Biology subjects

Guo, X.

Publications and source records attributed to Guo, X..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Image Processing in the Acute to Chronic Pain Signatures (A2CPS) Project

The Acute to Chronic Pain Signatures (A2CPS) project is a large-scale, multi-site initiative aimed at identifying biomarkers and biosignatures that predict the transition from acute to chronic pain. The project is collecting multimodal, longitudinal data from over 2,500 individuals at risk for developing chronic pain after surgery. Here we describe the neuroimaging component of A2CPS, including the acquisition protocols, processing pipelines, and contents of the initial data release. The imaging protocol includes structural, diffusion, resting-state and task-based functional magnetic resonance imaging (MRI) data. Data are collected across multiple clinical sites using different scanner manufacturers, with attention to protocol harmonization and quality control. The processing pipeline integrates several established neuroimaging tools to extract potential biomarkers, including measures of brain structure, connectivity, and pain-related neural signatures. The first data release includes pre-surgical imaging data for 595 participants, with high quality ratings across modalities (98.7% of sMRI, 99.8% of dMRI, and 94.6% of fMRI images were rated as acceptable or better). Initial analyses demonstrate expected relationships between brain-derived measures and clinical variables, such as associations between brain age and psychological factors. This dataset represents a valuable resource for both pain research and neuroimaging methods development, with future releases planned to include additional participants and expanded analysis pipelines and processed data derivatives.

neuroscience↗

bioRxiv2024

NaDyNet: A Toolbox for Dynamic Network Analysis of Naturalistic Stimuli

Experiments with naturalistic stimuli (e.g., listening to stories or watching movies) are emerging paradigms in brain function research. The content of naturalistic stimuli is rich and continuous. The fMRI signals of naturalistic stimuli are complex and include different components. A major challenge is isolate the stimuli-induced signals while simultaneously tracking the brains responses to these stimuli in real-time. To this end, we have developed a user-friendly graphical interface toolbox called NaDyNet (Naturalistic Dynamic Network Toolbox), which integrates existing dynamic brain network analysis methods and their enhanced versions. The main features of NaDyNet are: 1) extracting signals of interest from naturalistic fMRI signals; 2) incorporating six commonly used dynamic analysis methods and three static analysis methods; 3) enhanced versions of these dynamic methods by adopting inter-subject analysis to eliminate the effects of non-interest signals; 4) performing K-means clustering analysis to identify temporally reoccurring states along with their temporal and spatial attributes. We then introduced the rationale for incorporating inter-subject analysis to improve existing dynamic brain network analysis methods, and presented numerous examples. We also summarized research progress in comparing methodological efficacy, offered our recommendations for method selection in dynamic network analysis, and discussed the limitations of current approaches and directions for future research. We hope that this open source toolbox will promote the development of naturalistic neuroscience. The toolbox is available at https://github.com/yuanbinke/Naturalistic-Dynamic-Network-Toolbox.

neuroscience↗

bioRxiv2024

RNA programmable cell targeting and manipulation with CellREADR

Methods that provide specific, easy, and scalable experimental access to animal cell types and cell states will have broad applications in biology and medicine. CellREADR - Cell access through RNA sensing by Endogenous ADAR (adenosine deaminase acting on RNA), is a programmable RNA sensor-actuator technology that couples the detection of a cell-defining RNA to the translation of an effector protein to monitor and manipulate the cell. The CellREADR RNA device consists of a 5 sensor region complementary to a cellular RNA and a 3 payload coding region; payload translation is gated by the removal of a STOP codon in the sensor region upon base pairing with the cognate cellular RNA through an ADAR-mediated A- to-I editing mechanism ubiquitous to metazoan cells. CellREADR thus highlights the potential for RNA-based monitoring and manipulation of animal cells in ways that are simple, versatile, and generalizable across tissues and species. Here, we describe a detailed protocol for implementing CellREADR experiments in cell cultures and in animals. The procedure includes sensor and payload design, cloning, validation and characterization in mammalian cell cultures. The in vivo animal protocol focuses on AAV-based delivery of CellREADR using brain tissue as examples. We describe current best practices, various experimental controls and trouble-shooting steps. Beginning from sensor design, the validation of RNA sensor-actuators in cell cultures can be completed in 2-3 weeks. The construction of AAV vectors and their in vivo validation and characterization will take additional 6-8 weeks.

molecular biology↗

bioRxiv2024

In Situ Integration of Porous Polyethylene Nanomembrane with Wound Exudates for Scarless Healing

Achieving scarless wound repair through innovative material designs, such as hydrogels infused with growth factors and cells, has been extensively explored. In this study, we introduce a scarless healing material called pgPE, which is based on a porous and biologically inert ultra-high molecular weight polyethylene (UHMWPE) nanomembrane. This highly flexible nanomembrane conforms closely to the wound site and effectively absorbs wound-associated species into its nanopores, forming pgPE in situ. The resulting pgPE creates an ideal environment that fosters physiological metabolism while acting as a barrier against pathogens. Our findings demonstrate that pgPE facilitates complete skin reconstruction, including the regeneration of hair follicles. Additionally, we characterized the immune microenvironment and hypoxic conditions, revealing that pgPE alleviates hypoxia and modulates immune responses, thereby promoting healing towards a scar-free outcome. The integration of wound-associated species within pgPE has been evidenced through three-dimensional Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) analysis of postmortem samples. This study highlights the potential of personalized solutions that align with physiological systems for enhanced wound healing.

bioengineering↗

bioRxiv2024

Engineered mitochondrial A-to-G editors with enhanced efficiency and targeting scope

Mitochondrial base editing is a powerful technology, but the current A-to-G mitochondrial DNA (mtDNA) base editors are reluctant to achieve high efficiency, which is critical for mtDNA engineering. Through laboratory evolution, TadA-8e variants were discovered with substantially increased activity and expanded targeting compatibility, especially for previously unfavorite sequence contexts, when applied to both nuclear and mitochondrial ABEs. Further engineering of the mtDNA editors (eTd-mtABEs) dramatically reduced both DNA and RNA off-targeting effects and enhanced strand-selective A-to-G editing with substitution of DddA to DNA nickases. Moreover, the eTd-mtABEs induced up to 145-fold editing frequencies compared to previous mtDNA adenine base editors in rat cells, and installed targeted mutations in all injected rat embryos with up to 74% efficiency in founders, resulting generation of SNHL and Leigh syndrome models with severe defects. It suggests that eTd-mtABEs are promising mtDNA engineering technology for basic research and for translational studies. HighlightsO_LIEngineered TadA variants enhance nuclear and mitochondrial ABE activity in all sequence contexts. C_LIO_LIAdditional mutations in eTd-mtABEs further minimize both DNA and RNA off-targeting effects. C_LIO_LIEngineered TadA variants are compatible to DNA nickase assisted strand-selective mtDNA editing. C_LIO_LIeTd-mtABEs enable highly efficient generation of rat mtDNA disease models with severe phenotypes. C_LI

bioengineering↗

bioRxiv2024

Spatiotemporal transcriptomic analyses reveal molecular gradient patterning during development and the tonotopic organization along cochlear axis

While cochlear tonotopic organization is essential for sound frequency discrimination, the spatiotemporal molecular programs shaping this architecture remain unresolved. Here, we integrate spatiotemporal transcriptomics (E17.5-P8-adult) with single-cell RNA-seq to construct a single-cell-resolution atlas of mouse cochlear development. As marked by differential gradient expression genes, distinct spatially and molecularly defined hair cell (HC) subtypes along the apical-basal axis were identified: such as the apical Myo7a+++/Calb1+++ outer hair cell (OHC) subtype, the basal Myo7a+/Calb1{square} OHC subtype, the apical vGlut3+++/Calb2+ inner hair cell (IHC) subtype, and the basal vGlut3+/Calb2+++ IHC subtype. In addition, the spatial data also demonstrate the developmental reversal of Myo7a/Calb2Nefh gradient patterns in HCs and spiral ganglion neurons (SGNs), revealing dynamic plasticity and complexity in frequency coding during development. Spatial analyses further demonstrate regional heterogeneity in cell communication intensity between HCs and SGNs, and also reveal core signaling hubs coordinating tonotopic organization, such as Fgf10-Fgfr2 pathway in the basal region and Ptn-Sdc pathway in the apical region HC or SGNs at P8 stage. Our study provides an open-access spatial database and reveals the morphological and molecular foundations underlying cochlear tonotopic organization, linking molecular and developmental mechanisms to auditory pathophysiology.

developmental biology↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗

bioRxiv2024

Receptor-based protein binding in the supramolecular network of velvet worm slime

The slime of velvet worms (Onychophora) is a protein-based bioadhesive that undergoes rapid, yet reversible transition from a fluid into stiff fibers used for prey capture and defense, but the mechanism by which this phase transition functions is largely unknown. Here, integrating transcriptomic and proteomic approaches with AI-guided structure predictions, we discover a group of evolutionarily conserved leucine-rich repeat (LRR) proteins in velvet worm slime that readily adopt a receptor-like, protein-binding "horseshoe" structure. Our structural predictions suggest dimerization of LRR proteins and support their interactions with conserved {beta}-sheets-rich domains of high-molecular-weight proteins, the primary building blocks of velvet worm slime fibers. This previously unknown functional context of LRR proteins is presumably involved in reversible, receptor-based supramolecular network formation in these adhesive biofibers and provides possible new avenues for fabricating fully recyclable (bio)polymeric materials. Significance StatementAnalyzing structure-function-relationships underlying reversible fiber formation in velvet worm slime may inspire avenues for the sustainable fabrication of protein-based polymeric materials. Here, we present evidence for an evolutionarily conserved mechanism of reversible fiber formation in velvet worm slime based on the receptor-like binding of fiber forming proteins by a leucine-rich repeat (LRR) protein. The structures of both protein components are highly conserved evolutionarily in the two distantly related velvet worm subgroups, indicating pervasive presence of this mechanism across species that has been maintained through the last [~]380 MY. Our results suggest that the ubiquitously occurring LRR motif--better known for its innate immunity and developmental roles--has a novel identified function in processing a biological material, which might contribute to the development of sustainable bio-inspired materials.

biochemistry↗

bioRxiv2024

The aberrant language network dynamics in autism ages 5-40 years

Language impairments across both structural components and pragmatic use are frequently observed in individuals with autism spectrum disorder (ASD). These difficulties are thought to stem from atypical brain development and abnormal network interactions, yet an integrative network-level model accounting for such impairments remains lacking. To bridge this gap, we applied the dynamic meta-networking framework of language, a theoretical model capturing domain-segregation dynamics during rest, to examine age-related changes (5-60 years) in cortical language networks in individuals with ASD. To further probe the biological underpinnings of these dynamics, we quantified spatial correspondences between network state hubs and gene co-expression modules as well as neurotransmitter receptor distributions. We identified distinct language meta-states characterized by domain-segregation connectivity patterns, which exhibited spatial alignment with gene co-expression modules and neurotransmitter systems. Individuals with ASD showed state-dependent developmental trajectories marked by age-related hypo- and hyper-connectivity. Critically, these network alterations strongly predicted verbal IQ and communicative difficulties, but were unrelated to social functioning or stereotyped behaviors. Our findings provide novel evidence that language-related network dynamics in ASD are developmentally altered, biologically grounded, and selectively linked to verbal and communicative impairments. These results advance a network-level model of language dysfunction in ASD and highlight potential mechanistic pathways for targeted interventions. Lay SummaryLanguage challenges are common in autism and can affect both learning language and using it in everyday conversations. In people aged 5-60, we found distinct, age-changing patterns in how the brains language areas connect at rest; these patterns align with basic biology (genes and brain chemicals) and strongly relate to verbal ability and daily communication, but not to social difficulties or repetitive behaviors. These results suggest clear, brain-based targets for earlier and more tailored support for language problems in autism.

neuroscience↗

bioRxiv2024

The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of integrated stress response (ISR) in regulating mitophagy, a key mitochondrial stress pathway. Our findings show that the ISR suppresses mitophagy under non-depolarizing mitochondrial stress by positively regulating mitochondrial protein import, independent of ATF4 activation. Mitochondrial protein import is regulated by the rate of protein synthesis under both depolarizing and non-depolarizing stress. Without ISR, increased protein synthesis overwhelms the mitochondrial import machinery, reducing its efficiency. Under depolarizing stress, mitochondrial import is heavily impaired even with active ISR, leading to significant PINK1 accumulation. In contrast, non-depolarizing stress allows more efficient protein import in the presence of ISR, resulting in lower mitophagy. Without ISR, mitochondrial protein import becomes severely compromised, causing PINK1 accumulation to reach the threshold necessary to trigger mitophagy. These findings reveal a novel link between ISR-regulated protein synthesis, mitochondrial import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

cell biology↗

bioRxiv2024

Activated carbon ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota

Type 2 diabetes (T2D) is a major public health concern worldwide and there has been increasing attention on the role of natural dietary drugs in diabetes therapy. However, the effects of these drugs on gut microbial composition, functional potentials and metabolisms remain unclear. Here, we conducted integrated 16S rRNA sequencing and metabolomic analyses in T2D GK rats and healthy Wistar rats that exposed to four natural dietary drugs (highly porous activated carbon, wheatgrass, dandelion and corn stigma). Oral administration of activated carbon and dandelion decreased the body weight gain in both high-fat diet (HFD) GK rats and Wistar rats. Significantly lower level of blood glucose was observed in GK rats with activated carbon intervention. A group of beneficial bacteria and metabolites were promoted, and the endotoxin-producing bacteria were inhibited by dietary drugs, especially for the activated carbon diet. Oral administration of activated carbon resulted in metabolic changes and anti-inflammatory effects that decreased both high-fat diet-induced obesity and diabetes. The beneficial effects of increased positive responders are related to improved carbohydrate and amino acid metabolism, regulated inflammatory mediators, with simultaneous reduction of detrimental compounds such as lipopolysaccharide (LPS) synthesis and modification of the gut microbiome. These findings highlight the effectiveness of natural dietary drugs, with a particular emphasis on activated carbon, and establish a foundation for tailoring the use of these drugs in T2D therapy. ImportanceOur findings highlight the significant hypoglycemic effect of activated carbon, demonstrating its potential to remodel the gut microbiota, improve carbohydrate and amino acid metabolism, regulate inflammatory mediators, and reduce detrimental compounds such as lipopolysaccharide (LPS). These results suggest that dietary intervention with activated carbon could be a noninvasive and accessible method for improving diabetes management, providing novel insights into the role of natural dietary drugs in metabolic health and diabetes therapy.

microbiology↗

bioRxiv2024

Mid1 deletion leads to cognitive dysfunction in Opitz syndrome by regulates neural rhythms through the inhibition of p-Creb by PP2Ac

MID1 is an E3 ubiquitin ligase of the tripartite motif (TRIM) subfamily of RING-containing protein1. MID1 is involved in many basic biological processes, especially during embryonic development. Mutation, truncation or complete deletion of MID1 gene is the cause of Opitz G/BBB syndrome (OS). OS is a rare genetic disease of nervous system, which is characterized by midline structural development defects during embryogenesis, including structural brain abnormalities, developmental retardation and mental retardation2. Although the function of MID1 has been studied for many years, the effect and mechanism of complete deletion of MID1 gene on OS nervous system still need to be further explored. Here we find that Mid1 gene is necessary for the normal development of hippocampus (HPC), and Mid1 gene knockout (Mid1-/y) mice showed a significant decrease in rhythm in HPC and abnormal synchronization of {gamma} rhythm in prefrontal cortex and hippocampus (PFC-HPC), showing decreased synaptic plasticity and learning and memory dysfunction.

neuroscience↗

bioRxiv2024

Rfx3 controls outer hair cell differentiation, maintenance, and hair bundle formation by regulating the expression of Insm1, Ikzf2, and Triobp genes

The RFX family of transcription factors plays crucial roles in the regulation of ciliogenesis and organ development. Mutations of RFX transcription factors lead to various genetic diseases, including ciliopathies and hearing loss, although the underlying mechanisms remain unclear. This study comprehensively analyzed the expression patterns of RFX family members during different inner ear developmental stages. Rfx3 and Rfx7 were identified as the dominantly expressed members in cochlear hair cells, exhibiting alternative splicing variants and dynamic subcellular localization at different stages. Integration of single-cell transcriptomics, ChIP-seq, and ATAC-seq data indicates that Rfx3 functions as either a transcriptional activator or repressor, binding to numerous genes related to ciliogenesis, hair bundle structures, and planar cell polarity. Rfx3 regulates the spatiotemporal expression of hair bundle gene Triobp in hair cells by binding to and modulating its intronic enhancer. Additionally, Rfx3 binds to hair cell differentiation and fate determination genes Tbx2, Insm1, and Ikzf2. The results demonstrate that Rfx3 and Rfx7 are dominantly expressed in outer hair cells, with their subcellular localization shifting to cytoplasm at later developmental stages. This suggests a previously unknown function of Rfx3 and Rfx7 beyond transcriptional regulation, highlighting their complex roles in hair cell differentiation and maintenance.

developmental biology↗

bioRxiv2024

Glucomannan engineering highlights the role of galactosyl modification in fine-tuning cellulose-glucomannan interaction in Arabidopsis cell walls

Widely found in most plant lineages, {beta}-mannans are structurally diverse polysaccharides that can bind to cellulose fibrils to form the complex polysaccharide architecture of the cell wall. Glucomannan backbones acquire variable patterns of galactosyl substitutions, depending on plant developmental stage and species. How the changes in polysaccharide structure influence its cell wall solubility or promote appropriate interaction with cellulose fibrils is poorly understood. Here, we show that fine-tuning of galactosyl modification on glucomannans is achieved by the differing acceptor recognition of mannan -galactosyltransferases (MAGTs). Biochemical analysis and 13C solid-state nuclear magnetic resonance spectroscopy of Arabidopsis with cell wall glucomannan engineered by MAGTs revealed that the degree of galactosylation strongly affects the interaction with cellulose. The findings indicate that plants tailor galactosyl modification on glucomannans for constructing an appropriate cell wall architecture, paving the way to convert properties of lignocellulosic biomass for better use.

bioengineering↗

bioRxiv2024

Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutieres Syndrome neuropathology

Microglia, the brains resident macrophages, can be reconstituted by surrogate cells - a process termed "microglia replacement." To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this systems power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutieres Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.

neuroscience↗

bioRxiv2024

Predicting speech-in-noise ability with static and dynamic auditory figure-ground analysis using structural equation modelling

Auditory figure-ground paradigms assess the ability to extract a foreground figure from a random background, a crucial part of central hearing. Previous studies have shown that the ability to extract static figures (with fixed frequencies) predicts real-life listening: speech-in-noise ability. In this study we assessed both fixed and dynamic figures: the latter comprised component frequencies that vary over time like natural speech. 159 participants (aged 18-79) with a range of peripheral hearing sensitivity were studied. We used hierarchal linear regression and structural equation modelling to examine how well speech-in-noise ability (for words and sentences) could be predicted by age, peripheral hearing, and static and dynamic figure-ground. Regression demonstrated that in addition to the audiogram and age, the low-frequency dynamic figure-ground accounted for significant variance of speech-in-noise, higher than the static figure-ground. The structural models showed that a combination of all types of figure-ground tasks predicted speech-in-noise with a higher effect size than the audiogram or age. Age influenced word perception in noise directly but sentence perception indirectly via effects on peripheral and central hearing. Overall, this study demonstrates that dynamic figure-ground explains more variance of real-life listening than static figure-ground, and the combination of both predicts real-life listening better than hearing sensitivity or age.

neuroscience↗

bioRxiv2024

British Version of the Iowa Test of Consonant Perception

The Iowa Test of Consonant Perception (ITCP) is a single-word closed-set speech- in-noise test with well-balanced phonetic features that provides a reliable testing option for real-world listening. Objectives. The current study aimed to establish a UK version of the test (B-ITCP) based on the British received pronunciation. Design. We conducted a validity test with 46 participants using the B-ITCP test, a sentence-in- noise test, and audiogram. Results. The B-ITCP demonstrated excellent test-retest reliability, cross-talker validity, and good convergent validity, consistent with the US results. Conclusions. These findings suggest that B-ITCP is a reliable measure of speech-in-noise perception, to facilitate comparative or combined studies in USA and UK. All materials (application and scripts) to run or construct the B-ITCP and ITCP are freely available online.

neuroscience↗

bioRxiv2024

Evoked resonant neural activity outperforms spectral markers in decoding sleep from the subthalamic nucleus

BackgroundDeep brain stimulation is a treatment for advanced Parkinsons disease and currently tuned to target motor symptoms during daytime. Parkinsons disease is associated with multiple nocturnal symptoms such as akinesia, insomnia and sleep fragmentation which may require adjustments of stimulation during sleep for best treatment outcome. ObjectivesThere is a need for a robust biomarker to guide stimulation titration across sleep stages. This study aimed to investigate whether evoked resonant neural activity (ERNA) is modulated during sleep. MethodsWe recorded local field potentials from the subthalamic nucleus of four Parkinsons patients with externalised electrodes while applying single stimulation pulses to investigate the effect of sleep on ERNA. ResultsWe found that ERNA features change with wakefulness and sleep stages, and are correlated with canonical frequency bands and heart rate. We further evaluated the performance of machine learning models in classifying non-REM sleep versus wakefulness and found that ERNA amplitude outperforms all spectral markers. ConclusionsGiven the heterogeneity of spectral features during sleep, their susceptibility to movement artefacts and superior classification accuracy of models using ERNA features, this study paves the way for ERNA as a marker for automatic stimulation titration during sleep and improved patient care.

neuroscience↗