Biology subjects

Xie, C.

Publications and source records attributed to Xie, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

cell biology↗

bioRxiv2023

Low-threshold, high-resolution, chronically stable intracortical microstimulation by ultraflexible electrodes

Intracortical microstimulation (ICMS) enables applications ranging from neuroprosthetics to causal circuit manipulations. However, the resolution, efficacy, and chronic stability of neuromodulation is often compromised by the adverse tissue responses to the indwelling electrodes. Here we engineer ultraflexible stim-Nanoelectronic Threads (StimNETs) and demonstrate low activation threshold, high resolution, and chronically stable ICMS in awake, behaving mouse models. In vivo two-photon imaging reveals that StimNETs remain seamlessly integrated with the nervous tissue throughout chronic stimulation periods and elicit stable, focal neuronal activation at low currents of 2 A. Importantly, StimNETs evoke longitudinally stable behavioral responses for over eight months at markedly low charge injection of 0.25 nC/phase. Quantified histological analysis show that chronic ICMS by StimNETs induce no neuronal degeneration or glial scarring. These results suggest that tissue-integrated electrodes provide a path for robust, long-lasting, spatially-selective neuromodulation at low currents which lessen risks of tissue damage or exacerbation of off-target side-effects.

neuroscience↗

bioRxiv2022

An in vivo platform for rebuilding functional neocortical tissue

Recent progress in cortical stem cell transplantation has demonstrated its potential to repair the brain. However, current transplant models have yet to demonstrate that the circuitry of transplant-derived neurons can encode useful function to the host. This is likely due to missing cell types within the grafts, abnormal proportions of cell types, abnormal cytoarchitecture, and inefficient vascularization. Here, we devised a transplant platform for testing neocortical tissue prototypes. Dissociated mouse embryonic telencephalic cells in a liquid scaffold were transplanted into aspiration-lesioned adult mouse cortices. The donor neuronal precursors differentiated into upper and deep layer neurons that exhibited synaptic puncta, projected outside of the graft to appropriate brain areas, became electrophysiologically active within one month post-transplant, and responded to visual stimuli. Interneurons and oligodendrocytes were present at normal densities in grafts. Grafts became fully vascularized by 1-week post-transplant and vessels in grafts were perfused with blood. With this paradigm, we could also organize cells into layers. Overall, we have provided proof of concept for an in vivo platform that can be used for developing and testing neocortical-like tissue prototypes.

neuroscience↗

bioRxiv2022

Targeting the pathological network: feasibility of network-based optimization of transcranial magnetic stimulation coil placement for treatment of psychiatric disorders

It has been recognized that the efficacy of TMS-based modulation may depend on the network profile of the stimulated regions throughout the brain. However, what profile of this stimulation network optimally benefits treatment outcomes is yet to be addressed. The answer to the question is crucial for informing network-based optimization of stimulation parameters, such as coil placement, in TMS treatments. In this study, we aimed to investigate the feasibility of taking a disease-specific network as the target of stimulation network for guiding individualized coil placement in TMS treatments. We present here a novel network-based model for TMS targeting of the pathological network. First, combining E-field modeling and resting-state functional connectivity, stimulation networks were modeled from locations and orientations of the TMS coil. Second, the spatial anti-correlation between the stimulation network and the pathological network of a given disease was hypothesized to predict the treatment outcome. The proposed model was validated to predict treatment efficacy from the position and orientation of TMS coils in two depression cohorts and one auditory verbal hallucinations cohort. We further demonstrate the utility of the proposed model in guiding individualized TMS treatment for psychiatric disorders. In this proof-of-concept study, we demonstrated the feasibility of the novel network-based targeting strategy that uses the whole-brain, system-level abnormity of a specific psychiatric disease as a target. Results based on empirical data suggest that the strategy may potentially be utilized to identify individualized coil parameters for maximal therapeutic effects. HighlightsO_LIProposed a model of targeting pathological brain networks for pre-treatment TMS coil placement planning in the treatment of psychiatric disorders; C_LIO_LIValidated the network targeting model in three cohorts of patients with depression or auditory verbal hallucinations, via prediction of individual TMS treatment efficacy from the parameters of coil placement; C_LIO_LIDemonstrated the utility of the network targeting model in guiding individualized TMS coil placement. C_LI

neuroscience↗

bioRxiv2022

Pangenome-based dynamic trajectories of intracellular gene transfers in Poaceae unveil a high rate of unceasing integration and selective retention in Triticeae

Intracellular gene transfers (IGTs) between the nucleus and organelles, including plastids and mitochondria, constantly reshapes the nuclear genome during evolution. Despite the substantial contribution of IGTs to genome variation, the dynamic trajectories of IGTs at the pangenomic level remain elusive. Here, we propose a novel approach, IGTminer, to map the evolutionary trajectories of IGTs by collinearity and gene reannotation across multiple genome assemblies. IGTminer was applied to create a nuclear organelle gene (NOG) map across 67 genomes covering 15 Poaceae species, including important crops, revealing the polymorphisms and trajectory dynamics of NOGs. The NOGs produced were verified by experimental evidence and resequencing datasets. We found that most of the NOGs were recently transferred and lineage specific, and that Triticeae species tended to have more NOGs than other Poaceae species. Wheat had a higher retention rate of NOGs than maize and rice, and the retained NOGs were likely involved in the photosynthesis and translation pathways. Large numbers of NOG clusters were aggregated in hexaploid wheat during two rounds of polyploidization and contributed to the genetic diversities among modern wheat varieties. Finally, we proposed a radiocarbon-like model illustrating the transfer and elimination dynamics of NOGs, highlighting the unceasing integration and selective retention of NOGs over evolutionary time. In addition, we implemented an interactive webserver for NOG exploration in Poaceae. In summary, this study provides new resources and clues for the roles of IGTs in shaping inter- and intraspecies genome variation and driving plant genome evolution.

evolutionary biology↗

bioRxiv2022

The protozoan commensal Tritrichomonas musculis is a natural adjuvant for mucosal IgA.

Immunoglobulin(Ig) A antibodies are the most abundant antibodies supporting mucosal immune homeostasis and host-microbiota interactions. Driven by gut commensal microbes, IgA-secreting plasma cells (PC) differentiate through T cell-dependent (Td) or T cell independent (Ti) mechanisms. While commensal bacteria within the microbiota are known for their ability to promote IgA, the role of non-bacterial commensal microbes on the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T-cell dependent, IgA class-switch recombination and intestinal accumulation of IgA-secreting PC. T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells are central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, the commensal T.mu further improves the induction of IgA-secreting plasma cells and their peripheral dissemination, even against non-protozoan, orally ingested antigens, identifying T.mu as natural adjuvant for IgA. Collectively, these findings propose a previously unknown, protozoa-driven mode of IgA induction that supports intestinal immune homeostasis even against non-microbial antigens.

immunology↗

bioRxiv2022

Significantly amplified photoacoustic effect for silica-coated gold nanoparticles by interface heat transfer mechanisms

Plasmonic gold nanoparticles (AuNPs) are effective photoacoustic (PA) signal agents and have found important biomedical applications. The silica coating on the surface of AuNPs showed enhanced PA efficiency, however, the PA amplification mechanism remains unclear. Here, we systematically studied the silica coating effect on PA generation of AuNPs under different laser pulse durations. We experimentally demonstrated up to 4-fold PA amplification under thin silica coating (<5 nm) and a picosecond laser excitation. The theoretical model further suggests that the PA amplification originates from two interface heat transfer mechanisms including 1) the enhanced interface thermal conductance on the silica-water interface and 2) the electron-phonon energy transfer channel on the gold/silica interface. This study discovers a regime of large PA amplification and provides a new rationale for plasmonic nanoparticle design to achieve better PA efficiency.

bioengineering↗

bioRxiv2022

Longitudinal neural and vascular recovery following ultraflexible neural electrode implantation in aged mice

Flexible neural electrodes improve the recording longevity and quality of individual neurons by promoting tissue-electrode integration. However, the intracortical implantation of flexible electrodes inevitably induces tissue damage. Understanding the longitudinal neural and vascular recovery following the intracortical implantation is critical for the ever-growing applications of flexible electrodes in both healthy and disordered brains. Aged animals are of particular interest because they play a key role in modeling neurological disorders, but their tissue-electrode interface remains mostly unstudied. Here we integrate in-vivo two-photon imaging and electrophysiological recording to determine the time-dependent neural and vascular dynamics after the implantation of ultraflexible neural electrodes in aged mice. We find heightened angiogenesis and vascular remodeling in the first two weeks after implantation, which coincides with the rapid increase in local field potentials and unit activities detected by electrophysiological recordings. Vascular remodeling in shallow cortical layers preceded that in deeper layers, which often lasted longer than the recovery of neural signals. By six weeks post-implantation vascular abnormalities had subsided, resulting in normal vasculature and microcirculation. Putative cell classification based on firing pattern and waveform shows similar recovery time courses in fast-spiking interneurons and pyramidal neurons. These results elucidate how structural damages and remodeling near implants affecting recording efficacy, and support the application of ultraflexible electrodes in aged animals at minimal perturbations to endogenous neurophysiology.

neuroscience↗

bioRxiv2022

Chiral Derivatization-enabled Discrimination and Visualization of Proteinogenic Amino Acids by Ion Mobility Mass Spectrometry

The importance of chiral amino acids (AAs) in living organisms has been widely recognized since the discovery of endogenous D-AAs as potential biomarkers in several metabolic disorders. Chiral analysis by ion mobility spectrometry-mass spectrometry (IMS-MS) has the advantages of high speed and sensitivity but is still in its infancy. Here, a N-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (FDAA) derivatization is combined with trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) for chiral AA analysis. For the first time, we demonstrate the simultaneous separation of 19 pairs of chiral proteinogenic AAs in a single fixed condition TIMS-MS run. The utility of this approach presents for mouse brain extracts by direct-infusion TIMS-MS. The robust separation ability in complex biological sample was proven in MALDI TIMS mass spectrometry imaging (MSI) as well by directly depositing 19 pairs of AAs on a tissue slide following on-tissue derivatization. In addition, endogenous chiral amino acids were also detected and distinguished. The developed methods show compelling application prospects in biomarker discovery and biological research. Entry for the Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/498692v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@19af718org.highwire.dtl.DTLVardef@d457d7org.highwire.dtl.DTLVardef@d2f932org.highwire.dtl.DTLVardef@e64831_HPS_FORMAT_FIGEXP M_FIG C_FIG The combination of chiral derivatization and trapped ion mobility-mass spectrometry provides the first insights into the separation of 19 pairs of chiral proteinogenic D/L-amino acids in a single run and further visualization of chiral amino acids under complex biological matrix.

biochemistry↗

bioRxiv2022

MorphoGNN: Morphological Embedding for Single Neuron with Graph Neural Networks

With the development of optical imaging systems, neuroscientists can now obtain large datasets of morphological structure at a single neuron scale positioned across the whole mouse brain. However, the enormous amount of morphological data challenges the classic approach of neuron classification, indexing and other analysis tasks. In this paper, we propose MorphoGNN, a single neuron morphological embedding based on the graph neural networks (GNN). This method learns the spatial structure information between the nodes of reconstructed neuron fibers by its nearest neighbors on each layer and captures the lower-dimensional representation of a single neuron through an end-to-end model. This model is composed of densely connected edge convolution (EdgeConv) layers and a double pooling operator, regularized with joint cross-entropy loss and triplet loss. An increasing population of the neighbor nodes meets the need of learning more information with features expanding at the deep layer. We tested the proposed embeddings on the neuron classification and retrieval tasks. Our method achieves competitive performance both on the general point cloud dataset and the neuron morphology dataset.

neuroscience↗

bioRxiv2022

Actuating tension-loaded DNA clamps drives membrane tubulation

Membrane dynamics in living organisms can arise from proteins adhering to, assembling on, and exerting force on cell membranes. Programmable synthetic materials, such as self-assembled DNA nanostructures, offer the capability to drive membrane remodeling events in a way that resembles protein-mediated dynamics, but with user-defined outcomes. An example showcasing this capability is the tubular deformation of liposomes by DNA nanostructures with purposely designed shapes, surface modifications, and self-assembling properties. However, stimulus-responsive membrane tubulation mediated by DNA structure reconfiguration remains challenging. Here we present the triggered formation of membrane tubes in response to specific DNA signals that actuate membrane-bound DNA clamps from an open state to various predefined closed states, releasing pre-stored energy to activate membrane deformation. Using giant unilamellar vesicles (GUVs) as a model system, we show that the timing and efficiency of tubulation, as well as the width of membrane tubes, are modulated by the conformational change of DNA clamps, marking a solid step toward spatiotemporal control of membrane dynamics in an artificial system.

synthetic biology↗

bioRxiv2022

Tyrosine phosphorylation tunes chemical and thermal sensitivity of TRPV2 ion channel

Transient receptor potential vanilloid 2 (TRPV2) is a multimodal ion channel widely regulating central and peripheral functions. Its important involvement in immune responses has been suggested such as in the macrophages phagocytosis process. However, the endogenous signaling cascades controlling the gating of TRPV2 remain to be understood. Here, we report that enhancing tyrosine phosphorylation remarkably alters the chemical and thermal sensitivities of TRPV2 endogenously expressed in rat bone marrow-derived macrophages. We identify that the protein tyrosine kinase JAK1 mediates TRPV2 phosphorylation at the molecular sites Tyr(335), Tyr(471), and Tyr(525). JAK1 phosphorylation is required for maintaining TRPV2 activity and the phagocytic ability of macrophages. We further show that TRPV2 phosphorylation is dynamically balanced by protein tyrosine phosphatase non-receptor type 1 (PTPN1). PTPN1 inhibition increases TRPV2 phosphorylation, further reducing the activation temperature threshold to [~]40 {degrees}C. Our data thus unveil an intrinsic mechanism where the phosphorylation/dephosphorylation dynamic balance sets the basal chemical and thermal sensitivity of TRPV2. Targeting this pathway will aid therapeutic interventions in physiopathological contexts.

physiology↗

bioRxiv2022

A scalp geometry parameter-space for optimization and implementation of conventional TMS coil placement

Transcranial magnetic stimulation efficacy is largely dependent upon coil position and orientation. A good method for describing coil placement is required for both computational optimization (planning) and actual placement (implementation). In coordinate dependent parameter-spaces (CDPs), three-dimensional coordinates are used to represent coil position and three orthogonal unit vectors are used to represent coil orientation. A CDP can precisely describe arbitrary coil placement; therefore it offers great advantage in computational optimization which checks through all possible placements. However, a neuronavigation system is usually required to accurately implement the optimized CDP parameters on a participants head. Routine clinical practice, on the other hand, often uses the International 10-20 system to describe coil placement. Although the 10-20 system can only perform modeling and placement at limited scalp landmarks, it allows the synthesis of different individuals targeting effects to find group-optimal parameters; it also allows manual placement, which is important for commonly-seen use cases without individual MRI scans and navigation devices. This study proposes a new scalp geometry based parameter-space (SGP), integrating the advantages of CDP and 10-20 methods. Our SGP 1) can quantitatively specify all possible conventional coil positions and orientations on an individuals scalp, which is important for electrical modeling and optimization, 2) maintains inter-individual correspondence, which is important for synthesizing TMS effects from different individuals and studies. 3) enables fast and simple manual implementation. Demonstration experiments were conducted to illustrate the application of an SGP-based framework for both individual and group-based optimization. A measurement experiment was performed to evaluate speed, precision and reliability of SGP-based manual implementation; results show it surpasses previous manual placement methods.

neuroscience↗

bioRxiv2022

In vitro and in vivo venom-inhibition assays identify metalloproteinase-inhibiting drugs as potential treatments for snakebite envenoming by Dispholidus typus

Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by Dispholidus typus (boomslang) results in venom induced consumption coagulopathy, whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for D. typus envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at $6,000/vial, typically unaffordable for most snakebite patients. We therefore investigated the in vitro and in vivo preclinical efficacy of four SVMP inhibitors to neutralise the effects of D. typus venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS. The venom of D. typus exhibited an SVMP-driven procoagulant phenotype in vitro. Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom in vitro, whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenomation, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for D. typus snakebite envenomation. These two drugs have been previously shown to be effective against Echis ocellatus venom induced consumption coagulopathy (VICC) in preclinical models, and thus we conclude that marimastat and DMPS may be valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.

pharmacology and toxicology↗

bioRxiv2021

Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson's disease and dopaminergic neuron dysfunction

2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinsons disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase and {beta} (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.

neuroscience↗

bioRxiv2021

A magnetic field prevents alcoholic liver disease by reducing oxidative stress

The radical-pair recombination change will affect the generation of free radicals, which can be regulated by static magnetic fields (SMFs) in a SMF setting dependent way. It is well known that alcohol consumption leads to significantly increased free radical levels and health risks, which lacks effective treatment method besides alcohol abstinence. Here we compared different SMF settings and found that a downward SMF of [~]0.1 T with magnetic flux of [~]4.5x10-3 Wb could effectively alleviate alcohol-induced liver damage and lipid accumulation, and improve liver function. The inflammation, reactive oxygen species (ROS) level and oxidative stress were significantly reduced. EPR (electron paramagnetic resonance) experiments also confirmed the reduced amount of free radical by SMF treatment. Moreover, the lifespan of heavy alcohol drinking mice was also significantly changed due to the SMF effects on liver cell ROS level, DNA synthesis and liver cell regeneration. Our study shows that moderate SMFs with specific parameters have great promises to be developed into a physical method to reduce alcohol-induced liver damage in the future.

physiology↗

bioRxiv2021

Deeplearning based MHC epitope prediction for cancer neoantigen discovery

Neoantigens are important for cancer immunotherapies or cancer vaccine development, but identification of neoantigens is challenging. The high binding affinity between the mutated peptide and MHC (major histocompatibility complex) molecules of the patients is a necessary factor for a somatic mutation on the tumor genome to form a neoantigen. MHC epitope prediction tools can be used for the identification of neoantigens. This research investigates MHC epitope prediction by utilizing Tri-peptide similarity as features for the XGBoost classifier. This model was tested on experimentally validated cancer neoantigen peptides.

bioinformatics↗

bioRxiv2021

Evolution of a new testis-specific functional promotor within the highly conserved Map2k7 gene of the mouse

Map2k7 (synonym Mkk7) is a conserved regulatory kinase gene and a central component of the JNK signaling cascade with key functions during cellular differentiation. It shows complex transcription patterns and different transcript isoforms are known in the mouse (Mus musculus). We have previously identified a newly evolved testis specific transcript for the Map2k7 gene in the subspecies M. m. domesticus. Here, we identify the new promotor that drives this transcript and find that its transcript codes for an open reading frame (ORF) of 50 amino acids. The new promotor was gained in the stem lineage of closely related mouse species, but was secondarily lost in the subspecies M. m. musculus and M. m. castaneus. A single mutation can be correlated with its transcriptional activity in M. m. domesticus and cell culture assays demonstrate the capability of this mutation to drive expression. A mouse knock-out line in which the promotor region of the new transcript is deleted reveals a functional contribution of the newly evolved promotor to sperm motility and to the spermatid transcriptome. Our data show that a new functional transcript (and possibly protein) can evolve within an otherwise highly conserved gene, supporting the notion of regulatory changes contributing to the emergence of evolutionary novelties.

evolutionary biology↗