Biology subjects

Hao, C.

Publications and source records attributed to Hao, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Growth rate structures the dynamics of bacterial trait evolution

Bacterial species span orders of magnitude in growth rate, yet how its evolution is embedded within the broader evolutionary dynamics of other bacterial traits remains poorly understood. We integrated experimentally measured growth rates for 283 bacterial species with 11 genomic, metabolic, ecological and environmental traits, and used multivariate Ornstein-Uhlenbeck models to characterize how growth rate and associated traits coevolve across evolutionary time. Growth rate was best explained by models assuming distinct slow- and fast-growing evolutionary regimes, and evolved toward adaptive optima more rapidly than any other trait examined over longer evolutionary timescales, both when modelled independently and jointly with other traits. Coevolution between growth rate and associated traits was primarily structured by growth-rate regimes, suggesting growth rate serves as a pacemaker of evolution. At instantaneous timescales, six of the eight traits coevolving with growth rate showed unidirectional coupling, including all four environmental traits, with the direction varying among traits. In contrast, ribosomal RNA operon copy number and GC percentage exhibited reciprocal coupling with growth rate. These findings recast bacterial growth strategy from a correlate of trait variation to a major organizing axis shaping bacterial trait evolution across distinct evolutionary timescales.

evolutionary biology↗

bioRxiv2026

Incorporation of single-neuron projectome-based connectivity motifs enhances the cortex-specific performance of artificial neural networks

The organizational principles of natural neural networks could inspire the new architecture design of artificial neural networks (ANNs). Analysis of single-neuron connectomes of mouse brains revealed distinct profiles of three-node connectivity motifs in various cortical areas and hippocampal formation. A connectome-informed neural network algorithm ("CINA") was developed to incorporate natural connectivity motifs into ANN algorithms represented by recurrent neural network (RNN) and transformer-based large language model (LLM). We found that incorporation of the average profile of cortical motifs improved the RNNs performance in noise-resistant categorization and motor learning benchmark tasks, as compared with RNNs with random connectivity. Notably, incorporating cortex-specific motifs further elevated the RNNs performance in tasks related to the cortical function, and this effect was enhanced by artificially increasing the bias in the motif profile. Similar experimental results were verified on an LLM using Motif-Transformer for natural language question answering and brain-signal decoding tasks. Graph-theoretic analyses showed that incorporating natural motifs drove the emergence of modular and small-world properties in ANNs. Together, we demonstrated not only connectome-inspired optimization of ANN architecture but also functional significance of specific motif profiles in various cortices.

neuroscience↗

bioRxiv2026

DigiMus: a connectome-informed spiking framework for multi-region mouse neural-behavior modeling

Computational models are increasingly used to relate mouse brain structure, neural activity and behavior, but most models still learn from task data with limited constraints from biological circuit organization. Here we present DigiMus, a connectome-informed spiking framework for multi-region-capable mouse neural-behavior modeling. DigiMus combines leaky integrate-and-fire spiking dynamics with brain-region-specific motif regularization in a trainable sequence-modeling architecture, allowing directed three-node circuit motifs derived from 38,481 reconstructed neuronal morphologies across approximately 50 brain regions to guide recurrent coupling during learning. We evaluate DigiMus on 18 rule-based cognitive tasks spanning sensorimotor mapping and perceptual decision-making, and on three mouse neural decoding datasets involving auditory discrimination, fixed-interval licking and visual decoding. Across synthetic tasks, DigiMus showed stable performance relative to TCN, LSTM and Transformer baselines, with stronger advantages in more complex decision-making settings. In real neural datasets, single-region instantiations of DigiMus produced small, consistent and dataset-dependent improvements over a structure-free sequence baseline, while retaining motif-prior signatures in trained connectivity. Internal state analyses further linked task-dependent state dynamics to behavioral error patterns. These results suggest that connectome-derived structural priors can shape neural sequence models, and establish DigiMus as a modular, connectome-informed workflow for mouse neural-behavior modeling and hypothesis generation, rather than a complete digital reconstruction.

neuroscience↗

bioRxiv2026

β-Amyloid and Glutathione Dysregulation Cooperatively Drive Lipid Peroxidation and Ferroptosis in Neuron-Like Cells

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by {beta}-amyloid (A{beta}) accumulation and oxidative stress, with aging being its greatest risk factor. Age-related decline in antioxidant defenses, particularly glutathione (GSH), may increase neuronal vulnerability to A{beta}-mediated toxicity; however, the mechanisms linking redox dysregulation to neuronal death remain incompletely understood. In this study, we investigated how impaired GSH homeostasis influences neuronal susceptibility to A{beta}-associated injury. Human SH-SY5Y neuron-like cells were engineered to express either wild-type APP695 or the familial AD-associated APPSwe/Ind mutant, and intracellular GSH depletion was induced using both pharmacological and genetic approaches. GSH depletion markedly sensitized APPSwe/Ind-expressing cells to cell death, accompanied by increased plasma membrane lipid peroxidation, elevated malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels, and enhanced lactate dehydrogenase (LDH) release. This cell death was not prevented by the pan-caspase inhibitor Z-VAD-FMK but was effectively rescued by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), indicating a ferroptotic mechanism. Similar ferroptotic responses were observed when A{beta} oligomers were combined with intracellular GSH depletion. Mechanistically, A{beta} and GSH depletion synergistically increased transferrin receptor-1 expression and intracellular iron levels while markedly suppressing glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis. Importantly, inhibition of autophagy with bafilomycin A1 restored GPX4 expression and rescued cells from ferroptotic death, suggesting that autophagy-mediated GPX4 degradation contributes to this process. Collectively, our findings demonstrate that GSH dysregulation synergizes with A{beta} to induce lipid peroxidation and ferroptosis in neuron-like cells. These results identify impaired redox homeostasis as a critical driver of neuronal vulnerability in AD and suggest that preserving GSH levels or targeting ferroptotic pathways may offer promising therapeutic strategies for neurodegeneration.

neuroscience↗

bioRxiv2026

A novel TaNF-YC10-TaNF-YB1-TabHLH95 module coordinates starch biosynthesis in wheat endosperm

Wheat grain weight and flour quality largely depend on starch biosynthesis, yet the mechanisms by which transcription factors coordinate this process remain poorly understood. In this study, using an integrative strategy that combines genome-wide association analysis with yeast two-hybrid library screening, we identify TaNF-YC10, a Nuclear Factor Y transcription factor, as a positive regulator of starch accumulation in the wheat endosperm. Loss of TaNF-YC10 reduces starch content and alters starch granule size distribution, whereas overexpression enhances starch accumulation and increases grain weight. TaNF-YC10 binds and activates core starch biosynthetic-related genes, including AGPL1, GBSS1, YUC11, and NF-YB7, and forms higher-order transcriptional complexes with TaNF-YB1 and TabHLH95 to coordinate multiple regulatory pathways. TaNF-YC10-A1-Hap2 is associated with higher starch content and thousand grain weight and has been selected during wheat breeding in China. Collectively, our findings establish TaNF-YC10 as a pivotal transcriptional hub in starch regulation and highlight its potential as a target for genetic improvement of grain yield in wheat.

plant biology↗

bioRxiv2025

Complexes between Netrin G Ligands and Chiral Nanoparticles Promote Axons Regeneration under Near-Infrared Illumination

Chiral nanoparticles combine functionalities of inorganic materials and large biomacromolecules enabling stimulation of neurons. However, multiple challenges remain in their use for central nervous system including identifying suitable cell signaling pathways and traversing the blood-brain barrier. In this study, we show that glutathione-coated Ni(OH)2 nanoparticles form nanoscale complexes with netrin-G1 ligands (NGL-1), critical for neuronal regeneration. NGL-1 features a semispherical pocket with a 2.5 nm radius of curvature, fitting well with nanoparticles sized 3 {+/-} 1.2 nm. D-NPs with D-glutathione surface ligands activate D-glutathione receptors on epithelial cells, facilitating their transport into the brain. When illuminated with 980 nm light, the nanoparticle-protein complex stimulates axon regeneration through localized IGF-1 production. This approach successfully regenerated (a) hippocampal neurons in Alzheimers disease mice and (b) dorsal root ganglion neurons in spinal cord-injured mice. The nanoparticles were thoroughly tested for safety and excreted intact. The local, rather than systemic, IGF-1 upregulation minimizes its side effects.

neuroscience↗

bioRxiv2025

Dominant spinal muscular atrophy linked mutations in the cargo binding domain of BICD2 result in altered interactomes and dynein hyperactivity

Cytoplasmic dynein-1 (dynein) is responsible for the transport of most cellular cargo towards the minus end of microtubules. Dynein activation requires the multi-subunit dynactin complex and an activating cargo adaptor. The adaptors serve to link dynein with cargo and to fully activate the motor. Mutations in one of these activating adaptors, Bicaudal-D2 (BICD2), are associated with a neurodegenerative disease called Spinal Muscular Atrophy with Lower Extremity Predominance (SMALED2). The molecular defect that underlies SMALED2 is largely unknown. In addition to interacting with dynein, BICD2 has also been shown to associate with KIF5B, a plus-end directed microtubule motor. We hypothesized that interactome changes associated with mutant versions of BICD2, and the resulting differences in cargo transport, might underlie the etiology of SMALED2. To test our hypothesis, we first defined the interactome of wild-type BICD2. This led to the identification of known BICD2 interacting proteins in addition to potentially novel cargo such as components of the HOPS complex, a six-subunit complex involved in endo-lysosomal trafficking. We next determined the interactome of three SMALED2 linked mutants in BICD2, two of which reside in the cargo binding domain. Interestingly, all three mutations resulted in BICD2-mediated dynein hyper-activation. Furthermore, all three mutants were associated with interactome changes. One of these mutants, BICD2_R747C, was deficient in binding to HOPS complex components and the nucleoporin RANBP2. In addition, this mutant also resulted in a gain of function interaction with GRAMD1A, a protein localized to the endoplasmic reticulum. This gain of function interaction resulted in mis-localization of GRAMD1A in BICD2_R747C expressing cells. Collectively, our results suggest that dynein hyperactivity, interactome changes, and cargo transport defects might contribute to the symptoms associated with SMALED2.

cell biology↗

bioRxiv2025

Synergistic Antitumor Activity of SUMO1 degrader and Oxaliplatin through G6PD Inhibition in Colorectal Cancer

Colorectal cancer (CRC) stands as one of the primary causes of death despite advancements in targeted therapies and chemotherapeutic methods. The oxaliplatin-based chemotherapy, such as the FOLFOX, remains limited by its toxic side effects and the development of drug resistance. The current studies demonstrate redox homeostasis as an important therapeutic target in cancer cells through the discovery of glucose-6-phosphate dehydrogenase (G6PD) as their major controller of oxidative stress and survival. In this study, we investigated the therapeutic potential of HB007 in combination with FOLFOX in CRC. Treatment with HB007 decreased the enzyme activity of G6PD and generated high ROS concentrations, which subsequently induced intrinsic apoptosis. When combined with FOLFOX, which also induces ROS and inhibits G6PD activity, HB007 showed synergistic cytotoxicity in vitro, in colon patient-derived 3D organoids, and in vivo patient-derived xenograft model, including FOLFOX-resistant tumors. The combination treatment mechanistically targeted G6PD activity, disrupted redox balance, and activated apoptosis without affecting G6PD protein level. These findings suggest that G6PD inhibition by HB007 enhances the efficacy of FOLFOX, suggesting a strategy to overcome chemoresistance and improve therapy in advanced CRC.

cancer biology↗

bioRxiv2025

Revealing Multidimensional Associations in Life History Traits Across Four Animal Taxa

Life-history traits jointly determine survival, growth, and reproduction, yet their evolutionary interdependence remains poorly understood. Most comparative studies focus on pairwise trade-offs or composite axes, overlooking the complexity of multivariate coevolution. Here, we integrate phylogenetic path analysis and multivariate Ornstein-Uhlenbeck models to investigate the coevolution of five key life-history traits across amniotes. We show that life-history evolution proceeds through modular coevolutionary pathways with distinct tempos among traits and taxa. Despite loading similarly on the fast-slow axis of mammals and birds, clutch size and clutch frequency evolve independently at both instantaneous and long-term timescales, with clutch frequency adapting rapidly, whereas clutch size evolves slowly over macroevolutionary time. Lifespan, development time, and offspring size exhibit positive coevolution at instantaneous scales across clades, but follow distinct adaptive modes with varying directions over longer timescales. These patterns become evident only through the integrated multivariate comparative approaches.

evolutionary biology↗

bioRxiv2025

A Robust Fluorogenic Substrate for Chikungunya Virus Protease (nsP2) Activity

Chikungunya virus (CHIKV) is an emerging pathogen with pandemic potential. CHIKV infection in humans is transmitted by mosquitoes and induces common symptoms of high fever, arthralgia and myalgia. Because no specific antiviral drugs for treatment of CHIKV infection are available, drug development remains a central goal. The chikungunya virus protease nsP2 (CHIKVP) has emerged as a key drug target due to its indispensable role in viral replication via cleavage of the viral polyprotein. To date, effective tools for screening for CHIKVP inhibitors that reflect the most critical polyprotein cleavage sites have been lacking, hampering drug-development efforts. We found that the recognition ability of CHIKVP is sensitive to the length of peptide substrates. In this study, we report a robust fluorogenic substrate comprising a 15-mer peptide derived from the nsP3/4 junction from the CHIKV polyprotein. This peptide is flanked by an ACC-Lys(dnp) donor-quencher pair. Our new substrate acc-CHIK15-dnp shows a 20-fold improved signal-to-noise ratio as compared to the previously reported edab8 substrate, which is also based on the nsP3/4 junction. We found acc-CHIK15-dnp is recognized only by CHIKVP but not by other alphavirus proteases. This is surprising due to the high level of sequence conservation in the alpha virus polyprotein junctions and indicates that the P-side residues are more important than the P-side sequence for effective CHIKVP cleavage. The robust signal-to-noise ratio obtained using acc-CHIK15-dnp derived from the nsP3/4 cleavage site enabled much improved small molecule HTS on CHIKV relative to other fluorogenic reporters.

biochemistry↗

bioRxiv2024

Cooperation shapes bacterial niche breadth evolution and patterns of diversification

Bacteria exhibit varying niche breadths, with generalists thriving in diverse environments and specialists confined to specific habitats. This variability reflects the adaptability of bacteria to their environment and may influence their speciation and extinction rates. We used phylogenetic causal inference and diversification analysis techniques to investigate the influence of cooperation on bacterial niche breadth evolution and patterns of diversification across 25,785 species. We found: (1) a positive correlation between the proportion of genes for cooperation and niche breadth; (2) a decreased proportion of genes for cooperation promotes niche contraction; and (3) species with a higher proportion of genes for cooperation show increased speciation and extinction rates when their niche breadths are narrower. Our study highlights the role of genes for cooperation in shaping both niche breadth and diversification of bacteria, underscoring their critical function in maintaining the ecological versatility and diversity of bacteria.

evolutionary biology↗

bioRxiv2023

Small-molecule degraders reduce Aβ production through CAPRIN1-mediated lysosomal degradation of APP in Alzheimer iPSC-derived neurons

Overexpression of amyloid precursor protein (APP) is a key driver of amyloid {beta} (A{beta}) pathology, making APP a compelling therapeutic target in Alzheimers disease (AD). Here, we identify small molecules that selectively degrade APP in human neurons through a targeted protein degradation approach. Structural analyses reveal that these compounds act as molecular glues, binding at the interface between cytoplasmic activation/proliferation-associate protein 1 (CAPRIN1) and APP and stabilizing their interaction within a ternary complex. In neurons derived from induced pluripotent stem cells (iPSCs) from sporadic and familial AD patients, these compounds promote CAPRIN1-dependent degradation of both wild-type and mutant APP through the endo-lysosomal pathway. The lead compound, 0152, is blood-brain barrier permeable, and its administration significantly reduces A{beta} production and amyloid burden in the brains of 5xFAD mice. These findings demonstrate that molecular glue degraders harness the CAPRIN1-dependent lysosomal pathway for selective APP degradation, offering a targeted therapeutic strategy for AD.

neuroscience↗

bioRxiv2023

Artificial intelligence-assisted stimulated Raman molecular cytology enables accurate and rapid intraoperative assessment of the surgical margin in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly mortal cancer whose only potentially curative treatment is surgical resection. Intraoperative assessment of its surgical margins is vital for patient survival. Frozen-section biopsy is routinely performed for this purpose. However, its high dependence on pathologists experience frequently poses diagnostic discrepancies. The essential invasiveness of PDAC also causes sampling errors. This study developed an intelligent molecular cytology approach with improved diagnostic objectivity and broader sampling coverage. Our method, Multi-Instance Cytology with Learned Raman Embedding (MICLEAR), is characterized by compositional information provided by label-free Raman imaging. First, 4085 cells were brushed off from the pancreases of 41 patients and imaged using stimulated Raman scattering microscopy. Then, a contrastive learning-based cell embedding model was developed to compress each cells morphological and compositional information into a compact cell vector. Finally, a multi-instance learning-based diagnosis model using cell vectors was employed to predict the likelihood of a patients margin being positive. MICLEAR achieved 80% sensitivity, 94.1% specificity, and an AUC of 0.86 on 27 patients for validation, comprising 10 with positive margins and 17 with negative ones, within approximately 8 minutes per patient. It may hold promises for more efficient and accurate intraoperative assessment of PDAC surgical margins.

biophysics↗

bioRxiv2023

SOCfinder: a genomic tool for identifying cooperative genes in bacteria

Bacteria cooperate by working collaboratively to defend their colonies, share nutrients, and resist antibiotics. Nevertheless, our understanding of these remarkable behaviours primarily comes from studying a few well-characterized species. Consequently, there is a significant gap in our understanding of microbial cooperation, particularly in natural environments. To address this gap, we can use bioinformatic tools to identify cooperative traits and their underlying genes across diverse species. Existing tools address this challenge through two approaches. One approach is to identify genes that encode extracellular proteins, which can provide benefits to neighbouring cells. An alternative approach is to predict gene function using annotation tools. However, these tools have several limitations. Not all extracellular proteins are cooperative, and not all cooperative behaviours are controlled by extracellular proteins. Furthermore, existing functional annotation methods frequently miss known cooperative genes. Here, we introduce SOCfinder as a new tool to find cooperative genes in bacterial genomes. SOCfinder combines information from several methods, considering if a gene is likely to (1) code for an extracellular protein, (2) have a cooperative functional annotation, or (3) be part of the biosynthesis of a cooperative secondary metabolite. We use data on two extensively-studied species (P. aeruginosa & B. subtilis) to show that SOCfinder is better at finding known cooperative genes than existing tools. We also use theory from population genetics to identify a signature of kin selection in SOCfinder cooperative genes, which is lacking in genes identified by existing tools. SOCfinder opens up a number of exciting directions for future research, and is available to download from https://github.com/lauriebelch/SOCfinder. Data SummaryAll code and associated files are available at https://github.com/lauriebelch/SOCfinder. Impact StatementBacteria cooperate by secreting many molecules outside the cell, where they can provide benefits to other cells. While we know much about how bacteria cooperate in the lab, we know much less about bacterial cooperation in nature. Is cooperation equally important in all species? Are all cooperations equally vulnerable to cheating? To answer these questions, we need a way of identifying cooperative genes across a wide range of genomes. Here, we provide such a method - which we name SOCfinder. SOCfinder allows users to find cooperative genes in any bacterial genome. SOCfinder opens up a number of exciting directions for future research. It will allow detailed studies of non-model species, as well as broad comparative studies across species. These studies will allow cooperation in the wild to be studied in new ways.

evolutionary biology↗

bioRxiv2023

Design of SARS-CoV-2 protease inhibitors with improved affinity and reduced sensitivity to mutations

Inhibitors of the SARS-CoV-2 main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function on these mutants are thus urgently needed. We hypothesized that the covalent HCV protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more tightly than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to NTV. A crucial feature of ML2006a4 is a novel derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Finally, ML2006a4 is less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory drug design can preemptively address potential resistance mechanisms.

microbiology↗

bioRxiv2022

Signatures of kin selection in a natural population of the bacteria Bacillus subtilis

Laboratory experiments have suggested that bacteria perform a range of cooperative behaviours, which are favoured because they are directed towards relatives (kin selection). However, there is a lack of evidence for cooperation and kin selection in natural bacterial populations. Molecular population genetics offers a promising method to study natural populations, because theory predicts that kin selection will lead to relaxed selection, which will result in increased polymorphism and divergence at cooperative genes. Examining a natural population of Bacillus subtilis, we found consistent evidence that putatively cooperative traits have higher polymorphism and greater divergence than putatively private traits expressed at the same rate. In addition, we were able to eliminate alternative explanations for these patterns, and found more deleterious mutations in genes controlling putatively cooperative traits. Overall, our results suggest cooperation favoured by kin selection, with an average relatedness of r=0.77 between interacting individuals.

evolutionary biology↗

bioRxiv2022

Myostatin gene deletion alters gut microbiota stimulating fast-twitch glycolytic muscle growth

The host genome may influence the composition of the intestinal microbiota, and intestinal microbiota performs an important role in muscle growth and development. Here, we showed that Myostatin (MSTN), a key factor for muscle growth, deletion alters muscularis, plica, and intestinal barrier in pigs. Mice transplanted with MSTN-/- pig intestinal flora showed increase in the cross-sectional area of myofibers and fast-twitch glycolytic muscle mass. The microbes responsible for the production of short chain fatty acids (SCFAs) were enriched in both MSTN-/- pigs and recipient mice, and SCFAs levels were elevated in the colon contents. We demonstrated that valeric acid can stimulate type IIb myofiber growth by activation of the Akt/mTOR pathway via GPR43 and improve muscle atrophy induced by dexamethasone. This is the first study to identify the MSTN gene-gut microbiota-SCFA axis and its regulatory role in fast-twitch glycolytic muscle growth.

microbiology↗

bioRxiv2022

Tissue fibroblasts are a critical source of prostacyclin and anti-thrombotic

Prostacyclin is one of the bodies fundamental signalling pathways. It has long been considered principally anti-thrombotic hormone derived from the vascular endothelium. The role of non-vascular sources in prostacyclin synthesis has not been systematically evaluated, however, due to a lack of tools resulting in an underappreciation of its role in other contexts. Here we used cellspecific knockout mice and human tissues to show that lung, and other tissues, are powerful producers of prostacyclin independent of their vascular components. Instead, in mice and humans, lung prostacyclin synthesis is associated with fibroblasts. The fibroblast-derived prostaglandins enter the circulation and provide systemic anti-thrombotic protection. These observations define a new paradigm in prostacyclin biology in which fibroblast/non-vascular-derived prostacyclin works in parallel with endothelium-derived prostaglandins to control cardiovascular health and potentially a broad range of other biology. These results may explain how local diseases of the lung and elsewhere result in cardiovascular risk.

pharmacology and toxicology↗