Biology subjects

Luo, A.

Publications and source records attributed to Luo, A..

At least 19 recordsLinked to original sources

bioRxiv2026

AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung

Lung function requires an elastic extracellular matrix (ECM). However, the adult lung does not regenerate the elastic architecture established during development, and deposition of fibrous ECM characterizes many lung diseases. We generated a multimodal, single-nuclei atlas across development, homeostasis, aging, and fibrosis to identify lung fibroblast populations, transcriptional programs, and regulatory logic governing these divergent matrix outcomes. We discovered differential AP-1 transcription factor activity orchestrates distinct ECM programs via preferential binding to TPA-responsive elements (TRE) in fibrosis and cAMP-responsive elements (CRE) in development. Antagonizing AP-1 TRE-signaling in lung fibroblasts repressed the fibrotic program and re-engaged a developmental, elastogenic state, and MEK inhibition produced similar transcriptional phenotypes. Pathological fibroblasts in interstitial lung diseases upregulated TRE motif activity, and expression of downstream fibrosis signatures positively correlated with disease severity. These results uncover AP-1 as a critical signaling hub governing lung fibroblast ECM deposition that can potentially be exploited to improve disease outcomes.

cell biology↗

bioRxiv2026

Large-scale functional coupling and computational modelling reveal frontotemporal hotspots in distributed network connectivity during working memory recognition, encoding, and retrieval

Working memory depends on coordinated activity across distributed brain networks, but how these interactions support recognition, encoding, and retrieval remains unclear. Here, we analyzed intracranial local field potentials from 1,652 sites in 36 epilepsy patients performing a naturalistic card-matching task. Phase-amplitude and phase-phase coupling revealed widespread condition-dependent interactions, with frontal and temporal regions emerging as recurrent network hubs. Event-related analyses showed reproducible within-trial coupling dynamics across participants. Directed phase transfer entropy further identified frequency-specific information flow, including frontal regions acting as a theta-band source and an alpha-band sink. Finally, a time-delay-embedded hidden Markov model identified task-locked latent states with condition-dependent occupancy trajectories and distinct coherence profiles. Together, these results suggest that working memory is implemented through dynamic, directionally organized large-scale networks, in which frontotemporal hubs coordinate flexible transitions among distributed neural states rather than operating in isolation.

neuroscience↗

bioRxiv2026

A human intracranial map of consciousness returning from anesthesia

How consciousness arises from the brain remains a central yet unsolved question. Although substantial effort has been devoted to characterizing the neural correlates of conscious perception during wakefulness, how consciousness re-emerges from unconscious states remains poorly understood. Here, we took advantage of the rare opportunity to record human intracranial local field potentials from propofol-induced general anesthesia through the transition to behavioral engagement and subsequent full wakefulness, capturing both the stable states of unconsciousness and consciousness and the reconstituting neural dynamics that bridge them. Anesthesia cannot be defined by any single electrophysiological signature; rather, it is an organized low-frequency regime characterized by a constellation of coordinated neural phenomena, including aperiodic slow waves, alpha/beta periodicity, global alpha synchronization, and slow-wave-alpha/beta phase-amplitude coupling. Following anesthetic cessation, this regime progressively dissolved as neural excitability and dynamical complexity climbed. The appearance of conscious behavior coincided with a fast and dramatic transformation in high-gamma activity, from stochastic and unpredictable bursts to structured responses that were distributed, task-selective, and event-locked. These findings suggest that the recovery of consciousness is a multiscale reorganization in which distinct neural underpinnings rise and fall. Together, this work charts an electrophysiological map of how conscious cognition is extinguished, reconfigured, and restored in the human brain.

neuroscience↗

bioRxiv2026

Multitrophic interaction networks mediate biodiversity effects on ecosystem multifunctionality

Biodiversity loss threatens the multifunctionality of ecosystems on which human well-being ultimately depends. Changes in multitrophic species interactions may be key to explaining the ecological consequences of biodiversity loss, but research explicitly linking species interactions and ecosystem multifunctionality remains rare. To assess interaction-mediated biodiversity effects and underlying mechanisms, characterizing the structure of species interaction networks is invaluable. Using comprehensive species interaction and ecosystem functioning data from a large-scale tree biodiversity experiment, we find consistent effects of the structure of species interaction networks on ecosystem multifunctionality across multiple types of antagonistic and mutualistic interactions. While positive effects of network size align with expected positive effects of multitrophic species diversity, positive effects of niche overlap among interacting species and negative effects of highly connected species (i.e. high linkage density) reveal additional, interaction-mediated drivers of multifunctionality. Specifically, the effects of niche overlap suggest benefits of functionally similar species, and the effects of linkage density underscore the importance of specialized interactions in promoting ecosystem multifunctionality. These findings emphasize that to effectively safeguard ecosystem service provisioning, ecosystem management and biodiversity conservation not only need to account for biodiversity changes at multiple trophic levels, but also explicitly for how species interact among each other.

ecology↗

bioRxiv2026

Cavity-nesting bees combine forest nesting habitats with surrounding floral resources in a subtropical forest diversity experiment

Wild bees face declines, and forests may serve as critical habitats for pollinators. However, how forest composition and the associated floral environment shape pollen provisioning and resource partitioning among cavity-nesting bees remains poorly understood. Here, we leveraged BEF-China, a large-scale subtropical forest biodiversity experiment with experimentally controlled plant (tree and shrub) communities, to investigate how forest composition and spatial context shape pollen provisioning, resource partitioning, and reproductive success of cavity-nesting bees. We used DNA metabarcoding to analyze floral composition of pollen provisioned by five cavity-nesting bee species, with samples collected from BEF-China across three years (2022- 2024). By comparing pollen taxonomic composition from whole-nest pooled samples and individual brood-cell samples with the experimentally planted species pool, we characterized dietary patterns and temporal dynamics of five bee species. Bees primarily relied on floral resources from the surrounding landscape, with planted trees providing essential but temporally restricted pollen supplements during specific phenological stages. Co-occurring bee species exhibited staggered nesting phenology and distinct dietary preferences for different plant families, with fine-scale resource differentiation even during periods of phenological overlap. Our results suggest that managed forests support cavity-nesting bees by providing critical woody floral resources during specific phenological gaps and offering stable nesting environments. To mitigate pollinator declines, forest management should prioritize maintaining diverse, phenologically complementary flowering vegetation within and surrounding forest stands. This ensures temporal continuity of pollen availability throughout the nesting season, which is particularly crucial for restoring pollinator services in simplified forest landscapes.

ecology↗

bioRxiv2026

Moisture reduces saproxylic bee, wasp, and parasitoid diversity in lying and standing deadwood

Saproxylic insect community assembly is structured by deadwood and forest habitat gradients, as well as biotic interactions such as competition, predation, and parasitism. However, co-variation between abiotic and biotic conditions limits our ability to disentangle their contributions. Furthermore, a focus on beetles in temperate and boreal forests has left important taxonomic and geographic knowledge gaps. Here, we tested how experimentally manipulated tree diversity, deadwood position (lying vs. standing), and biotic interactions with a dominant antagonist (ant exclusion) structure communities of deadwood-cavity-nesting bees, wasps, and their parasitoids in a subtropical forest. Lying deadwood supported less diverse and abundant communities than standing deadwood while retaining approximately twice as much moisture. Moreover, host emergence declined along moisture gradients within each deadwood type. Together, these patterns identify substrate moisture as an important factor limiting bee and wasp communities nesting in deadwood - reflecting reduced brood production, survival, or both - and as a candidate driver for their positive association with standing deadwood in forests. By contrast, neither ant exclusion nor observed ant occurrence was associated with host or parasitoid responses. Because standing deadwood is typically scarce in managed forests, our findings support retaining or creating standing deadwood structures alongside lying deadwood and, more broadly, promoting dry and elevated nesting substrates for cavity-nesting bees and wasps in conservation and restoration measures.

ecology↗

bioRxiv2025

The Dishevelled C-terminus interacts with the centrosomal protein Kizuna to regulate microtubule organization during ciliogenesis.

Microtubules (MTs) serve as dynamic scaffolds that support diverse cellular processes, including cell division, intracellular transport, and epithelial morphogenesis. In ciliated cells, MTs not only form the axonemal backbone of cilia but also work in tandem with actin to build an apical meshwork that anchors and orients basal bodies. However, the mechanisms regulating apical MT organization during ciliogenesis remain poorly understood. Here, we identify the centrosomal protein Kizuna (Kiz) as a critical regulator of apical MT architecture. Kiz interacts with the C-terminus of Dishevelled 2 (Dvl-C), inducing an open conformation and enabling the recruitment of Protein Kinase C delta (PKC{delta}) to stabilize the apical MT meshwork. This Dvl2-Kiz-PKC{delta} signaling axis is essential for ciliogenesis across multiple contexts, including the formation of primary cilia in the eye, multicilia in the mucociliary epidermis (MCE), and mono-motile cilia in the left-right organizer, the gastrocoel roof plate (GRP). These findings reveal a conserved molecular mechanism linking Dvl2 conformational dynamics to MT organization and highlight Kizuna as a key mediator coupling non-canonical Wnt signaling to ciliogenesis, left-right patterning, and the organization of the apical actin microtubule meshwork in ciliated cells of embryos.

developmental biology↗

bioRxiv2025

A Phage Ejectosome Protein Moonlights to Inhibit CBASS Anti-Viral Defense System

A family of prokaryotic antiviral systems collectively known as the cyclic oligonucleotide-based signaling system (CBASS) is found in many bacterial species. Phage defense in CBASS is mediated by the action of a specific effector activated by the cognate cyclic oligonucleotide, often resulting in abortive infection. In the prototypical Type II-A CBASS, phage defense is initiated by the production of cyclic GMP-AMP (cGAMP) by enzymes known as cGAS/DncV-like nucleotidyltransferases (CD-NTases) within the bacterial host, and subsequent activation of the CapV phospholipase by cGAMP leads to cell lysis, thereby limiting phage replication within the host population. Phage proteins that degrade cGAMP, sequester cGAMP, or prevent cGAMP synthesis have been identified in phages to evade CBASS protection. However, some phages are resistant to CBASS protection despite not encoding these proteins, suggesting that additional counter-defense mechanisms exist. To identify new anti-CBASS mechanisms in phages, we exploited bacterial host sensitivity to the antimicrobial compound sulfamethoxazole (SMX) as an indirect read-out for CBASS activity. Bacteria with active CBASS are more sensitive to SMX; therefore, we postulated that any viral proteins produced inside the bacterial host that target CBASS could increase bacterial SMX resistance. Using this screen, we identified that the Gp15 protein from the vibriophage ICP3 increases SMX resistance in Vibrio cholerae El Tor biotype that encodes an active CBASS. Gp15 is an essential virion protein involved in DNA ejection and conserved in many phages. Expression of Gp15 of another coliphage increases SMX resistance in Escherichia coli expressing an active CBASS, and it allows CBASS-sensitive phage to infect the bacterial host with CBASS, demonstrating an important role of Gp15 in phage defense evasion. Unlike other known anti-CBASS proteins, Gp15 does not degrade or sequester cGAMP, and it does not reduce the cellular level of cGAMP. Gp15 also does not interfere with CapV binding to cGAMP. Instead, Gp15 directly inhibits cGAMP-activated CapV serine hydrolase activity in a stoichiometric manner. Together, our study reveals a new mechanism for CBASS antagonism, in which a phage DNA ejection protein moonlights to inhibit a CBASS effector, thereby evading anti-phage defense.

microbiology↗

bioRxiv2025

Tissue transcriptomics of endomyocardial biopsies reveals widespread molecular perturbations independent of leukocyte-rich foci in human myocarditis

BackgroundMyocarditis is an inflammatory disease of the myocardium, classically defined and graded by histologic criteria that emphasize immune infiltrates and focal cardiomyocyte injury. The broader transcriptional landscape and intercellular signaling networks underlying human myocarditis, particularly among non-immune cells, remain poorly understood. MethodsWe performed integrated spatial transcriptomic profiling of 38 endomyocardial biopsy (EMBx) specimens using two complementary platforms: 10X Visium FFPE and GeoMx Digital Spatial Profiling (DSP). The cohort included cases of histologically confirmed myocarditis, borderline myocarditis, and controls. For 10X Visium, data was refined by excluding leukocyte-enriched spots and enriching for cardiomyocyte-specific regions based on canonical marker expression. For GeoMx, immunohistochemistry-guided segmentation enabled targeted transcriptomic analysis of disparate cardiac cellular compartments. Differential gene expression was analyzed independently for each platform and subsequently integrated. These results were further leveraged to infer molecular interaction networks and ligand-receptor relationships in myocarditis relative to controls. ResultsBoth platforms revealed widespread gene expression changes consistent with immune activation in myocarditis and borderline myocarditis, particularly within cardiomyocyte-enriched regions. These included upregulation of HLA-A, HLA-DQA1, B2M, and CD74 in myocarditis, consistent with activation of major histocompatibility complex (MHC) class I and II related pathways. Molecular interaction analysis identified STAT1 and ISG15 as likely central immune signaling nodes. Ligand-receptor inference highlighted HLA-A, HLA-E, and HLA-DQA1 as key receptor hubs interacting with immune ligands such as IFNG, CD8A, and several members of the (NK) killer-cell immunoglobulin-like receptor (KIR) family. ConclusionsOur findings demonstrate that human myocarditis is characterized by widespread transcriptional dysregulation beyond immune cell foci, including upregulation of genes typically associated with professional antigen-presenting cells in cardiomyocytes. These insights extend our current understanding of myocarditis pathophysiology and suggest new opportunities for its diagnosis and therapeutic targeting.

immunology↗

bioRxiv2025

GPX4 Promotes Optic Nerve Regeneration and RGC Neuroprotection

Preventing retinal ganglion cells (RGCs)s soma and axon degeneration and promoting optic nerve (ON) regeneration holds great promise for effective glaucoma treatment. To explore potential neural repair strategies, we focused on glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation. GPX4 is upregulated in surviving RGCs after acute ON crush or chronic ocular hypertension insult, and also in regenerating RGCs. AAV-mediated RGC-specific overexpression of GPX4 promotes significant ON regeneration and RGC survival, along with visual functional preservation, demonstrating the detrimental role of lipid peroxidation in glaucoma and the therapeutic potential of modulating lipid peroxidation through GPX4 in optic neuropathies.

neuroscience↗

bioRxiv2025

Genetic correlation-guided mega-analysis of DO mice provides mechanistic insight and candidate genes for age-related pathologies

Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analysis in DO mice, fewer techniques have been implemented to facilitate integrated, cross-study analysis. Here, we implement Haseman-Elston regression to estimate genetic correlations among 7,233 phenotypes measured across eleven independent DO mouse studies. We used this network of genetic correlations to cluster phenotypes according to shared genetics, which enhanced the power to detect quantitative trait loci (QTL). This approach empowered the detection of 884 QTL for 383 meta-phenotypes, explaining an average of 40.36% of the total genetic variance per mega-analysis. We leveraged this network for insights into specific areas of biology, including lifespan, frailty, immune composition, histological and functional lung phenotypes, and histological phenotypes of the aorta. We found the genetics of lifespan to share limited correlation with the genetics of frailty but stronger correlation with the genetics of immune cell composition. Additionally, mega-analyses driven by genetic correlations identified candidate genes (e.g. Cdkn2b) associated with degraded extracellular matrix in the aorta. Finally, an ensemble of genetic analyses implicated pulmonary neuroendocrine cell signaling and/or differentiation as a key driver of multiple lung pathophenotypes.

genetics↗

bioRxiv2025

An Eocene Origin of Passerine Birds Estimated Using Bayesian Tip Dating with Fossil Occurrences

Passerine birds are among the most diverse and species-rich groups of vertebrates, but the timescale of their evolution has been difficult to resolve with confidence. The fossil record of early passerines is relatively sparse and molecular-clock estimates of the passerine crown age have varied widely, with most previous studies relying on external fossil calibrations or assumptions relating to Gondwanan vicariance. In this study, we estimated the passerine evolutionary timescale by incorporating a set of 43 passerine fossils selected through a detailed assessment, while using a Bayesian tip-dating approach with the unresolved fossilized birth-death process. Our analyses ultimately place the passerine crown age in the Eocene, which largely closes the gap between molecular and palaeontological estimates of the passerine evolutionary timescale. Our date estimates are somewhat influenced by the prior probability density for the starting time of the diversification process. Through a simulation study, we show that the effect of the starting-time prior can be attenuated by the inclusion of morphological data for fossil and extant taxa. Overall, our study demonstrates that incorporating a curated, comprehensive set of fossils is effective in producing a well-resolved estimate of the passerine evolutionary timescale, while highlighting potential avenues for refining this estimate using Bayesian tip-dating analyses.

evolutionary biology↗

bioRxiv2025

Binomial order is a speech marker of psychosis and thought disorder

Thought disorder, characterized by disruptions in syntactic and semantic elements in language, is a core symptom of psychotic disorders. Understanding this language impairment is key to uncovering the underlying neuropathology and predicting treatment outcomes for individuals with schizophrenia and other psychotic disorders. Binomial ordering preferences (e.g. "salt and pepper" instead of "pepper and salt"), may be a quantifiable correlate of thought disorder and underlying linguistic impairments. We tested whether atypical binomial ordering can serve as a linguistic marker for psychosis symptoms. Participants with early-stage psychotic disorders and controls were recruited, and video-recorded interviews were transcribed for analysis. Identified binomial pairs were assessed using both the Google N-gram database and a logistic regression model to determine ordering preferences. Results showed that while both psychotic participants and controls preferred conventional binomial orderings, participants with psychotic disorders exhibited a higher rate of atypical binomial orderings. The use of atypical orderings was correlated with thought disorder, but not with other psychiatric symptoms or medications. Tracking binomial ordering can be a valuable marker of thought disorder but future studies are needed to determine whether this link remains stable or if it changes with disease progression.

neuroscience↗

bioRxiv2024

Crosslinking-mediated Interactome Analysis Identified PHD2-HIF1α Interaction Hotspots and the Role of PHD2 in Regulating Protein Neddylation

Prolyl Hydroxylase Domain protein 2 (PHD2) targets Hypoxia Inducible Factor alpha subunits (HIF) for oxygen-dependent proline hydroxylation that leads to subsequent ubiquitination and degradation of HIF. In addition to HIF proteins, growing evidence suggested that PHD2 may exert its multifaceted function through hydroxylase-dependent or independent activities. Given the critical role of PHD2 in diverse biological processes, it is important to comprehensively identify potential PHD2 interacting proteins. In this study, we engineered HeLa cells that stably express HTBH-tagged PHD2 to facilitate the identification of PHD2 interactome. Using DSSO-based cross-linking mass spectrometry (XL-MS) technology and LC-MSn analysis, we mapped PHD2-HIF1 interaction hotspots and identified over 300 PHD2 interacting proteins. Furthermore, we validated the COP9 Signalosome (CSN) complex, a major deneddylase complex, as a novel PHD2 interactor. DMOG treatment promoted interaction between PHD2 and CSN complex and enhanced the deneddylase activity of the CSN complex, resulting in increased level of free Cullin and reduced target protein ubiquitination. This mechanism may serve as a negative feedback regulation of the HIF transcription pathway.

biochemistry↗

bioRxiv2024

Multi-dimensionality of tree communities structure host-parasitoid networks and their phylogenetic composition

Environmental factors can influence ecological networks, but these effects are poorly understood in the realm of the phylogeny of host-parasitoid interactions. Especially, we lack a comprehensive understanding of the ways that biotic factors, including plant species richness, overall community phylogenetic and functional composition of consumers, and abiotic factors such as microclimate, determining host-parasitoid network structure and host-parasitoid community dynamics. To address this, we leveraged a five-year dataset of trap-nesting bees and wasps and their parasitoids collected in a highly-controlled, large-scale subtropical tree biodiversity experiment. We tested for effects of tree species richness, tree phylogenetic and functional diversity, and species and phylogenetic composition on species and phylogenetic diversity of both host and parasitoid communities and the composition of their interaction networks. We show that multiple components of tree diversity and canopy cover impacted both, species and phylogenetic composition of hosts and parasitoids. Generally, phylogenetic associations between hosts and parasitoids reflected non-randomly structured interactions between phylogenetic trees of hosts and parasitoids. Further, host-parasitoid network structure was influenced by tree species richness, tree phylogenetic diversity, and canopy cover. Our study indicates that the composition of higher trophic levels and corresponding interaction networks are determined by plant diversity and canopy cover especially via trophic links in species-rich ecosystems.

ecology↗

bioRxiv2024

Cardiaca adipokinetic hormone and hedgehog signaling combine to generate intracellular waves of Ca++ in starved Drosophila melanogaster fat body

The Drosophila melanogaster fat body combines the functions of the vertebrate liver and fat. It plays a central role in metabolism where it integrates information about nutritional status to regulate fat utilization. During feeding, signaling through the Insulin Receptor causes lipogenesis, while fasting leads to signaling through the cardiaca Adipokinetic Hormone Receptor (AKHR) and mobilization of lipid stores. Here we examine intracellular calcium levels in the fat body during fasting. In fasting early third instar larvae, spikes of intracellular calcium are generated in the fat body lobes on either side of the brain. These spikes propagate through a narrow connection into the main lobes of the fat body that lie along the length of the larva. The spikes of intracellular Ca++ are dependent on the corpora cardiaca AKH expressing neurons and AKHR. Unexpectedly, the spikes also require Hedgehog (Hh) signaling from the midgut enterocytes and within the fat body. When Hh signaling is blocked, the Ca++ levels in the fat body are elevated and the spiking behavior lost. Hh signaling appears to regulate fat body intracellular Ca++ using both the transcription factor Cubitus interruptus and the trimeric G protein Gi. AKH/Hh signaling in the fat body lobes on either side of the brain appears to function as a pulse generator to initiate Ca++ spikes that then propagate through the main lobes of the fat body. These studies show how signaling from the brain and the midgut and within the fat body are integrated to regulate a key intracellular second messenger.

physiology↗

bioRxiv2023

XCP-D: A Robust Pipeline for the post-processing of fMRI data

Functional neuroimaging is an essential tool for neuroscience research. Pre-processing pipelines produce standardized, minimally pre-processed data to support a range of potential analyses. However, post-processing is not similarly standardized. While several options for post-processing exist, they tend not to support output from disparate pre-processing pipelines, may have limited documentation, and may not follow BIDS best practices. Here we present XCP-D, which presents a solution to these issues. XCP-D is a collaborative effort between PennLINC at the University of Pennsylvania and the DCAN lab at the University at Minnesota. XCP-D uses an open development model on GitHub and incorporates continuous integration testing; it is distributed as a Docker container or Singularity image. XCP-D generates denoised BOLD images and functional derivatives from resting-state data in either NifTI or CIFTI files, following pre-processing with fMRIPrep, HCP, and ABCD-BIDS pipelines. Even prior to its official release, XCP-D has been downloaded >3,000 times from DockerHub. Together, XCP-D facilitates robust, scalable, and reproducible post-processing of fMRI data.

neuroscience↗

bioRxiv2023

A general exposome factor explains individual differences in functional brain network topography and cognition in youth

Our minds and brains are highly unique. Despite the long-recognized importance of the environment in shaping individual differences in cognitive neurodevelopment, only with the combination of deep phenotyping approaches and the availability of large-scale datasets have we been able to more comprehensively characterize the many inter-connected features of an individuals environment and experience ("exposome"). Moreover, despite clear evidence that brain organization is highly individualized, most neuroimaging studies still rely on group atlases to define functional networks, smearing away inter-individual variation in the spatial layout of functional networks across the cortex ("functional topography"). Here, we leverage the largest longitudinal study of brain and behavior development in the United States to investigate how an individuals exposome may contribute to functional brain network organization leading to differences in cognitive functioning. To do so, we apply three previously-validated data driven computational models to characterize an individuals multidimensional exposome, define individual-specific maps of functional brain networks, and measure cognitive functioning across broad domains. In pre-registered analyses replicated across matched discovery (n=5,139, 48.5% female) and replication (n=5,137, 47.1% female) samples, we find that a childs exposome is associated with multiple domains of cognitive functioning both at baseline assessment and two years later - over and above associations with baseline cognition. Cross-validated ridge regression models reveal that the exposome is reflected in childrens unique patterns of functional topography. Finally, we uncover both shared and unique contributions of the exposome and functional topography to cognitive abilities, finding that models trained on a single variable capturing a childs exposome can more accurately and parsimoniously predict future cognitive performance than models trained on a wealth of personalized neuroimaging data. This study advances our understanding of how childhood environments contribute to unique patterns of functional brain organization and variability in cognitive abilities.

neuroscience↗