Biology subjects

Mu, X.

Publications and source records attributed to Mu, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Inhibition of the Lysosomal Amino Acid Sensor SLC38A9 by the Membrane Microprotein SPAR

Long noncoding RNAs encode for microproteins that regulate cellular functions. Small regulatory peptide of amino acid response (SPAR) is a microprotein in the lysosome that responds to amino acid availability of the cell. In this study, we investigated the interactions between SPAR and SLC38A9, a lysosomal amino acid transporter and receptor involved in the mechanistic target of rapamycin 1 (mTORC1) pathway. We found that SPAR binds SLC38A9 and inhibits arginine transport in SLC38A9. Moreover, the downstream recruitment of Rag GTPases is also inhibited when SPAR is present in SLC38A9 liposomes. Docking model shows potential interactions between SPAR and SLC38A9. Together, these findings reveal the mechanism of mTORC1 inhibition through microprotein SPAR and illustrates the power of non long coding RNAs in altering cellular functions. Statement of SignificanceMicroproteins encoded from long noncoding RNAs are emerging as critical regulators of many pathways. This study investigates a novel mechanism of SPAR microprotein that directly regulates the mechanistic target of rapamycin complex1 (mTORC1) signaling pathway through the lysosomal amino acid transporter SLC38A9. SPAR blocks both arginine transport and the downstream recruitment of Rag GTPases. These findings provide critical results in how SPAR controls cellular amino acid availability, while broadly highlighting the powerful regulatory mechanism of microproteins in cellular processes.

biochemistry↗

bioRxiv2026

Laser-integrated nanophotonic neural probes with on-chip sensors for addressable photostimulation

Studying the role of individual neurons in behavior and disease requires tools for controlling neural activity with high spatiotemporal resolution. Implantable nanophotonic neural probes are capable of delivering targeted photostimulation to enable genetically distinct neurons to be selectively controlled, yet face barriers to achieving scalable emitter densities and lack sensors for monitoring feedback signals relevant to device operation. To address this, we developed laser-integrated nanophotonic neural probes, which feature hybrid-integrated laser diodes (LD) and thermo-optic photonics switches for scalable emitter addressing and on-chip sensors for monitoring optical power and temperature during photo-stimulation. Devices were fabricated at a commercial silicon photonics foundry on 200-mm diameter silicon-on-insulator (SOI) wafers in an active visible-light platform and were controlled using a custom-developed electronic circuit board. Each device features a hybrid-integrated InGaN LD which couples 450-nm light into a reconfigurable photonic switching tree for delivering spatially resolved photostimulation through 16 emitters along a 3-mm implantable shank. Using the on-chip photodetectors, we demonstrate how devices can enable switching tree calibration as well as output power monitoring during photostimulation. Furthermore, using the on-chip temperature sensors, we show how device temperature perturbations resulting from LD and thermo-optic switch activation can be directly monitored during photostimulation to ensure temperature fluctuations remain below 1 {degrees}C. We validate our design by delivering high spatiotemporal photostimulation during an in vivo optogenetic experiment with simultaneous Neuropixels recording to monitor evoked responses. Overall, these scalable integrated devices offer a pathway for neuroscientists to conduct fiberless optogenetic experiments with greater control and precision.

neuroscience↗

bioRxiv2026

The SoxC transcription factors regulate multiple early retinal lineages and function in parallel with Atoh7 to promote retinal ganglion cell genesis

Retinal development is orchestrated by a network of transcription factors that guide multipotent retinal progenitor cells (RPCs) to fate-committed lineages, ultimately producing seven major retinal cell classes. Among these, retinal ganglion cells (RGCs) serve as the sole output neurons of the retina, relaying visual and non-visual information to the brain. RGC specification requires a cascade of transcriptional regulators, including the basic helix-loop-helix (bHLH) factor Atoh7, which confers competence to RPCs, and Pou4f2 and Isl1, which drive terminal differentiation and subtype diversification. Previous studies demonstrate that the SoxC group transcription factors (Sox4, Sox11, and Sox12) are also involved in RGC genesis, but their precise integration into the Atoh7-driven regulatory hierarchy remains undefined. To address this question, we used the retina-specific Vsx2-Cre line to generate Sox4/Sox11 double conditional knockout (dcKO) and Sox4/Sox11/Atoh7 triple knockout (tKO) mice. Immunohistochemistry revealed profound lineage disruption and reduced progenitor proliferation and survival in both dcKO and tKO retinas; not only RGC genesis but also that of horizontal and amacrine (H&As) cells were severely compromised, whereas photoreceptor cells (PHCs) production increased. These results indicate that Sox4 and Sox11 are involved in the coordinated generation of the different early retinal lineages. Like the Atoh7-null retina, RGC precursors still formed in the SoxC dcKO retina, but their genesis was almost completely abolished in the tKO retina. Our findings indicate that the SoxC factors act in parallel with Atoh7 as a major upstream regulatory input to initiate RGC fate. Bulk RNA-seq revealed the SoxC-dependent transcriptional programs and signaling pathways and confirmed the lineage changes demonstrated by marker analysis. CUT&Tag analysis identified the genome-wide binding sites and thereby the target genes of Sox11, further illuminating the mechanisms underlying functions of the SoxC factors in multiple retinal cell states/types during development.

developmental biology↗

bioRxiv2026

EnzCast: Prediction of Patient-Specific Enzymatic Kinetics through Multi-Modal Deep Learning and Isoform-Resolved Bayesian Inference based on Single-Cell Transcriptomics

Enzyme kinetic parameters underpin mechanistic biology but remain sparse in physiological context. We present EnzCast, a multi-modal framework jointly predicting Km, kcat, kcat/Km, and Ki from protein sequence, 3D structure, substrate chemistry, and experimental conditions, paired with IsoKin, an isoform-resolved Bayesian framework converting EnzCast priors into patient-specific in vivo kinetics. Trained on KinBench, the largest curated kinetics database, task-adaptive EnzCast achieved R2 = 0.413, 0.455, 0.227, and 0.105 for Km, Ki, kcat, and kcat/Km, surpassing all baselines on catalytic tasks. Systematic condition scans recovered compartment-specific pH direction inversion and pathway-level temperature responses. In a 20-patient colorectal cancer single-cell cohort, IsoKin reduced posterior uncertainty by 73.3% and 77.3%, revealing cell-type-specific rewiring. Orthogonal validation--scFEA flux, DepMap essentiality (permutation P = 0.0008) and TCGA survival-- provided mixed but directionally consistent support. Together, EnzCast and IsoKin bridge in vitro prediction, condition-aware biochemical interrogation and patient-resolved in vivo inference.

bioinformatics↗

bioRxiv2026

Nanosecond laser-driven proton FLASH spares normal tissue cells by sustaining mitochondrial homeostasis and attenuating ferroptosis

Radiotherapys clinical utility remains fundamentally constrained by the collateral damage to healthy tissues. Ultra-high-dose-rate (UHDR) irradiation, or, FLASH-radiotherapy (FLASH-RT) has emerged as a transformative paradigm to mitigate such toxicity. However, the biological effects of FLASH-RT on the high-efficiency of tumor killing and normal tissue sparing remain poorly understood. In this work, we utilized a petawatt-class laser-plasma acceleration (LPA) platform to deliver discrete 12.9-nanosecond proton pulses at an extreme instantaneous dose rate of 1.94x107 Gy/s. This temporal singularity achieved a profound sparing effect in normal bronchial epithelial cells, evidenced by a nine-fold reduction in the lethal coefficient (from 0.47 to 0.05 Gy-1), while maintaining full tumoricidal potency against lung adenocarcinoma. Mechanistically, we demonstrated that LPA-FLASH could effectively bypass the ATF3-mediated stress response and circumvent the subsequent ferroptotic cascade. This molecular evasion could preserve the mitochondrial cristae integrity and trigger an adaptive bioenergetic ATP surge--a hallmark of metabolic resilience exclusively in healthy tissue cells. Therefore, our findings identify ferroptosis-mediated mitochondrial integrity as a unifying framework for selective normal-tissue protection at the physical limits of radiation delivery, and establish LPA-FLASH-RT as a potent, compact modality for next-generation oncology.

cell biology↗

bioRxiv2025

pH-dependent regulation in SLC38A9

Cells rely on precise metabolic control to adapt to environmental cues. The mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, with amino acids serving as key signals. Lysosomes, which act as nutrient recycling centers, maintain amino acid homeostasis by breaking down macromolecules and releasing amino acids for cellular use. SLC38A9, a lysosomal amino acid transporter, functions as both a transporter and a sensor in the mTORC1 pathway. Here, we investigated whether SLC38A9 activity is regulated by pH. We show that arginine uptake by SLC38A9 is pH-dependent, and that the histidine residue His544 serves as the pH sensor. Mutating His544 abolishes the pH dependence of arginine uptake without impairing overall transport activity, indicating that His544 is not directly involved in substrate binding. Instead, protonation or deprotonation of His544 appears to influence transport through SLC38A9. To explore this mechanism, we compared two structures of SLC38A9 that we determined, one at high pH and one at low pH, and proposed a working model for pH-induced activation. These findings highlight the role of local ionic changes in modulating lysosomal transporters and underscore the intricate regulatory mechanisms that govern SLC38A9 function and, ultimately, mTORC1 signaling.

molecular biology↗

bioRxiv2025

Nanophotonic neural probes for in vivo photostimulation, electrophysiology, and microfluidic delivery

Implantable silicon neural probes with integrated optical emitters and electrodes are emerging tools for simultaneous optogenetic stimulation and electrophysiological recording in deep brain regions. In parallel, neural probes with microfluidic channels have been developed for localized drug delivery and neurochemical sampling. However, thus far, such fluidic probes have lacked optical and electrical functionalities or been limited to a low number of optical emitters and/or electrodes, constraining their utility in multimodal investigations of neural circuits. Here, we introduce foundry-fabricated silicon nanophotonic neural probes with monolithically integrated microfluidics. Each probe has 16 silicon nitride grating coupler emitters, 18 titanium nitride microelectrodes, and one embedded microfluidic channel. We evaluate the photonic, electrophysiological, and microfluidic functionalities in vivo in optogenetic, blue-light-sensitive mice. With our multifunctional neural probes, we demonstrate local suppression of epileptic seizure activity (induced by microfluidic injection of 4-aminopyridine) using photostimulation. Through foundry-compatible microfluidics integration, this work advances the versatility of nanophotonic neural probes and presents new possibilities for multimodal neuroscience experiments leveraging this scalable neurotechnology.

neuroscience↗

bioRxiv2025

Neurotrophin-3 produced by motor neurons non-cell autonomously regulate the development of pre-motor interneurons in the developing spinal cord

The development of multicellular organisms requires proper interplays between cell-autonomous genetic programs controlled by combinations of transcription factors that regulate the differentiation of distinct cell populations and non-cell autonomous processes that coordinate the proliferation, the fate, the survival, the respective location, and the proper interactions of these populations. During the development of the nervous system, non-cell autonomous mechanisms determine neuronal fate, survival, distribution, axon guidance, and connectivity. Although similar processes are suggested to be at work in the formation of spinal motor circuits, the molecular mechanisms involved remain mostly elusive. Here, we provide evidence that the Onecut transcription factors regulate a non-cell autonomous mechanism that modulate pre-motor interneuron development. We show that conditional inactivation of the Onecut factors in spinal motor neurons affects the differentiation and the positioning of pre-motor interneuron populations. We identify that Neurotrophin-3 produced by motor neurons under the control of the Onecut factors non-cell autonomously regulate the production and the distribution of pre-motor interneuron populations. Thus, we elucidated one of the non-cell autonomous mechanisms that coordinate the formation of the spinal motor circuits.

neuroscience↗

bioRxiv2025

Chromosome-level genome assemblies of five Sinocyclocheilus species

Sinocyclocheilus, a genus of tetraploid fishes, is endemic to the karst regions of Southwest China. All species within this genus are classified as second-class national protected species due to their unique and fragile habitat. However, absence of high-quality genomic resources has hindered various research efforts to elucidate their phylogenetic relationships and the origin of polyploidy. To address these academic challenges, we at first constructed a high-quality genome assembly for the most abundant representative, golden-line barbel (Sinocyclocheilus grahami), by integration of PacBio long-read and Hi-C sequencing technologies. The final scaffold-level genome assembly of S. grahami is 1.6 Gb in length, with a scaffold N50 up to 30.7 Mb. A total of 42,205 protein-coding genes were annotated. Subsequently, 93.1% of the assembled genome sequences (about 1.5 Gb) and 93.8% of the total predicted genes were successfully anchored onto 48 chromosomes. Furthermore, we obtained chromosome-level genome assemblies for four other Sinocyclocheilus species (including S. anophthalmus, S. maitianheensis, S. anshuiensis, and S. rhinocerous) based on homologous comparison. These genomic data we present in this study provide valuable genetic resources for in-depth investigation on cave adaptation and improvement of economic values and conservation of diverse Sinocyclocheilus fishes.

genomics↗

bioRxiv2024

Filamin A mediates embryonical palatal fusion by linking mechanotransduction with β-Catenin/Smad2

To decipher potential mechanisms underlying cleft palate (CP), we used advanced bioinformatic integrated with literature mining and genome-wide association study (GWAS). Re-analysis of RNA-seq data (GSE45568, GSE185279) combined with literature mining highlighted the roles of Filamin A (Flna) and Epithelial-Mesenchymal Transition (EMT) in palatal development. Immunofluorescence of in vivo palatal shelves showed increased Flna in medial edge epithelial (MEE) cells and EMT cells located in an epithelial triangle. Inhibition of TGF-{beta} or RhoA and mechanical stimuli impacted Flna expression in ex vivo cultured palatal shelves. Re-analysis of scRNA-seq data (GSE155928) highlighted a correlation between Flna and Ctnnb1 in EMT cells. Flna knockdown affected {beta}-catenin/Smad2 expression in cultured palatal shelves and HaCaT cells. Epithelium-specific knockout of Flna delayed palatal fusion in female mice but not males. Mendelian randomization analysis suggested that parental habitual physical activity (HPA) was causally associated with lower risk of CP in their offspring. Together, these findings suggested that parental HPA could benefit their offsprings palatal development through Flna by linking mechanotransduction with the Wnt/TGF-{beta}/Smad signaling pathways during palatal fusion.

developmental biology↗

bioRxiv2023

Dispersal and evolution of the invasive snail Pomacea canaliculata, an intermediate host of Angiostrongylus cantonensis: A field study around its initial introduction site in China

Eosinophilic meningitis caused by Angiostrongylus cantonensis is an emerging infectious disease in mainland China. The invasive snail (Pomacea canaliculata) is one of the main intermediate host of the zoonotic nematode. To gain insights into the spatial distribution, phenotypic variation and dispersal pattern of the snail populations. A field survey was conducted using modified nested sampling and selecting ditches as the main habitats. Snail distribution and abundance were displayed with predictions based on an inverse distance-weighted model. Correlation and spatial autocorrelation were analyzed among the measured parameters. The findings of this study demonstrate the well-established and abundant presence of P. canaliculata in ditches. A total of 564 sampling sites were assessed, with measurements taken on 10,145 snails having shell heights greater than 1.5 cm. The average population density was determined to be 20.31 {+/-} 11.55 snails per square meter. Morphological analysis revealed an average snail body mass of 8.93 {+/-} 3.95 g, shell height of 3.38 {+/-} 0.66 cm, a sex ratio of 2.39 {+/-} 1.01 female to male, and a shell color ratio of 9.34 {+/-} 7.52 brown to yellow. Among these measurements, body mass was found to be significantly correlated with shell height (r = 0.88, p < 0.01) and shell color (r = 0.55, p < 0.05). Spatial-correlation analysis proved that shell height was the only factor significantly spatially autocorrelated (MI = 0.27, z = 2.20, p = 0.03), although weak autocorrelations appeared in body mass and shell color. The observed geographic variations of phenotypic traits indicated a human-mediated evolving process of the snail populations and a potential complexity of the parasite transmission system. These findings may enhance the assessment of the epidemiological health risk posed by angiostrongyliasis and inform strategies for controlling infectious snails.

ecology↗

bioRxiv2023

Implantable nanophotonic neural probes for integrated patterned photostimulation and electrophysiology recording

Optogenetics has transformed neuroscience by allowing precise manipulation of neural circuits with light [1-5]. However, a central difficulty has been to deliver spatially shaped light and record deep within the brain without causing damage or significant heating. Current approaches form the light beam in free space and record the neural activity using fluorescence imaging or separately inserted electrodes [6-9], but attenuation limits optical penetration to around 1 mm of the brain surface [10]. Here, we overcome this challenge with foundry-fabricated implantable silicon neural probes that combine microelectrodes for electrophysiology recordings with nanophotonic circuits that emit light with engineered beam profiles and minimal thermal impact. Our experiments reveal that planar light sheets, emitted by our neural probes, excited more neurons and induced greater firing rate fatigue in layers V and VI of the motor and somatosensory cortex of Thy1-ChR2 mice at lower output intensities than low divergence beams. In the hippocampus of an epilepsy mouse model, we induced seizures, a network-wide response, with light sheets without exceeding the[~] 1{whitebullet}C limit for thermally induced electrophysiological responses [11-13]. These findings show that optical spatial profiles can be tailored for optogenetic stimulation paradigms and that the probes can photostimulate and record neural activity at single or population levels while minimizing thermal damage to brain tissue. The neural probes, made in a commercial silicon photonics foundry on 200-mm silicon wafers, demonstrate the manufacturability of the technology. The prospect of monolithically integrating additional well-established silicon photonics devices, such as wavelength and polarization multiplexers, temperature sensors, and optical power monitors, into the probes holds the potential of realizing more versatile, implantable tools for multimodal brain activity mapping.

bioengineering↗

bioRxiv2023

3D Printed Ti3C2Tx MXene/PCL Scaffolds for Guided Neuronal Growth and Photothermal Stimulation

The exploration of neural circuitry is essential for understanding the computational mechanisms and physiology of the brain. Despite significant advances in materials and fabrication techniques, controlling neuronal connectivity and response in three dimensions continues to present a formidable challenge. Here, we present a method for engineering the growth of three-dimensional (3D) neural circuits with the capability for optical stimulation. We fabricated bioactive interfaces by melt electrospinning writing (MEW) of 3D printed polycaprolactone (PCL) scaffolds followed by coating with titanium carbide (Ti3C2Tx MXene). Beyond enhancing hydrophilicity, cell adhesion, and electrical conductivity, the Ti3C2Tx MXene coating enabled optocapacitance-based neuronal stimulation due to illumination-induced local temperature increases. This work presents a strategy for additive manufacturing of neural tissues with optical control for functional tissue engineering and neural circuit computation.

bioengineering↗

bioRxiv2023

On-Demand Expansion Fluorescence and Photoacoustic Microscopy (ExFLPAM)

Expansion microscopy (ExM) is a promising technology that enables nanoscale imaging on conventional optical microscopes by physically magnifying the specimens. Here, we report the development of a strategy that enables i) on-demand labeling of subcellular organelles in live cells for ExM through transfection of fluorescent proteins that are well-retained during the expansion procedure; and ii) non-fluorescent chromogenic color-development towards efficient bright-field and photoacoustic imaging in both planar and volumetric formats, which is applicable to both cultured cells and biological tissues. Compared to the conventional ExM methods, our strategy provides an expanded toolkit, which we term as expansion fluorescence and photoacoustic microscopy (ExFLPAM), by allowing on-demand fluorescent protein labeling of cultured cells, as well as non-fluorescent absorption contrast-imaging of biological samples.

bioengineering↗

bioRxiv2023

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/525073v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@2e8406org.highwire.dtl.DTLVardef@1dde495org.highwire.dtl.DTLVardef@c9f42eorg.highwire.dtl.DTLVardef@be2799_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2022

lincRNA RP24-315D19.10 promotes endometrialdecidualization via upregulation of hnRNPA2B1

Sufficient decidualization is necessary to maintain successful pregnancy. The physiological function and underlying molecular mechanisms of intergenic long non-coding RNA (lincRNAs) in this process remain largely unknown. Herein, we identified a lincRNA, RP24-315D19.10, which is highly expressed during mouse decidualization during early pregnancy, by performing RNA-sequencing (RNA-seq) analysis and weighted gene co-expression network analysis (WGCNA). Detailed cell and molecular assays revealed that lincRNA RP24-315D19.10 knockdown blocked decidualization in primary mouse endometrial stromal cells (mESCs), suggesting that RP24-315D19.10 is a promoting factor for decidualization. Mechanistically, cytoplasmic RP24-315D19.10 directly interacted with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and upregulated its protein level. Moreover, we found that hnRNPA2B1 is involved in the regulation of decidualization through loss- and gain-of-function studies in vitro. Clinically, patients diagnosed with spontaneous miscarriage were found to have lower hnRNPA2B1 levels than healthy individuals, suggesting that RP24-315D19.10-regulated hnRNPA2B1 may participate in the development and progression of early spontaneous abortion. Our study indicates that RP24-315D19.10 enhances endometrial decidualization in a hnRNPA2B1-dependent manner, providing further insights into this physiological process.

molecular biology↗

bioRxiv2022

Age-related seroprevalence trajectories of seasonal coronaviruses in children

Four seasonal coronaviruses, including HCoV-NL63 and HCoV-229E, HCoV-OC43 and HCoV-HKU1 cause approximately 15-30% of common colds in adults. However, the frequency and timing of early infection with four seasonal coronaviruses in the infant are still not well studied. Here, we evaluated the serological response to four seasonal coronaviruses in 1886 children under 18-year-old to construct the viral infection rates. The antibody levels were also determined from the plasma samples of 485 pairs postpartum women and their newborn babies. This passive immunity waned at one year after birth and the resurgence of the IgGs were found thereafter with the increase of the age. Taken together, our results show the age-related seroprevalence trajectories of seasonal coronaviruses in children and provide useful information for deciding vaccine strategy for coronaviruses in the future.

immunology↗

bioRxiv2022

The shifting epigenetic landscape and roles of key transcription factors during early retinal cell differentiation

How the diverse neural cell types emerge from multipotent neural progenitor cells during central nervous system development remains poorly understood. Recent scRNA-seq studies have delineated the developmental trajectories of individual neural cell types in many neural systems including the neural retina. Further understanding of the formation of neural cell diversity requires knowledge about how the epigenetic landscape shifts along individual cell lineages and how key transcription factors regulate these changes. In this study, we dissect the changes in the epigenetic landscape during early retinal cell differentiation by scATAC-seq and identify globally the enhancers, enriched motifs, and potential interacting transcription factors underlying the cell state/type specific gene expression in individual lineages. Using CUT&Tag, we further identify the enhancers bound directly by four key transcription factors, Otx2, Atoh7, Pou4f2, and Isl1, and uncover their roles in shaping the epigenetic landscape and controlling gene expression in a sequential and combinatorial fashion along individual retinal cell lineages such as retinal ganglion cells (RGCs). Our results reveal a general paradigm in which transcription factors collaborate and compete to regulate the emergence of distinct retinal cell types such as RGCs from multipotent retinal progenitor cells (RPCs).

developmental biology↗