uncover a pivotal role of rare DPT cells with immune suppressive features in fostering cancer dissemination through direct interactive clustering with CTCs. It lays a foundation for developing innovative biomarkers and therapeutic strategies to prevent and target cancer metastasis, ultimately benefiting cancer care. Brief summaryOur findings uncover a fostering role of immune-suppressive T cells in contact with circulating tumor cells and identify therapeutic approaches to eliminate devastating cancer metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/646421v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@13b7862org.highwire.dtl.DTLVardef@15c97b2org.highwire.dtl.DTLVardef@1eb4fd2org.highwire.dtl.DTLVardef@1c588e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Effect of the S2' site cleavage on SARS-CoV-2 spike

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2 site, before membrane fusion can occur. We report here a cryo-EM structure of S2 fragment after the S2 cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2 cleavage accelerates membrane fusion, probably by stabilizing fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

biochemistry↗

bioRxiv2025

Milk-derived extracellular vesicles mitigate NF-κB pathway and NLRP3 inflammasome formation in Long Evans neonates.

Exposure to a maternal high fat diet (HFD) during perinatal (prenatal and postnatal combined) life increases offsprings risk of developing metabolic diseases (obesity, type II diabetes and hypertension), impairs immunity, behaviour, and neurodevelopment. Exclusive breast/chest milk feeding is a potential solution to reduce the negative developmental effects of HFD, mainly chronic systemic pro-inflammation. This study focuses on analyzing anti-inflammatory effects of a group of biological nanovesicles found in human milk, entitled milk-derived extracellular vesicles (MEVs). Specifically, we characterized the modulation of the nuclear factor {kappa}B (NF-{kappa}B) signaling pathway and NLR family pyrin domain containing 3 (NLRP3) inflammasome formation by MEVs in male and female neonatal rats with perinatal HFD exposure in the liver and hypothalamus. Female Long Evans dams were placed on a HFD or a control diet (CHD), with matching sucrose levels, 4 weeks before breeding and remained on the diets through gestation and lactation. HFD and CHD offspring received human MEVs through oral gavage twice a day from postnatal day (PND) 4 to 11. Transcript and protein abundance of candidate targets in the NF-{kappa}B signaling pathway and NLRP3 inflammasome were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western immunoblotting, respectively. Our results indicate that MEV treatment attenuates the activation of NF-{kappa}B pathway and NLRP3 inflammasome formation at critical checkpoints, in males and females with perinatal HFD exposure in liver and the hypothalamus. Taken together, our data suggests that MEVs may elicit anti-inflammatory benefits postnatally that mitigates gestational HFD exposure.

developmental biology↗

bioRxiv2025

Bisphosphonates Trigger Anti-Ageing Effects Across Multiple Cell Types and Protect Against Senescence

Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in [~]400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro. Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

cell biology↗

bioRxiv2025

Genome sequence assembly and annotation of MATA and MATB strains of Yarrowia lipolytica

Yeast is commonly utilized in molecular and cell biology research, and Yarrowia lipolytica is favored by bio-engineers due to its ability to produce copious amounts of lipids, chemicals, and enzymes for industrial applications. Y. lipolytica is a dimorphic yeast that can proliferate in aerobic and hydrophobic environments conducive to industrial use. However, there is limited knowledge about the basic molecular biology of this yeast, including how the genome is duplicated and how gene silencing occurs. Genome sequences of Y. lipolytica strains have offered insights into this yeast species and have facilitated the development of new industrial applications. Although previous studies have reported the genome sequence of a few Y. lipolytica strains, it is of value to have more precise sequences and annotation, particularly for studies of the biology of this yeast. To further study and characterize the molecular biology of this microorganism, a high-quality reference genome assembly and annotation has been produced for two related Y. lipolytica strains of the opposite mating type, strain E122 (MATA) and 22301-5 (MATB). The combination of short-read and long-read sequencing of genome DNA and short-read and long-read sequencing of transcript cDNAs allowed the genome assembly and a comparison with a distantly related Yarrowia strain.

genomics↗

bioRxiv2025

Genetic association between posterior parietal cortex and intelligence

The identification of intelligence-associated loci raises questions for functional association of brain regions and for different intelligence concepts of either a general capability or discrete abilities. By generating single-nucleus transcriptomic atlas of mouse posterior parietal cortex (PPC), which is implicated in quantification behavior, we find that human intelligence-associated gene homologs are significantly enriched in certain specific neurons within the PPC. We also find 73% of the human intelligence gene homologs are highly enriched in PPC. In addition to PPC, several regions at different locations, not cortex next to PPC, are also significantly associated with intelligence genes. The separate locations of these cortex regions and their regional-specific expressed intelligence genes raise the possibility for discrete intelligence capabilities. Animal behavior analysis reveals that mutations for two top intelligence-associated genes with specific expression in either PPC or entorhinal cortex (ENT) affect quantification or learning and memory, respectively. Finally, five patients with PPC resection in the left hemisphere also display quantification defects, but not other cognitive abilities. Together, our studies provide the first genetic and functional evidence for the involvement of PPC in intelligence. Our data also support the model of multiple intelligence over a general capability for intelligence.

genetics↗