Biology subjects

He, M.

Publications and source records attributed to He, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Dynamic interplay between RNA N6-methyladenosine modification and porcine reproductive and respiratory syndrome virus infection

N6-methyladenosine (m6A) has attracted significant attention for its role in various biological processes, including RNA stability, translation, and the immune response. Understanding the role of m6A in viral infections is crucial to deep the complex interaction between virus and host cells. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a significant pathogen affecting swine health worldwide. Here, we firstly identified the m6A peaks in the PRRSV genome by m6A RNA immunoprecipitation sequencing (m6A-seq). Seven m6A-enriched regions within the PRRSV genome were detected, with one located in the N protein-coding region and the others distributed across nonstructural protein-coding regions. Notably, the Nsp2-coding region contained the highest m6A peak, spanning approximately 178 nucleotides. Functional analyses demonstrated a positive correlation between m6A modification levels and PRRSV replication in porcine alveolar macrophages (PAMs), as modulating the expression of m6A methyltransferases and demethylases significantly influenced viral replication. Moreover, treatment with the universal methylation inhibitor 3-deazaadenosine (3-DAA) effectively suppressed PRRSV replication, suggesting its potential as a novel anti-PRRSV therapeutic. To further elucidate the role of m6A in PRRSV infection, we analyzed the m6A landscape in PAMs infected with pandemic and highly pathogenic PRRSV strains. Among the 4,677 transcripts exhibiting altered m6A modification levels, the MAPK14 gene as well as other genes in p38/MAPK signaling pathway potentially emerged as the preliminary targets of m6A-mediated epigenetic regulation during PRRSV infection. These findings provide new insights into the epigenetic mechanisms underlying PRRSV infection and may facilitate the development of targeted anti-PRRSV strategies and therapeutics. IMPORTANCEThe involvement of m6A in viral genome has broader implications for our understanding of virus evolution and pathogenicity. The ability of viruses to adapt to their hosts and exploit host cellular mechanisms is a critical factor in their success as pathogens. As m6A is a modification that can be manipulated by both host and virus, studying its role in viral infections may reveal new insights into viral evolution. Understanding how different viruses utilize m6A could inform strategies for developing antiviral therapies that target these interactions. Such therapies could disrupt the ability of viruses to exploit m6A modifications, potentially reducing their virulence and enhancing host defenses.

microbiology↗

bioRxiv2024

Cross-tissue Graph Attention Networks for Semi-supervised Gene Expression Prediction

High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with Graph Attention Networks (gemGAT), a novel approach leveraging Graph Attention Networks (GATs) to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene co-expressions and non-linear relationships. Validated through extensive experiments with Genotype-Tissue Expression (GTEx) data and a case study from the Alzheimers Disease Neuroimaging Initiative (ADNI), gemGAT demonstrates superior performance over existing methods by efficiently capturing non-linear gene co-expressions. This advancement underscores gemGATs potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.

bioinformatics↗

bioRxiv2024

Interpretable PROTAC degradation prediction with structure-informed deep ternary attention framework

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional ligands that form ternary complexes with Protein Of Interests (POIs) and E3 ligases, exploiting the ubiquitin-proteasome system to degrade disease-associated proteins, promising to drug the undruggable. While PROTAC research primarily relies on costly and time-consuming wet experimental approaches, deep learning offers a promising avenue to accelerate development and reduce expenses. However, existing deep learning methods for PROTAC degradation prediction often overlook the significance of hierarchical molecular representation and protein structural information, hindering effective data modeling. Moreover, their black-box nature limits the interpretability of computational outcomes, failing to provide intuitive insights into substructure interactions within the PROTAC system. This study introduces PROTAC-STAN, a structure-informed deep ternary attention network (STAN) framework for interpretable PROTAC degradation prediction. PROTAC-STAN represents PROTAC molecules across atom, molecule, and property hierarchies and incorporates structure information for POIs and E3 ligases using a protein language model infused with structural data. Furthermore, it simulates interactions among three entities at the atom and amino acid levels via a novel ternary attention network tailored for the PROTAC system, providing unprecedented insights into the degradation mechanism. By integrating hierarchical PROTAC molecule representation, structural embedding of POI and E3 ligase, and ternary attention network modeling interactions, our approach substantially improves prediction accuracy by 10.95% while enabling significant model interpretability via atomic and residue level visualization of molecule and complex. Experiments on the refined public PROTAC dataset demonstrate that PROTAC-STAN outperforms state-of-the-art baselines in overall performance. The excellent performance of PROTAC-STAN is anticipated to establish it as a foundational tool in future research on PROTAC-related drugs, thereby accelerating the development of this field.

bioinformatics↗

bioRxiv2024

Improved split prime editors enable efficient in vivo genome editing

Prime editor (PE) is a precise genome-editing tool that enables all 12 possible base-to-base conversions, as well as insertions and deletions, that does not require DSBs or donor DNA. The efficient delivery of prime editors in vivo is critical for realizing the full potential of prime editing in disease modeling and therapeutic correction. Although PE has been divided into two halves and delivered using dual adeno-associated viruses (AAVs), editing efficiency at different gene loci varies among split sites, and efficient split sites within Cas9 nickase are limited. In this study, by screening multiple split sites, we demonstrated that 1115 (Asn) is an efficient split site when delivering PE by dual-AAV. Besides, we utilized a feature reported by others recently that RNase could be detached from the Cas9n and designed split sites in the first half of Cas9n. We found that split-PE-367 enabled high prime editing efficiency with Rma intein. To test the editing efficiency in vivo, dual-AAV split-ePE3-367 was packaged in AAV9 and delivered by tail vein injection in mice, achieving 24.4% precise genome editing 4 weeks after injection. Our findings establish an alternative split-PE architecture that could achieve robust gene editing efficiency, facilitating the potential utility both in model organisms and as a therapeutic modality.

genomics↗

bioRxiv2024

High-throughput Generation of Collagen Microbeads for 3D Cell Culture and Extracellular Vesicle Production

Collagen type I, a fundamental component of natural extracellular matrices across species, is an attractive material for the development of tissue engineering constructs. Nevertheless, the poor mechanical properties and thermal instability hinder its use for specific construction of 3D cultures and 3D printing. In this study, we present a microfluidic high-throughput approach for producing high-quality and uniform collagen microbeads without introducing any chemical modification. We achieved rapid and uniform collagen droplet fabrication with sizes spanning from 50 {micro}m to 1200 {micro}m in a production rate of up to 10000 droplets per minute. The resulting collagen microbeads can serve as numerous microbioreactors which are suspended in the culture medium without precipitation and are ideal for 3D cell growth. We demonstrated excellent cell compatibility, facilitating cell attachment and proliferation, as well as promoting extracellular vesicle secretion from collagen microbeads. This technology is facile and versatile for high throughput 3D cell culture, heterogeneous tissue modeling, and extracellular vesicle production, which is essential in drug delivery and drug screening.

bioengineering↗

bioRxiv2024

Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naive localised prostate cancer

Localised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naive localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease. Statement of SignificanceOur study leverages single-cell RNA-sequencing and spatial transcriptomics to provide a comprehensive cellular annotation of hormone therapy-naive localised PCa. We reveal widespread molecular perturbations in epithelial cells and map distinct fibroblast populations to specific anatomical niches. Notably, we identify a novel peri-neural phenotype associated with nerves, which merits further functional characterisation and exploration as a potential therapeutic target.

cancer biology↗

bioRxiv2024

Identification of leptolin as a novel anti-obesity adipokine

Adipokines are key factors in regulating energy homeostasis. We identified a novel adipokine; we named it Leptolin. In humans, leptolin levels in white adipose tissue were positively corrected with exercise, and negatively associated with body mass index. Leptolin levels were positively correlated with lipolysis-promoting gene expression. Elevated leptolin in plasma of athletes, whereas lowered leptolin in plasma of obese individuals were observed. Leptolin gene-knockout mice exhibited increased adiposity and body weight, and decreased energy expenditure. Leptolin gene-overexpression mice showed obesity-resistant phenotypes. Treatment with leptolin promoted fat mobilization and energy expenditure, and reduced body weight, without affecting food-intake and motor activity. Together, leptolin, a novel adipokine with a capacity to improve metabolic status, may serve as a new therapeutic agent for obesity and metabolic disorders.

physiology↗

bioRxiv2024

Haplotype-resolved genome assembly of upland switchgrass provides insights into cold tolerance

Switchgrass (Panicum virgatum L.) is a bioenergy and forage crop. Upland switchgrass exhibits superior cold tolerance than lowland ecotype, but the underlying molecular mechanisms remain unclear. Here, we presented a high-quality haplotype-resolved genome of the upland ecotype Jingji31 and conducted multi-omics analysis to understand its cold tolerance. The divergence between upland and lowland ecotypes of switchgrass occurred after the differentiation of the two subgenomes (K and N). Under cold stress, the K subgenome has more differentially expressed genes (DEGs). Transcriptome analysis revealed ecotype-specific differential expressions among members of the cold-responsive (COR) gene families. Specifically, certain members of the AFB1, ATL80, HOS10, and STRS2 gene families exhibited opposite expression changes between the two ecotypes, potentially contributing to their differential cold tolerance. By using haplotype-resolved genome, we identified more cold-induced allele-specific expressions (ASEs) in the upland ecotype, and these ASEs were significantly enriched in the COR gene families. Genome-wide association study detected an association signal on Chr3K related to overwintering rate, which overlapped with a selective sweep region and contained a cytochrome P450 (CYP450) gene highly expressed under cold stress. Heterologous overexpression of CYP450 in rice alleviated leaf wilting and improved cold tolerance. Our study provides a high-quality haplotype-resolved genome of upland switchgrass, to advance conceptual understanding of plant cold tolerance for breeding crops with enhanced cold adaptation.

genomics↗

bioRxiv2024

Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer

Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation ({micro}DES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation. In this study, we demonstrated that {micro}DES-based PROTAC loading in EVs significantly enhanced therapeutic function of PROTAC drug in vivo in the TNBC breast tumor mouse model. NSG mice with pre-established MDA-MB-231 tumors and treated with intraperitoneal injection of EVs for tumor inhibition study, which showed significantly higher HDAC 3 and 8 degradation efficiency and tumor inhibition than PROTAC only group. The liver, spleen, kidney, lung, heart, and brain were collected for safety testing, which exhibited improved toxicity. The EV delivery of PROTAC drug enhances drug stability and bioavailability in vivo, transportability, and drug targeting ability, which fills an important gap in current development of PROTAC therapeutic functionality in vivo and clinical translation. This novel EV-based drug transfection and delivery strategy could be applicable to various therapeutics for enhancing in vivo delivery, efficacy, and safety.

bioengineering↗

bioRxiv2024

Extracellular Vesicle-Associated Neutrophil Elastase Activates Hepatic Stellate Cells and Promotes Liver Fibrogenesis via ERK1/2 Pathway

Liver fibrosis associated with increased mortality is caused by activation of hepatic stellate cells and excessive production and accumulation of extracellular matrix in response to fibrotic insults. It has been shown that in addition to liver inflammation, systemic inflammation also contributes to liver fibrogenesis. A deeper understanding of mechanisms that control liver fibrotic response to intra-and extra-hepatic inflammation is essential to develop novel clinical strategies against this disease. Extracellular vesicles (EV) have been recognized as immune mediators that facilitate activation of hepatic stellate cells. In inflammatory diseases, activated neutrophils release neutrophil elastase (NE) bound to EV, which has been identified as a significant contributor to inflammation by promoting immune cell activation. Here, we aimed to explore the role of inflammation derived plasma EV-associated NE in liver fibrogenesis and its potential mechanisms. We show EV-associated NE induces activation, proliferation and migration of hepatic stellate cells by promoting activation of the ERK1/2 signaling pathway. This effect did not occur through EV without surface NE, and Sivelestat, a NE inhibitor, inhibited activation of the ERK1/2 signaling pathway mediated by EV-associated NE. Moreover, we found plasma EV-associated NE increases deposition of collagen1 and -smooth muscle actin in the liver of a mouse model of liver fibrosis (Mdr2-/-). Notably, this effect does not occur in control mice without preexisting liver disease. These data suggest that EV-associated NE is a pro-fibrogenic factor for hepatic stellate cell activation via the ERK1/2 signaling pathway in pre-existing liver injuries. Inhibition of the plasma EV-associated NE in inflammatory conditions may be a therapeutic target for liver fibrosis in patients with inflammatory diseases.

cell biology↗

bioRxiv2024

Ultra-low photodamage three-photon microscopy assisted by neural network for monitoring regenerative myogenesis

Three-photon microscopy (3PM) enables high-resolution three-dimensional (3D) imaging in deeply situated and highly scattering biological specimens, facilitating precise characterization of biological morphology and cellular-level physiology in vivo. However, the use of fluorescent probes with relatively low three-photon absorption cross-sections necessitates high-peak-power lasers for excitation, which poses inherent risks of light-induced damage. Additionally, the low repetition frequency of these lasers prolongs scanning time per pixel, hampering imaging speed and exacerbating the potential for photodamage. Such limitations hinder the application of 3PM in studying vulnerable tissues, including muscle regeneration. To address this critical issue, we developed the Multi-Scale Attention Denoising Network (MSAD-Net), a precise and versatile denoising network suitable for diverse structures and varying noise levels. Our network enables the use of lower excitation power (1/4-1/2 of the common power) and shorter scanning time (1/6-1/4 of the common time) in 3PM while preserving image quality and tissue integrity. It achieves an impressive structural similarity index (SSIM) of up to 0.9932 and an incredibly fast inference time of just 80 milliseconds per frame which ensured both high fidelity and practicality for downstream applications. By utilizing MSAD-Net-assisted imaging, we comprehensively characterize the biological morphology and functionality of muscle regeneration processes through deep in vivo five-channel imaging under extremely low excitation power and short scanning time, while maintaining a high signal-to-background ratio (SBR) and excellent axial spatial resolution. Furthermore, we conducted high axial-resolution dynamic imaging of vascular microcirculation, macrophages, and ghost fibers. Our findings provide a deeper understanding of the mechanisms underlying muscle regeneration at the cellular and tissue levels.

developmental biology↗

bioRxiv2024

Identifying Causal Relations between Gut Microbiome, Metabolic Dysfunction-Associated Fatty Liver Disease and the Novel Mediators of Blood Metabolites

BackgroundResearch has established connection between gut microbiome and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the causal relationships and the roles of potential mediating factors, such as blood metabolites, remain unclear. MethodsWe conducted a bidirectional and mediation Mendelian randomization (MR) study using the genome-wide summary statistics of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n =8,299), and the largest MAFLD GWAS data (1,483 cases and 17,781 controls). We used the inverse-variance weighted estimation method as our primary approach. The multivariable Mendelian randomization (MVMR) and two-step MR approaches were used to prioritize the most likely causal metabolites as mediators. Additionally, we conducted linkage disequilibrium score regression (LDSC) analyses to assess genetic correlations, and downstream gene-based analyses to investigate the shared biological mechanism. ResultsBy testing the causal effects of 205 bacterial pathways and 207 taxa on MAFLD, we identified 5 microbial taxa causally associated with MAFLD, notably the species Parabacteroides merdae (OR [95%CI] = 1.191[1.022-1.388], p = 0.025). Among 1,399 blood metabolites, 53 showed causal associations with MAFLD, with pregnenetriol sulfate identified as a mediator for genus Parabacteroides on MAFLD (proportion mediated = 16.30%). LDSC analysis also provided suggestive evidence for a potential genetic correlation between them (rg= 2.124, p=0.009). ConclusionsThe study suggested a novel causal relationship between gut microbial taxa and MAFLD, especially the genus Parabacteroides merdae and blood metabolite pregnenetriol sulfate might mediate this relationship. ImportanceOur study reveals novel insights into how the intersection of microorganisms living in the human gut, known as the gut microbiome, influences the development of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a condition increasingly recognized as a major global health concern. By identifying specific gut microbiome taxa and metabolites that contribute to the onset and progression of MAFLD, our findings enhance comprehension of this prevalent condition and unveil promising prospects for its prevention and intervention. We discovered that certain gut bacteria can affect the levels of blood metabolites, which in turn impact the livers health. This work carries significant implications for novel strategies for MAFLD prevention and treatment, including interventions aimed at modifying the gut microbiome. Our research underscores the gut-liver connection and its implications for metabolic diseases, contributing to future therapeutic developments that could improve public health worldwide. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/606637v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1b16347org.highwire.dtl.DTLVardef@ecf53eorg.highwire.dtl.DTLVardef@d8cb5borg.highwire.dtl.DTLVardef@10efe44_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Coordinated regulation of chemotaxis and resistance to copper by CsoR in Pseudomonas putida

Copper is an essential enzyme cofactor in bacteria, but excess copper is highly toxic. Bacteria can cope with copper stress by increasing copper resistance and initiating chemorepellent response. However, it remains unclear how bacteria coordinate chemotaxis and resistance to copper. By screening proteins that interacted with the chemotaxis kinase CheA, we identified a copper-binding repressor CsoR that interacted with CheA in Pseudomonas putida. CsoR interacted with the HPT (P1), Dimer (P3), and HATPase_c (P4) domains of CheA and inhibited CheA autophosphorylation, resulting in decreased chemotaxis. The copper-binding of CsoR weakened its interaction with CheA, which relieved the inhibition of chemotaxis by CsoR. In addition, CsoR bound to the promoter of copper-resistance genes to inhibit gene expression, and copper-binding released CsoR from the promoter, leading to increased gene expression and copper resistance. P. putida cells exhibited a chemorepellent response to copper in a CheA-dependent manner, and CsoR inhibited the chemorepellent response to copper. Besides, the CheA-CsoR interaction also existed in proteins from several other bacterial species. Our results revealed a mechanism by which bacteria coordinately regulated chemotaxis and resistance to copper by CsoR.

microbiology↗

bioRxiv2024

Smooth Muscle Cells-Expressed Bmal1 Regulates Vascular Calcification Independent of the Canonical Circadian Pathway

Vascular calcification is a major cardiovascular issue that increases morbidity and mortality in diabetes patients. While dysregulation of the circadian master regulator Basic Helix-Loop-Helix ARNT-Like Protein 1 (Bmal1) in vascular smooth muscle cells (VSMC) under diabetic conditions has been suggested, its role in vascular calcification is unclear. In VSMC, Bmal1 was upregulated under high glucose treatment and in aortic tissues from a diabetic mouse model. RNA sequencing from isolated VSMC between Bmal1 deletion and wildtype mice indicated Bmal1s pro-calcification role. Indeed, reduced levels of the osteogenic master regulator, Runt-Related Transcription Factor 2 (Runx2), were found in Bmal1 deletion VSMC under diabetic conditions. Alizarin red staining showed reduced calcification in Bmal1 deletion VSMC in vitro and vascular rings ex vivo. Furthermore, in a diabetic mouse model, SMC-Bmal1 deletion showed reduced calcium deposition in aortas. Collectively, diabetes-upregulated circadian regulator Bmal1 in VSMC contributes to vascular calcification. Maintaining normal circadian regulation may improve vascular health in diabetes.

molecular biology↗

bioRxiv2024

Muscone-specific olfactory protein reveals the putative scent-marking pheromone in the Sunda pangolin (Manis javanica)

The Sunda pangolin (Manis javanica) is a burrowing and nocturnal animal, and they have poor vision, thus, intraspecies communication relies on olfaction, such as mating, warning, and scent-marking. However, the intraspecies pheromone in pangolins remains unknown. In this study, all the odorant-binding proteins in Sunda pangolins were functionally expressed, and they were screened against a panel of 32 volatiles that were derived from the pangolins urine, feces, and anal gland secretions. Reverse chemical ecology identified that M. javanica odorant-binding protein 3 (MjavOBP3) possesses the highest binding affinity to muscone. A subsequent behavior-tracking assay showed that only males can sense muscone; thus, we hypothesize that muscone is a male-specific scent-marking pheromone. Meanwhile, the structural study showed that Tyr117 contributes the most to muscones binding, which was further validated by site-directed mutagenesis. The findings clarify the scent-marking mechanism in pangolins, and muscone could potentially be used to support the monitoring and conservation of this endangered animal. Author SummaryThe Sunda pangolin is an endangered mammal that is native to Southeast Asia and is threatened due to its economic value. They are cave-living and nocturnal, poor vision; thus, their intraspecies communication is highly reliant on olfaction. Although they are generally solitary, they have been observed to have some social aspects in the wild, such as breeding and territorial behaviors, which are mediated by scents. However, no previous study has investigated the type of pheromones and how they are detected. Using the reverse chemical ecology approach, MjavOBP3 was found to bind to muscone with high affinity, and behavior-tracking assay was performed under well-controlled artificial rearing conditions, which showed only male pangolins can recognize muscone, suggesting its potential male-specific pheromone role.

zoology↗

bioRxiv2024

Imaging demyelinated axons after spinal cord injuries with PET tracer 3F4AP

Spinal cord injuries (SCI) often lead to lifelong disability. Among the various types of injuries, incomplete and discomplete injuries, where some axons remain intact, offer potential for recovery. However, demyelination of these spared axons can worsen disability. Demyelination is a reversible phenomenon, and drugs like 4-aminopyridine (4AP), which target K+ channels in demyelinated axons, show that conduction can be restored. Yet, accurately assessing and monitoring demyelination post-SCI remains challenging due to the lack of suitable imaging methods. In this study, we introduce a novel approach utilizing the positron emission tomography (PET) tracer, [18F]3F4AP, specifically targeting K+ channels in demyelinated axons for SCI imaging. Rats with incomplete contusion injuries were imaged up to one month post-injury, revealing [18F]3F4APs exceptional sensitivity to injury and its ability to detect temporal changes. Further validation through autoradiography and immunohistochemistry confirmed [18F]3F4APs targeting of demyelinated axons. In a proof-of-concept study involving human subjects, [18F]3F4AP differentiated between a severe and a largely recovered incomplete injury, indicating axonal loss and demyelination, respectively. Moreover, alterations in tracer delivery were evident on dynamic PET images, suggestive of differences in spinal cord blood flow between the injuries. In conclusion, [18F]3F4AP demonstrates efficacy in detecting incomplete SCI in both animal models and humans. The potential for monitoring post-SCI demyelination changes and response to therapy underscores the utility of [18F]3F4AP in advancing our understanding and management of spinal cord injuries.

neuroscience↗

bioRxiv2024

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally

The stability of functional brain network is maintained by homeostatic plasticity, which restores equilibrium following perturbation. As the initiation site of action potentials, the axon initial segment (AIS) of glutamatergic projection neurons (PyNs) undergoes dynamic adjustment that exerts powerful control over neuronal firing properties in response to changes in network states. Although AIS plasticity has been reported to be coupled with the changes of network activity, it is poorly understood whether it involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input to the AIS of cortical PyNs, specifically from chandelier cells (ChCs), are sufficient to drive homeostatic tuning of the AIS within 1-2 weeks, while those from parvalbumin-positive basket cells do not. This tuning is reflected in the morphology of the AIS, the expression level of voltage-gated sodium channels, and the intrinsic neuronal excitability of PyNs. Interestingly, the timing of AIS tuning in PyNs of the prefrontal cortex corresponds to the recovery of changes in social behavior caused by alterations of ChC synaptic transmission. Thus, homeostatic plasticity of the AIS at postsynaptic PyNs may counteract deficits elicited by imbalanced ChC presynaptic input. TeaserAxon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.

neuroscience↗

bioRxiv2024

A Mixed Effect Similarity Matrix Regression Model (SMRmix) for Integrating Multiple Microbiome Datasets at Community Level and its Application in HIV

BackgroundRecent studies have highlighted the importance of human microbiota in our health and diseases. However, in many areas of research, individual microbiome studies often offer inconsistent results due to the limited sample sizes and the heterogeneity in study populations and experimental procedures. This inconsistency underscores the necessity for integrative analysis of multiple microbiome datasets. Despite the critical need, statistical methods that incorporate multiple microbiome datasets and account for the study heterogeneity are not available in the literature. MethodsIn this paper, we develop a mixed effect similarity matrix regression (SMRmix) approach for identifying community level microbiome shifts between outcomes. SMRmix has a close connection with the microbiome kernel association test, one of the most popular approaches for such a task but is only applicable when we have a single study. SMRmix enables researchers to consolidate findings from diverse microbiome studies. ResultsVia extensive simulations, we show that SMRmix has well-controlled type I error and higher power than some potential competitors. We applied the SMRmix to two real-world datasets. The first, from the HIV-reanalysis consortium, integrated data from 17 studies on gut dysbiosis in HIV. Our analysis confirmed consistent associations between the gut microbiome and HIV infection as well as MSM (men who have sex with men) status, demonstrating greater power than competing methods. The second dataset involved 11 studies on the gut microbiome in colorectal cancer; analysis with SMRmix confirmed significant dysbiosis in affected individuals compared to healthy controls. ConclusionThe development of SMRmix enables the integration of multiple studies and effectively managing study heterogeneity, and provides a powerful tool for uncovering consistent associations between diseases and community-level microbiome data.

bioinformatics↗