Biology subjects

Gao, X.

Publications and source records attributed to Gao, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma

PurposeAdenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental DesignWe leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-{psi} or a STING agonist. ResultsmIF demonstrated that ACC tumors are immunologically cold, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-{psi} or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. ConclusionsLow/absent HLA/B2M expression may explain ACC tumors immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.

cancer biology↗

bioRxiv2024

Single-Cell Analysis Reveals Critical Role of Macrophage Epsin in Regulating Origin of Foam Cell in Atherosclerosis

Atherosclerosis is a chronic inflammatory condition characterized by the excessive accumulation of fat and lipid molecules, leading to the formation of foam cells and plaques in arterial walls. Dysfunction of vascular smooth muscle cells (VSMCs), fibroblast, endothelial cells, and macrophages is often associated with this pathology. We found that epsins accelerate atherosclerosis progression in individuals on a Western diet (WD). Using ApoE-deficient (ApoE-/-) and macrophage-specific epsin deletion in ApoE-/- backgrounds (LysM-DKO/ApoE-/-) mice fed a WD for 16 weeks, we observed significantly reduced foam cell formation in LysM-DKO/ApoE-/- mice compared to ApoE-/- mice. Single-cell RNA sequencing identified 20 major cell types, including seven VSMC and five macrophage subtypes. Among the VSMC subtypes, modulating VSMC1 was involved in inflammation and migration, while modulating VSMC2 was associated with VSMC phenotype switching. In atherosclerotic mice, populations of modulating VSMC1, VSMC2, foamy-Trem2, and inflammatory macrophages increased, but significantly decreased in epsin-deficient mice. Modulating VSMC2 transition into macrophages occurred with a probability of 0.57 in ApoE-/- mice, compared to 0.01 in LysM-DKO/ApoE-/- mice. Epsin deletion also reversed endothelial dysfunction and downregulated cholesterol and glucose-mediated signals, as well as inflammatory ligands Il1b and C1qa. Our findings suggest that epsin deletion reduces foam cell formation and rewires VSMC and endothelial functions, offering a novel therapeutic strategy for atherosclerosis.

cell biology↗

bioRxiv2024

MED26-enriched condensates drive erythropoiesis through modulating transcription pausing

The Mediator complex regulates various aspects of hematopoietic development, but whether composition of the Mediator complex undergoes dynamic changes for diversifying transcription and functional outputs is unknown. Here, we found that MED26, a subunit in the core Mediator complex, played a distinctive role in facilitating transcription pausing essential for erythroid development. While most Mediator subunits drastically decreased during this process, MED26 remained relatively abundant. Intriguingly, in the early stages, more than half of MED26 occupancy sites did not co-localize with MED1, a representative Mediator subunit, suggesting these subunits exert context-dependent gene regulation. We revealed that MED26-enriched loci were associated with RNA polymerase pausing. MED26 manifested a markedly preferential recruitment of pausing-related factors, leading to an increase in Pol pausing critical for genome-wide transcription repression during erythropoiesis. Moreover, MED26 exhibited pronounced condensate-forming capability, which was necessary for its function in promoting erythropoiesis and recruiting pausing-related factors. Collectively, this study provides mechanistic insights into the functional coordination of distinct Mediator subunits during development and highlights the switch of transcription condensates towards a MED26 enriched form, which modulates transcription pausing to facilitate transcription repression and erythroid development.

cell biology↗

bioRxiv2024

A bone-derived protein primes rapid visual escape via GPR37 receptor in a subpopulation of VTA GABAergic neurons

Rapid escape against visual threats is critical for survival. Whether it requires a permissive mechanism is unknown. Here, we show that osteocalcin (OCN), a protein produced by bone and persisted in the brain, primes rapid visual escape response by increasing excitability of VTA GABAergic neuron subpopulation via OCN-GPR37-cAMP-THIK-1 (K2P13.1) pathway. Knock-out of OCN or its receptor GPR37, and conditional knock-out of GPR37 in VTA GABAergic or glutamatergic neurons caused delayed escape. Reconstituting OCN-GPR37 signaling specifically in VTA was sufficient to restore normal response. Single-cell transcriptomics combined with electrophysiology showed that OCN decreases potassium currents in a subpopulation of VTA GABAergic neurons via GPR37-induced cAMP reduction and subsequent THIK-1 suppression. This elevation of excitability in VTA neuron subpopulation can be recapitulated by HM4Di, an inhibitory chemogenetic GPCR commonly used to suppress neuronal activity. Our study demonstrated that visual behavior requires a bone-derived protein that tunes electrophysiology of central nervous system neurons. Graph AbstractO_ST_ABSIn briefC_ST_ABSThe bone-brain axis regulates visual escape behavior. Osteocalcin (OCN), a small protein secreted by bone, plays a permissive role in rapid visual escape. This is achieved through GPR37 receptor expressed in a subpopulation of VTA GABAergic neurons. OCN-GPR37 signaling increases neuronal excitability by decreasing K+ current via THIK-1 channel suppression. HighlightsO_LIThe bone-derived protein osteocalcin and its receptor GPR37 in VTA are required for rapid visual escape response. C_LIO_LIGPR37 is expressed in a subpopulation of VTA GABAergic neurons and primes rapid visual escape. C_LIO_LIOsteocalcin-GPR37 signaling increases neuronal excitability by suppressing THIK-1 (K2P13.1) channel via cAMP reduction. C_LIO_LIActivation of HM4Di increases excitability of subpopulation of VTA GABAergic neurons and enhances rapid visual escape. C_LI O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/607510v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1b7ef5dorg.highwire.dtl.DTLVardef@c3eea2org.highwire.dtl.DTLVardef@167dd75org.highwire.dtl.DTLVardef@1fc5613_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

B cells targeting parasites capture spatially linked antigens to secure T cell help

Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and viruses 1,2. In these contexts, B cells internalize the entire antigen or pathogen, and present a range of antigens to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens (such as parasites) that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help may enhance the initiation and maintenance of humoral immune responses to complex pathogens.

immunology↗

bioRxiv2024

PRMT7 mediated PTEN activation promotes bone formation in female mice

Although the epigenetic mechanisms underlying bone formation are recognized, their specific roles and regulatory pathways remain largely unexplored. In this study, we unveil PRMT7 as a novel epigenetic modulator of MSCs osteogenic commitment. The conditional knockout of Prmt7 in mice reveals significantly impaired osteogenesis and bone regeneration exclusively in females, affecting both long bones and craniofacial structures, with no discernible impact in males. Our findings demonstrate that PRMT7 orchestrates osteogenic differentiation through a methyltransferase-dependent manner. Mechanistically, PRMT7 modulates MSCs osteogenic differentiation through the activation of PTEN. Specifically, PRMT7 augments PTEN transcription by increasing H3R2me1 levels at the PTEN promoter. Furthermore, PRMT7 interacts with the PTEN protein, and its deficiency leads to the ubiquitination and subsequent degradation of nuclear PTEN, revealing an unprecedented pathway. Crucially, PTEN overexpression ameliorates the osteogenic deficits observed in Prmt7-deficient mice. Our research positions PRMT7 as a potential therapeutic target to enhance bone formation and offers novel molecular insights into the PRMT7-PTEN regulatory axis, underscoring its significance in bone biology and regenerative medicine. Subject Categories Developmental Biology, Musculoskeletal System, Epigenetics, Post-translational Modifications

developmental biology↗

bioRxiv2024

The connectional diaschisis and normalization of cortical language network dynamics after basal ganglia and thalamus stroke

Stroke affecting the basal ganglia and thalamus can lead to language deficits. In addition to the lesions direct impact on language processing, connectional diaschisis involving cortical-subcortical interactions also plays a critical role. This study investigated connectional diaschisis using the "dynamic meta-networking framework of language" in patients with basal ganglia and thalamus stroke, analyzing longitudinal resting-state fMRI data collected at 2 weeks (n = 32), 3 months (n = 19), and one year post-stroke (n = 23). As expected, we observed dynamic cortico-subcortical interactions between cortical language regions and subcortical regions in healthy controls (HC, n = 25). The cortical language network exhibited dynamic domain-segregation patterns in HCs, severely disrupted in the acute phase following stroke. The connectional diaschisis manifested as dual effects characterized by both hypo- and hyper-connectivity, which positively and negatively correlated with language deficits, respectively. State-specific changes in nodal and topological properties were also identified. Throughout language recovery, cortical language network dynamics gradually normalized toward sub-optimal domain-segregation patterns, accompanied by the normalization of nodal and topological properties. These findings underscore the crucial role of cortico-subcortical interactions in language processing.

neuroscience↗

bioRxiv2024

How do we imagine a speech? A triple network model for situationally simulated inner speech

Inner speech is a silent verbal experience and plays central roles in human consciousness and cognition. Despite impressive studies over the past decades, the neural mechanisms of inner speech remain largely unknown. In this study, we adopted an ecological paradigm called situationally simulated inner speech. Unlike mere imaging speech of words, situationally simulated inner speech involves the dynamic integration of contextual background, episodic and semantic memories, and external events into a coherent structure. We conducted dynamic activation and network analyses on fMRI data, where participants were instructed to engage in inner speech prompted by cue words across 10 different contextual backgrounds. Our seed-based co-activation pattern analyses revealed dynamic involvement of the language network, sensorimotor network, and default mode network in situationally simulated inner speech. Additionally, frame-wise dynamic conditional correlation analysis uncovered four temporal-reoccurring states with distinct functional connectivity patterns among these networks. We proposed a triple network model for deliberate inner speech, including language network for a truncated form of overt speech, sensorimotor network for perceptual simulation and monitoring, and default model network for integration and sense-making processing. HighlightsO_LIIn ten contextual backgrounds, subjects were instructed to perform situationally simulated inner speech based on cue words. C_LIO_LIThe ventral parts of the bilateral somatosensory areas and middle superior temporal gyrus were as centers for seed-based co-activation pattern analyses. C_LIO_LIA triple network model of language network, sensorimotor network, and default mode network was proposed for deliberate inner speech. C_LI

neuroscience↗

bioRxiv2024

A systematic evaluation of dynamic functional connectivity methods using simulation data

Numerous dynamic functional connectivity (dFC) methods have been proposed to study time-resolved network reorganization in rest and task fMRI. However, a comprehensive comparison of their performance is lacking. In this study, we compared the efficacy of seven dFC methods (and their enhanced versions) to track transient network reconfiguration using simulation data. The seven methods include flexible least squares (FLS), dynamic conditional correlation (DCC), general linear Kalman filter (GLKF), multiplication of temporal derivatives (MTD), sliding-window functional connectivity with L1-regularization (SWFC), hidden Markov models (HMM), and hidden semi-Markov models (HSMM). Multiple datasets of non-fMRI-BOLD and fMRI-BOLD signals with predefined covariance structures, signal-to-noise ratio levels, and sojourn time distributions were simulated. We adopted inter-subject analysis to eliminate the effects of signals of non-interest, resulting in enhanced methods: ISSWFC, ISMTD, ISDCC, ISFLS, ISKF, ISHMM, and ISHSMM. Efficacy was defined as the spatiotemporal association between simulated and estimated data. We found that all enhanced dFC methods outperformed their original versions. Efficacies depend on several factors, such as considering the neurovascular effect in simulated data, the covariance structure between two time series, state sojourn distribution, and signal-to-noise ratio levels. These results highlight the importance of selecting appropriate dFC methods in fMRI study.

neuroscience↗

bioRxiv2024

Large-scale genome analyses provide insights into Hymenoptera evolution

The order Hymenoptera includes a large number of species with diverse lifestyles and is known for its significant contributions to natural ecosystems. To better understand the evolution of this diverse order, we performed large-scale comparative genomics on 131 species from 13 superfamilies, covering most representative groups. We used these genomes to reveal an overall pattern of genomic change in terms of gene content and evolutionary rate throughout hymenopteran history. We identified genes that possibly contributed to the evolution of several key innovations, such as parasitoidism, wasp-waist, sting, and secondary phytophagy. We also discovered the distinct genomic trajectories between the clade containing major parasitoid wasps (Parasitoida) and stinging species (Aculeata) since their divergence, which are involved in many aspects of genomic change, such as rapidly evolving gene families, gene gain and loss, and metabolic pathway evolution. In addition, we explored the genomic features accompanying the three independent evolution of secondary phytophagy. Our work provides insights for understanding genome evolution and the genomic basis of diversification in Hymenoptera.

genomics↗

bioRxiv2024

Optical Torque Calculations and Measurements for DNA Torsional Studies

The angular optical trap (AOT) is a powerful instrument for measuring the torsional and rotational properties of a biological molecule. Thus far, AOT studies of DNA torsional mechanics have been carried out using a high numerical aperture oil-immersion objective, which permits strong trapping, but inevitably introduces spherical aberrations due to the glass-aqueous interface. However, the impact of these aberrations on torque measurements is not fully understood experimentally, partly due to a lack of theoretical guidance. Here, we present a numerical platform based on the finite element method to calculate forces and torques on a trapped quartz cylinder. We have also developed a new experimental method to accurately determine the shift in the trapping position due to the spherical aberrations by using a DNA molecule as a distance ruler. We found that the calculated and measured focal shift ratios are in good agreement. We further determined how the angular trap stiffness depends on the trap height and the cylinder displacement from the trap center and found full agreement between predictions and measurements. As further verification of the methodology, we showed that DNA torsional properties, which are intrinsic to DNA, could be determined robustly under different trap heights and cylinder displacements. Thus, this work has laid both a theoretical and experimental framework that can be readily extended to investigate the trapping forces and torques exerted on particles with arbitrary shapes and optical properties. SIGNIFICANCEWe developed a simulation platform based on the finite element method for force and torque calculation for particles in an angular optical trap (AOT), with considerations of tightly focused Gaussian beam, spherical aberrations, and optically anisotropic particles. Experimental measurements of focal shift ratio, force, and torque under multiple conditions were in good agreement with predictions from the simulations. We also demonstrated that intrinsic DNA torsional properties can be robustly measured under different AOT measurement conditions, strongly validating our simulations and calibrations. Our platform can facilitate trapping particle design for single-molecule assays using the AOT.

biophysics↗

bioRxiv2024

Genome sequencing of 'Fuji' apple clonal varieties reveals evolutionary history and genetic mechanism of the spur-type morphology

Somatic variations arising during asexual reproduction can lead to the emergence of bud sports exhibiting advantageous traits, forming the basis for bud sport breeding in perennial plants. Here, we report a near-complete, fully phased genome assembly of Fuji apple, enabling comprehensive identification of somatic variants across 74 clonally propagated Fuji varieties. Phylogenetic analysis of Fuji sport varieties indicates that the emergence of spur-type and early maturation traits results from multiple independent formation events. A number of putative functional somatic variants are identified, including one spur-type specific deletion located in the promoter of the TCP transcription factor gene MdTCP11. DNA methylation level of the deletion-associated miniature inverted-repeat transposable element is lower in the spur-type varieties compared to the standard-type varieties, while the expression of MdTCP11 is significantly higher. Overexpression of MdTCP11 in apple decreases the plant height, highlighting its important role in the development of spur-type apple varieties. This study sheds light on the 80-year cloning history of Fuji and provides valuable candidate causative mutations for apple breeding.

plant biology↗

bioRxiv2024

Stabilizing mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes at the molecular level remains incompletely understood. Here, we discover a significant enrichment of RNA G-quadruplex (rG4) motifs around splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Focusing on cold-induced neuroprotective RBM3, we demonstrate that rG4s near splice sites of a cold-repressed poison exon are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Additionally, increasing intracellular potassium concentration stabilizes rG4s and enhances RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia. HighlightsO_LIrG4s are enriched near splice sites of cassette exons repressed upon cold shock C_LIO_LIrG4s act as RNA thermometers in mammals by controlling accessibility of splice sites C_LIO_LIrG4 stability mediates temperature-dependent RBM3 expression ex vivo and in vivo C_LIO_LIStabilizing rG4s in RBM3 exon 3a reduces brain damage in subarachnoid hemorrhage C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/594628v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@e1d625org.highwire.dtl.DTLVardef@b22d21org.highwire.dtl.DTLVardef@1b0faeaorg.highwire.dtl.DTLVardef@294ac1_HPS_FORMAT_FIGEXP M_FIG C_FIG Here is a refined model of RNA G-quadruplexes acting as evolutionarily conserved thermo- and potassium sensors, modulating alternative splicing in mammals. RNA G-quadruplexes (rG4s) function as reversible temperature sensors, impacting alternative splicing dynamics. In low temperatures or high potassium conditions, rG4s can mask surrounding splice sites, rendering these sites inaccessible, thereby promoting exon skipping. Conversely, at high temperatures or under low potassium conditions, rG4s become destabilized, allowing splice sites to be exposed, and facilitating efficient exon inclusion. RBM3, a well-known cold-induced protein with neuroprotective functions, harbors a poison exon with rG4s around splice sites, that, upon inclusion, triggers NMD (non-sense mediated decay) of the RBM3 mRNA. Under low temperatures or high potassium conditions, rG4s shield the splice sites, leading to poison exon skipping and increased RBM3 expression. Stabilization of these rG4s through increased K+ promotes poison exon skipping, enabling escape from NMD, and ultimately elevating RBM3 expression. Notably, 4-AP, a clinically used pan voltage-gated potassium channel blocker, protects against neuronal damage in a subarachnoid hemorrhage mouse model in an RBM-dependent manner. (ISS: intronic splicing silencer, ESE: exon splicing enhancer, ACA: anterior cerebral artery, MCA: middle cerebral artery, PPA: pterygopalatine artery, ICA: internal carotid artery, ECA: external carotid artery, CCA: common carotid artery)

molecular biology↗

bioRxiv2024

The muscarinic acetylcholine receptor in dermal papilla cells regulates hair growth

The role of cholinergic system in hair biology is poorly understood. In M4 muscarinic receptor (mAChR) knockout mice, the hair follicles have a prolonged telogen phase and fail to produce hair shafts. Here, we reported that hair growth was regulated by cholinergic system via mAChRs. Dermal papilla cells expressed different cholinergic biomarkers. Inhibiting AChE or activating mAChR in dermal papilla cells, culture vibrissae and skin epidermis promoted the hair growth. In cultured papilla cells treated with bethanechol, an agonist of mAChR, an activation of Wnt/{beta}-catenin signalling was illustrated by various indicative biomarkers, including phosphorylation of GSK-3{beta} and mRNA expression of various molecules for Wnt/{beta}- catenin signalling. Activation of Wnt/{beta}-catenin signalling was mediated by PI3K/AKT and ERK signalling upon the stimulation of bethanechol. In addition, an increase in hair shaft elongation was observed in mouse vibrissae upon the treatment of bethanechol, suggesting the cholinergic role in hair growth.

neuroscience↗

bioRxiv2024

Comparison of therapeutic effects between pulsed field ablation and cryoballoon ablation in the treatment of atrial fibrillation: a systematic review and me-ta-analysis

BackgroundPulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation surgery. Cryoballoon ablation (CBA), a conventional thermal ablation technique, enjoys widespread clinical application. In contrast, Pulsed field ablation (PFA) is a novel non thermal ablation technique for the treatment of atrial fibrillation (AF) patients, with safety comparable to traditional thermal ablation surgery. The present study aims to evaluate and compare the procedural efficiency and safety profiles of PFA and CBA in the management of AF. MethodWe performed a systematic search across PubMed, the Cochrane Library, and Embase databases, encompassing the literature up to February 2024, to inform our systematic review and meta-analysis. When assessing outcome indicators, the risk ratio (RR) and its corresponding 95% confidence interval (CI) were calculated for dichotomous variables. For continuous variables, the mean difference (MD) and the associated 95% CI were determined. In this context, an RR less than 1 and an MD less than 0 were considered advantageous for the PFA group. ResultIn this analysis, nine observational studies encompassing 2,875 patients with AF were included. Among these, 38% (n=1105) were treated with PFA, while 62% (n=1,770) received CBA. The results indicated that PFA was associated with a significantly shorter surgical duration compared to CBA, with a mean difference (MD) of -10.49 minutes (95% CI [-15.50, -5.49]; p<0.0001). Additionally, the PFA group exhibited a reduced risk of perioperative complications relative to the CBA group, with a risk ratio (RR) of 0.52 (95% CI 0.30-0.89; p=0.02). Nevertheless, no statistically significant differences were observed when comparing the two treatment cohorts concerning fluorescence irradiation time (MD 0.71; 95% CI [-0.45, 1.86]; p=0.23) and the recurrence of atrial arrhythmias during follow-up (RR 0.95; 95% CI 0.78-1.14; p=0.57). ConclusionThe outcomes of this investigation reveal that PFA holds a relative advantage over CBA in certain respects, notably by reducing both surgical duration and the incidence of perioperative complications. However, no significant distinction was identified between the two modalities concerning the duration of fluorescence irradiation or the rate of atrial arrhythmia recurrence. To enhance the robustness of these estimates, further research is needed, especially by incorporating additional randomized controlled trials.

physiology↗

bioRxiv2024

Transcriptome-wide identification of 5-methylcytosine by deaminase and reader protein-assisted sequencing

5-Methylcytosine (m5C) is one of the post-transcriptional modifications in mRNA and is involved in the pathogenesis of various diseases. However, the capacity of existing assays for accurately and comprehensively transcriptome-wide m5C mapping still needs improvement. Here, we develop a detection method named DRAM (deaminase and reader protein assisted RNA methylation analysis), in which deaminases (APOBEC1 and TadA-8e) are fused with m5C reader proteins (ALYREF and YBX1) to identify the m5C sites through deamination events neighboring the methylation sites. This antibody-free and bisulfite-free approach provides transcriptome-wide editing regions which are highly overlapped with the publicly available BS-seq datasets and allows for a more stable and comprehensive identification of the m5C loci. In addition, DRAM system even supports ultra-low input RNA (10ng). We anticipate that the DRAM system could pave the way for uncovering further biological functions of m5C modifications.

biochemistry↗

bioRxiv2024

Decoding Continuous Character-based Language from Non-invasive Brain Recordings

Deciphering natural language from brain activity through non-invasive devices remains a formidable challenge. Previous non-invasive decoders either require multiple experiments with identical stimuli to pinpoint cortical regions and enhance signal-to-noise ratios in brain activity, or they are limited to discerning basic linguistic elements such as letters and words. We propose a novel approach to decoding continuous language from single-trial non-invasive fMRI recordings, in which a three-dimensional convolutional network augmented with information bottleneck is developed to automatically identify responsive voxels to stimuli, and a character-based decoder is designed for the semantic reconstruction of continuous language characterized by inherent character structures. The resulting decoder can produce intelligible textual sequences that faithfully capture the meaning of perceived speech both within and across subjects, while existing decoders exhibit significantly inferior performance in cross-subject contexts. The ability to decode continuous language from single trials across subjects demonstrates the promising applications of non-invasive language brain-computer interfaces in both healthcare and neuroscience.

neuroscience↗

bioRxiv2024

Variation and interaction of distinct subgenomes contribute to growth diversity in intergeneric hybrid fish

Intergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and mRNA-seq analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratus red var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression of slc2a12 in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominant trans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple-allele traits in animals.

genetics↗