Biology subjects

Song, Y.

Publications and source records attributed to Song, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Emodin: an alveolar macrophage protector in acute pancreatitis induced lung injury

Emodin (EMO), an anthraquinone derivative from roots and leaves of various plants, has been widely used in many inflammatory diseases. Alveolar macrophages (AMs) play a critical role in maintaining alveolar homeostasis in the lung. To investigate the pathophysiological mechanism of AMs in acute pancreatitis-associated lung injury (AP-ALI) and the potential protective therapeutic of EMO for AP-ALI, AMs isolated from AP-ALI mice, murine cell line MH-S and RAW264.7 were pre-treated with EMO to assess its protective roles on regulating inflammation, pyroptosis, and mitophagy of macrophages in AP-ALI. The results showed that 1) in vivo, the relative quantity of AMs was significantly decreased across the time in API-ALI; however, the mitochondria flux presented earlier changes than the resident AMs alteration in our experimental system. EMO pretreatment significantly alleviated the severity of lung injury and improved the damaged alveolar structure, and further reversed the reduction of mitochondria impairment in AMs in mice. 2) In vitro, EMO significantly suppressed LPS/ATP associated NLRP3 inflammasome activation, enhanced mitophagy, and protected mitochondria damage. Furthermore, the data of mitophagy inhibition by 3-MA demonstrated that EMO protective effects were partially via manipulating mitophagy-mitochondria-alveolar macrophage axis. Our data shed light on the comprehensive understanding on EMO therapeutics in AP-ALI.

molecular biology↗

bioRxiv2024

CytoSignal Detects Locations and Dynamics of Ligand-Receptor Signaling at Cellular Resolution from Spatial Transcriptomic Data

Nearby cells within tissues communicate through ligand-receptor signaling interactions. Emerging spatial transcriptomic technologies provide a tremendous opportunity to systematically detect ligand-receptor signaling, but no method operates at cellular resolution in the spatial context. We developed CytoSignal to infer the locations and dynamics of cell-cell communication at cellular resolution from spatial transcriptomic data. CytoSignal is based on the simple insight that signaling is a protein-protein interaction that occurs at a specific tissue location when ligand and receptor are expressed in close spatial proximity. Our cellular-resolution, spatially-resolved signaling scores allow several novel types of analyses: we identify spatial gradients in signaling strength; separately quantify the locations of contact-dependent and diffusible interactions; and detect signaling-associated differentially expressed genes. Additionally, we can predict the temporal dynamics of a signaling interaction at each spatial location. CytoSignal is compatible with nearly every kind of spatial transcriptomic technology including FISH-based protocols and spot-based protocols without deconvolution. We experimentally validate our results in situ by proximity ligation assay, confirming that CytoSignal scores closely match the tissue locations of ligand-receptor protein-protein interactions. Our work addresses the fields current need for a robust and scalable tool to detect cell-cell signaling interactions and their dynamics at cellular resolution from spatial transcriptomic data.

bioinformatics↗

bioRxiv2024

Integrated Short-TE and Hadamard-edited Multi-Sequence (ISTHMUS) for Advanced MRS

BackgroundTo examine data quality and reproducibility using ISTHMUS, which has been implemented as the standardized MR spectroscopy sequence for the multi-site Healthy Brain and Child Development (HBCD) study. MethodsISTHMUS is the consecutive acquisition of short-TE PRESS (32 transients) and long-TE HERCULES (224 transients) data with dual-TE water reference scans. Voxels were positioned in the centrum semiovale, dorsal anterior cingulate cortex, posterior cingulate cortex and bilateral thalamus regions. After acquisition, ISTHMUS data were separated into the PRESS and HERCULES portions for analysis and modeled separately using Osprey. In vivo experiments were performed in 10 healthy volunteers (6 female; 29.5{+/-}6.6 years). Each volunteer underwent two scans on the same day. Differences in metabolite measurements were examined. T2 correction based on the dual-TE water integrals were compared with: 1) T2 correction based the default white matter and gray matter T2 reference values in Osprey; 2) shorter WM and GM T2 values from recent literature; and 3) reduced CSF fractions. ResultsNo significant difference in linewidth was observed between PRESS and HERCULES. Bilateral thalamus spectra had produced significantly higher (p<0.001) linewidth compared to the other three regions. Linewidth measurements were similar between scans, with scan-to-scan differences under 1 Hz for most subjects. Paired t-tests indicated a significant difference only in PRESS NAAG between the two thalamus scans (p=0.002). T2 correction based on shorter T2 values showed better agreement to the dual-TE water integral ratio. ConclusionsISTHMUS facilitated and standardized acquisition and post-processing and reduced operator workload to eliminate potential human error. HighlightsO_LIISTHMUS has been implemented into the HBCD study protocol. C_LIO_LIIt acquires both short-TE and Hadamard-edited transients. C_LIO_LIISTHMUS reduces operator workload. C_LIO_LIISTHMUS potentially allows improved T2 relaxation correction C_LI

bioengineering↗

bioRxiv2024

ScGOclust: leveraging gene ontology to compare cell types across distant species using scRNA-seq data

Basic biological processes are shared among animal species, yet their cellular mechanisms are profoundly diverse. Comparing cell type expression profiles across species reveals the conservation and divergence of cellular functions. With the increase of phylogenetic distance between species of interest, a gene-based comparison becomes limited. The Gene Ontology (GO) knowledgebase is the most comprehensive resource of gene functions, providing a bridge for comparing cell types between remote species. Here, we present scGOclust, a computational tool to construct cellular functional profiles using GO terms and facilitates systematic, robust comparisons within and across species. We use scGOclust to analyse and compare the heart, gut and kidney between mouse and fly. We show that scGOclust recapitulates the function spectrum of different cell types, characterises functional similarities between homologous cell types, and reveals functional convergence between unrelated cell types. Furthermore, we identify subpopulations in the fly crop by cross-species comparison of GO profiles. Finally, scGOclust resolved the analogy between Malpighian tubule and kidney segments.

bioinformatics↗

bioRxiv2023

Predicting the Structural Impact of Human Alternative Splicing

Protein structure prediction with neural networks is a powerful new method for linking protein sequence, structure, and function, but structures have generally been predicted for only a single isoform of each gene, neglecting splice variants. To investigate the structural implications of alternative splicing, we used AlphaFold2 to predict the structures of more than 11,000 human isoforms. We employed multiple metrics to identify splicing-induced structural alterations, including template matching score, secondary structure composition, surface charge distribution, radius of gyration, accessibility of post-translational modification sites, and structure-based function prediction. We identified examples of how alternative splicing induced clear changes in each of these properties. Structural similarity between isoforms largely correlated with degree of sequence identity, but we identified a subset of isoforms with low structural similarity despite high sequence similarity. Exon skipping and alternative last exons tended to increase the surface charge and radius of gyration. Splicing also buried or exposed numerous post-translational modification sites, most notably among the isoforms of BAX. Functional prediction nominated numerous functional differences among isoforms of the same gene, with loss of function compared to the reference predominating. Finally, we used single-cell RNA-seq data from the Tabula Sapiens to determine the cell types in which each structure is expressed. Our work represents an important resource for studying the structure and function of splice isoforms across the cell types of the human body.

bioinformatics↗

bioRxiv2023

Dysregulated Repeat Element Viral-like Immune Response in Hepatocellular Carcinoma

PurposeHepatocellular carcinoma (HCC) is a lethal malignancy driven by complex interactions between cancer cells, immune cells, and additional stromal cells in the tumor microenvironment (TME). The LINE1 retrotransposon is a ubiquitous repeat RNA whose de-repression leads to significant cancer cell-intrinsic and TME changes that promote aggressive tumor characteristics. We leveraged single cell spatial transcriptomic profiling to characterize the relationship between LINE1 and differences in the heterogeneous HCC TME. Experimental DesignWe applied our profiling methodology to a cohort of 23 tissue specimens collected from patients who had undergone liver resection or transplantation and validated it in a partially-overlapping similar cohort of 39 specimens using RNA in-situ hybridization (RNA-ISH). ResultsWe found that LINE1-high tumors and LINE1-high single HCC cells exhibited a de-differentiated, stem-like, and inflammatory phenotype. Furthermore, within individual tumors, LINE1 high cancer cells associated spatially with one another and excluded the larger, organized immune cell conglomerates seen in LINE1 low tumors. Finally, we found that LINE1 RNA expression correlated with worse overall survival in the larger expanded retrospective cohort. ConclusionsOur study is the first to show a clearly disorganized immune TME in HCC driven by LINE1 expression, and this observation correlated with poor survival for patients whose tumors expressed large amounts of the LINE1 repeat RNA. These results provide further evidence of how effective anti-tumor immune responses contribute to cures after definitive surgery and may lead to novel biomarkers or drug targets in HCC. TRANSLATIONAL RELEVANCEThe viral-like LINE1 retrotransposon is known to influence tumor cell state and the immune response in a variety of cancer. Here, we have used single cell spatial transcriptomic profiling to resolve repeat and coding gene RNA expression in a cohort of hepatocellular carcinoma (HCC) patients. LINE1 RNA expression in HCC tumor cells was correlated with an undifferentiated stem-like cancer state and a disorganized, sparse immune infiltrate. Using in situ hybridization on an expanded validation cohort, we noted significantly worsened survival in the LINE1 high group. Altogether, LINE1 repeat RNA is a tumor intrinsic biomarker of more aggressive features that can be used for risk stratification and a potential biomarker for response to immunotherapies that merits further investigation.

cancer biology↗

bioRxiv2023

Design and validation of a high-throughput in vitro model of the outer Blood-Retinal Barrier (oBRB) using the Curiochips Microphysiological System

Numerous diseases, including AMD (age-related macular degeneration), arise from the blood-retinal barrier and blood vessel abnormalities in the eye; unfortunately, there is a lack of reliable in-vitro models for their systematic study. This study describes a high-throughput microphysiological system (MPS) designed to model the outer Blood-Retinal Barrier (oBRB). The MPS platform is engineered to integrate seamlessly with high-content screening technologies, utilizing a design with a single oBRB model incorporating RPE (retina pigment epithelial cells) and endothelial cell co-culture to fit within a single 96-well. Arranged in the standard 96-well plate format, the platform allows high-throughput assessment of barrier integrity through 3D confocal imaging (ZO-1 staining), Trans Epithelial Electrical Resistance (TEER), and permeability measurements. The oBRB model enables the investigation of crosstalk among different cell types in co-culture. This includes assessing changes in the barrier integrity of the Retinal Pigment Epithelium (RPE) monolayer and investigating neovascularization events resulting from endothelial cell remodeling. The platform is positioned for utility in drug discovery and development efforts targeting diseases involving oBRB damage and choroidal neovascularization, such as age-related macular degeneration (AMD).

bioengineering↗

bioRxiv2023

scfetch: an R package to access and format single-cell RNA sequencing datasets from public repositories

BackgroundDownloading and reanalyzing the existing single-cell RNA sequencing (scRNA-seq) data provides an efficient choice to gain clues and new insights. However, no tool can fetch the diverse scRNA-seq data types (raw data, count matrix, and processed object) distributed in various repositories, process and load the downloaded data to R, convert formats between scRNA-seq objects, and benchmark the format conversion tools. FindingsHere, we present GEfetch2R, an R package with Docker image to (i) download diverse scRNA-seq data types, including raw data (SRA and ENA), count matrices (GEO, UCSC Cell Browser, and PanglaoDB), and processed objects (Zenodo, CELLxGENE, and HCA); (ii) process the downloaded data, load output/downloaded count matrices and annotations to R (SeuratObject/DESeqDataSet), filter the SeuratObject based on cell metadata and genes, and merge multiple SeuratObjects if applicable; (iii) convert formats between the widely used scRNA-seq objects, including SeuratObject, AnnData, SingleCellExperiment, CellDataSet/cell_data_set, and loom, and benchmark format conversion tools in terms of information kept, usability, running time, and scalability to guide the tool selection. Furthermore, GEfetch2R can also download, process, and load bulk RNA-seq raw data (SRA and ENA) and count matrices (GEO) to R (DESeqDataSet). ConclusionsGEfetch2R is an R package dedicated to facilitating researchers to access and explore the existing gene expression data from various public repositories. It can function as a data downloader (supports all three scRNA-seq and two bulk RNA-seq data types), a data processor (processes and loads the output/downloaded count matrices and annotations to R), and an object format converter (between the widely used scRNA-seq objects).

bioinformatics↗

bioRxiv2023

Is M1-L121E a good mimic on microbial rhodopsin? A viewpoint from excited-state dynamics

Microbial rhodopsin, an important photoreceptor protein, has been widely used in several fields, such as optogenetics, biotechnology, and biodevices etc. However, current microbial rhodopsins are all transmembrane proteins, which both complicates the investigation on the photoreaction mechanism and limits their further applications. Therefore, a suitable mimic for microbial rhodopsin can not only provide a better model for understanding the mechanism, but also can extend the applications. The human protein CRABPII turns out to be a good template for design mimics on rhodopsin, due to the convenience in synthesis and the stability after mutations. Recently, Geiger et al. designed a new CRABPII-based mimic M1-L121E on microbial rhodopsin with the correct 13-cis (13C) isomerization after irritation. However, it still remains a question how similar it is compared with the natural microbial rhodopsin, in particular in the aspect of the photoreaction dynamics. In this article, we investigated the excited-state dynamics of this mimic by measuring its transient absorption spectra. Our results reveal that there are two components in the solution of mimic M1-L121E at PH=8, known as protonated Schiff base (PSB) and unprotonated Schiff base (USB) states. In both states, the photoreaction process from 13-cis (13C) to all-trans (AT) is faster than that from the inverse direction. In addition, the photoreaction process in PSB state is faster than that in the USB state. In the end, we compared the isomerization time of the PSB state with the properties of the microbial rhodopsin, and confirmed that the mimic M1-L121E indeed captures the main feature of the rhodopsin and is a good model of microbial rhodopsin in the photoreaction dynamics. However, our results also reveal significant differences in the excited-state dynamics of the mimic relative to the natural microbial rhodopsin, including the slower PSB isomerization rates in both 13C-AT and AT-13C directions, as well as the unusual USB photoreaction dynamics at PH=8. Such unique properties have not been observed in the natural rhodopsin, which could further deepen the understanding in photoreaction mechanism of the photosensitive proteins.

biophysics↗

bioRxiv2023

Long-Term In Vivo Molecular Monitoring Using Aptamer-Graphene Microtransistors

Long-term, real-time molecular monitoring in complex biological environments is critical for our ability to understand, prevent, diagnose, and manage human diseases. Aptamer-based electrochemical biosensors possess the promise due to their generalizability and a high degree of selectivity. Nevertheless, the operation of existing aptamer-based biosensors in vivo is limited to a few hours. Here, we report a first-generation long-term in vivo molecular monitoring platform, named aptamer-graphene microtransistors (AGMs). The AGM incorporates a layer of pyrene- (polyethylene glycol)5-alcohol and DNase inhibitor-doped polyacrylamide hydrogel coating to reduce biofouling and aptamer degradation. As a demonstration of function and generalizability, the AGM achieves the detection of biomolecules such as dopamine and serotonin in undiluted whole blood at 37 {degrees}C for 11 days. Furthermore, the AGM successfully captures optically evoked dopamine release in vivo in mice for over one week and demonstrates the capability to monitor behaviorally-induced endogenous dopamine release even after eight days of implantation in freely moving mice. The results reported in this work establish the potential for chronic aptamer-based molecular monitoring platforms, and thus serve as a new benchmark for molecular monitoring using aptamer-based technology.

bioengineering↗

bioRxiv2023

HyperPRI: A Dataset of Hyperspectral Images for Underground Plant Root Study

Collecting and analyzing hyperspectral imagery (HSI) of plant roots over time can enhance our understanding of their function, responses to environmental factors, turnover, and relationship with the rhizosphere. Current belowground red-green-blue (RGB) root imaging studies infer such functions from physical properties like root length, volume, and surface area. HSI provides a more complete spectral perspective of plants by capturing a high-resolution spectral signature of plant parts, which have extended studies beyond physical properties to include physiological properties, chemical composition, and phytopathology. Understanding crop plants physical, physiological, and chemical properties enables researchers to determine high-yielding, drought-resilient genotypes that can withstand climate changes and sustain future population needs. However, most HSI plant studies use cameras positioned above ground, and thus, similar belowground advances are urgently needed. One reason for the sparsity of belowground HSI studies is that root features often have limited distinguishing reflectance intensities compared to surrounding soil, potentially rendering conventional image analysis methods ineffective. Here we present HyperPRI, a novel dataset containing RGB and HSI data for in situ, non-destructive, underground plant root analysis using ML tools. HyperPRI contains images of plant roots grown in rhizoboxes for two annual crop species - peanut (Arachis hypogaea) and sweet corn (Zea mays). Drought conditions are simulated once, and the boxes are imaged and weighed on select days across two months. Along with the images, we provide hand-labeled semantic masks and imaging environment metadata. Additionally, we present baselines for root segmentation on this dataset and draw comparisons between methods that focus on spatial, spectral, and spatialspectral features to predict the pixel-wise labels. Results demonstrate that combining HyperPRIs hyperspectral and spatial information improves semantic segmentation of target objects.

plant biology↗

bioRxiv2023

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats

Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but mechanisms linking mutant gene products to neuronal toxicity remain debatable. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs) but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved a MAPK signaling pathway that affects fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. In primary cultured neurons, GP but not other DPRs promote the "dying-back" axonopathy seen in ALS. Interestingly, GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclear membrane, promoting "dying-forward" neuropathy. All C9-DPR-mediated toxic effects observed in these studies are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. Finally, C9ORF72 human tissues confirmed a close association between GP and active P38 in degenerating motor neurons as well as GR-associated nuclear damage in the cortex. Collectively, our studies establish compartment-specific toxic effects of C9-DPRs associated with degeneration, suggesting that two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with ALS and/or FTD symptoms. Graphical AbstractActivation of protein kinases and inhibition of axonal transport, synaptic transmission, and nuclear structure are toxic effects common to unrelated FALS-related gene products. FALS-related mutant forms of SOD1 (mSOD1), FUS (mFUS), and C9-GP-DPRs (GP(n)) activate specific ASK1-MAPK pathway. Within axons, active ASK1-p38 pathway phosphorylates various substrates, including conventional kinesin, leading to the inhibition of fast axonal transport mediated by the translocation of this motor protein along microtubules. ASK1 can also inhibit synaptic transmission via JNK activation. Both pathways cause reductions in the availability of critical synaptic cargoes, synaptic dysfunction, and "dying-back" degeneration of neurons. On the other hand, C9- PR and GR-DPRs (PR(n) and GR(n)) activate other pathways, leading to aberrant alterations in nuclear structure and function and "dying-forward" degeneration of neurons, consistent with reports of transcriptional changes and activation of apoptosis in ALS. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/558663v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@162cbbeorg.highwire.dtl.DTLVardef@12e54caorg.highwire.dtl.DTLVardef@c0cdaborg.highwire.dtl.DTLVardef@1feb8d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Brain Glutathione and GABA+ levels in autistic children

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a large cohort of children aged 8-12 years with ASD (n=52) and typically developing children (TDC, n=49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder. Lay summaryAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered glutathione (GSH, an important antioxidant and neuromodulator) and gamma-aminobutyric acid (GABA, a major inhibitory neurotransmitter) levels have been proposed as potential contributors to the biology underlying ASD. Here, we used advanced edited Magnetic Resonance Spectroscopy (MRS) to measure levels of these low-concentration metabolites in four brain regions of a pediatric cohort. Contrary to our hypothesis, no significant difference was found between ASD and control subjects in either GSH or GABA levels in any brain region.

neuroscience↗

bioRxiv2023

The neurovascular coupling in the attention during visual working memory

How to focus attention during visual working memory (vWM) depends on ones ability to filter out distractors and expand the scope of targets. Although the spatiotemporal properties of attention processes in WM are well documented, it is still unclear how the mechanisms of neurovascular coupling (NVC) between electroencephalographic (EEG) signals and hemodynamic activity of attention during vWM. To investigate the NVC mechanism underlying attention during vWM, we recorded simultaneous functional near-infrared spectroscopy (fNIRS) and EEG data when humans were performing cued change-detection tasks. The multimodal data showed that the control and scope processes during vWM were involved in similar temporal profiles of frontal theta event-related synchronization (ERS) and posterior contralateral delay activities (CDA), and revealed similar distributions of hemodynamic activation within the frontal eye fields (FEF) and superior parietal lobule (SPL). These task-related features have a common NVC outcome across individuals: the higher EEG features (theta ERS or CDA amplitude), the greater the increment of local oxygenated hemoglobin (HbO) signals within the FEF and SPL. Moreover, when distractors should be filtered out, EEG-informed NVC is involved in a broader range of brain regions in the frontoparietal network (FPN). These results provided unique neurovascular evidence for the mechanisms of attention scope and control in vWM. Interestingly, there might be a negative relationship between behavioral metrics and theta-informed NVC strengths within the FEF for attention control. On a dynamic basis, the NVC features had higher discriminatory power for predicting behavior than EEG features and fNIRS features alone. Together, these results highlight what multimodal approaches can advance our understanding of the role of attention in vWM and how the fluctuations of NVC are associated with actual behavior.

neuroscience↗

bioRxiv2023

The origin, divergence and inter-subspecies hybridization of house mice (Mus musculus)

House mice (Mus musculus) are the ancestors of laboratory mouse strains and an excellent model for evolutionary biology. The origin, divergence and inter-subspecies hybridization of the three main subspecies (Mus musculus domesticus, M. m. musculus, M. m. castaneus) were not well-resolved. Population genomic analyses with 349 samples from Eurasia confirmed the Himalayas-India-Pakistan junctional region as the origin centre. The divergence of M. m. domesticus, M. m. musculus and M. m. castaneus occurred [~]333.6, 308.3 and 134.4 thousand years ago, respectively, which located in different interglacial stages in Pleistocene. Hybridization among M. m. domesticus, M. m. musculus, and M. m. castaneus after secondary contact during spread and gene flow between the ancestral population and different subspecies produced distinct genomic mixtures in populations from different regions of Eurasia. Long-distance introgression from M. m. musculus into M. m. castaneus and from M. m. castaneus into M. m. musculus happened in southern China and northern China, respectively. And extensive genomic introgression occurred on both autosomes and the X chromosomes. Genomic introgression in hybrids from East Asia and Europe revealed that the level of genomic differentiation, recombination rate and benefits for the survival and reproduction of hybrids determined the introgression capability of distinct genomic regions in inter-subspecies hybridization of house mice. Unidirectional introgression of the Y chromosome made all wild mice in East Asia hold the musculus-type Y chromosome. Our study provided comprehensive insights into the origin, divergence and inter-subspecies genomic introgression of house mice.

evolutionary biology↗

bioRxiv2023

RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury

IFN{gamma}, a type II interferon secreted by immune cells, augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNg levels in AM and thereby lungs innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury. HighlightsO_LIRGS2 levels are inversely correlated with IFN{gamma} in ARDS patients AM. C_LIO_LIRGS2 in alveolar macrophages regulate the inflammatory lung injury. C_LIO_LIDuring pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gq from inducing IFN{gamma} generation and AM inflammatory signaling. C_LI eToc BlurbAuthors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gq and RGS2 axis to prevent ALI.

immunology↗

bioRxiv2023

Structural insights into abscisic acid exporter AtABCG25

Cellular hormone homeostasis is essential for the precise spatial and temporal signaling responses and plant fitness. Abscisic acid (ABA) plays pivotal roles in orchestrating various developmental and stress responses and confers fitness benefits over ecological and evolutionary timescales in terrestrial plants. Cellular ABA levels is regulated by complex processes including biosynthesis, catabolism, and transport. AtABCG25 is the first identified ABA exporter through genetic screen which affects diverse ABA responses. Resolving the structure basis of ABCG25 in ABA exporting is critical for further manipulating ABA homeostasis and plant fitness. We utilized cryo-electron microscopy to elucidate the structural dynamics of AtABCG25, and successfully characterized different states including apo AtABCG25, ABA-bound AtABCG25 and ATP-bound AtABCG25(E232Q). Notably, AtABCG25 forms a homodimer, featuring a deep, slit-like cavity in the transmembrane domain. The critical residues in the cavity where ABA binds are precisely characterized. Moreover, ATP binding triggers the closure of nucleotide-binding domains and conformational transitions in the transmembrane domains. Collectively, these findings provide valuable insights into the intricate substrate recognition and transport mechanisms of ABA exporter ABCG25, paving the way towards genetical manipulating of ABA homeostasis and plant fitness.

plant biology↗

bioRxiv2023

Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor

Immune checkpoint inhibitors (ICIs) are widely used anti-cancer therapies that can cause morbid and potentially fatal immune-related adverse events (irAEs). ICI-related myocarditis (irMyocarditis) is uncommon but has the highest mortality of any irAE. The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood during irMyocarditis and identify biomarkers of clinical severity by leveraging single-cell (sc)RNA-seq coupled with T cell receptor (TCR) sequencing, microscopy, and proteomics analysis of 28 irMyocarditis patients and 23 controls. Our analysis of 284,360 cells from heart and blood specimens identified cytotoxic T cells, inflammatory macrophages, conventional dendritic cells (cDCs), and fibroblasts enriched in irMyocarditis heart tissue. Additionally, potentially targetable, pro-inflammatory transcriptional programs were upregulated across multiple cell types. TCR clones enriched in heart and paired tumor tissue were largely non-overlapping, suggesting distinct T cell responses within these tissues. We also identify the presence of cardiac-expanded TCRs in a circulating, cycling CD8 T cell population as a novel peripheral biomarker of fatality. Collectively, these findings highlight critical biology driving irMyocarditis and putative biomarkers for therapeutic intervention.

immunology↗