Biology subjects

Ko, H.

Publications and source records attributed to Ko, H..

27 records · Page 2Linked to original sources

bioRxiv2022

Genetic architecture of creativity and extensive genetic overlap with psychiatric disorders revealed from genome-wide association analyses of 241,736 individuals

Creativity is heritable and exhibits familial aggregation with psychiatric disorders, but its genomic basis and genetic relationship with psychiatric disorders remain largely unknown. Here, we conducted a genome-wide association study (GWAS) using an expanded, machine learning-based definition of creativity in individuals of European ancestry from the UK Biobank (n = 241,736) and identified 25 creativity-associated loci. Extensive genetic overlap with psychiatric disorders, including schizophrenia, major depression, bipolar I disorder, attention deficit/hyperactivity disorder, and anorexia nervosa, was demonstrated by the genetic correlation, polygenic risk score, and MiXeR analyses. The condFDR and conjFDR analyses identified additional loci for creativity and psychiatric disorders, as well as shared genetic loci between creativity and psychiatric disorders. This GWAS showed significant correlations with GWASs using traditional definitions of creativity and GWASs adjusted for educational attainment. Our findings contribute to the understanding of the genetic architecture of creativity and reveal its polygenic relationships with psychiatric disorders.

genomics↗

bioRxiv2022

Prediction of brain functions from structural connectome using graph neural network

AO_SCPLOWBSTRACTC_SCPLOWThe relationship between brain structure and function remains elusive, amidst the tremendous advances in brain mapping techniques. In this work, we attempt to partially disentangle this relationship by connecting task-evoked functional MRI (fMRI) responses with the underlying structural connectome using graph neural network (GNN). MRI data (n = 1,063) were collected from the Human Connectome Project. We demonstrate that our GNN-based model predicts task-evoked fMRI responses with high fidelity. Using a graph attention mechanism, it is possible to infer the subsets of neighboring cortical regions whose structural connections are important for the prediction of the functional responses of individual cortical regions. Notably, for each cortical region, such subset of neighboring cortical regions is predominantly localized to the ipsilateral hemisphere and much smaller than that with direct structural connections. We found that the higher cognitive functions subserved by the cingulo-opercular, dorsal attention, frontoparietal and default mode clusters may depend on neighboring cortical regions across a wide range of functional brain clusters in the ipsilateral hemisphere, whilst the sensory functions subserved by the visual1 and auditory clusters on neighboring cortical regions across much fewer functional brain clusters.

bioengineering↗

bioRxiv2022

Single-cell analysis of microglial transcriptomic diversity in subarachnoid hemorrhage

BackgroundSubarachnoid hemorrhage (SAH) is a severe stroke and the advanced treatment for SAH is still limited. Recent studies have shown that microglia-mediated neuroinflammation plays a critical role in the pathogenesis of SAH. Microglia can transform their states in response to central nervous system injury. However, the transcriptomic features of microglia remained unknown in SAH. Recent developed single-cell RNA sequencing (scRNA-seq) provides a possible way to solve this problem. MethodsEndovascular perforation (EVP) murine SAH model was established to reproduce experimental SAH. Microglia states are examined with immune staining and quantitate analysis. Post-SAH microglial single-cell suspension were harvest and sequenced using 10X scRNA-seq platform. Then, the detailed single-cell transcriptomic characterization of post-SAH microglia were analyzed with bioinformatics. ResultsTranscriptional analysis revealed at least ten diverse microglial subgroups, including SAH-associated microglia (SAM), inflammatory-associated microglia (IAM) and proliferation-associated microglia (PAM), which all exhibit distinct marker gene expression patterns. Microglia subsets interaction reveals the functional relationship between elevated signaling pathways and microglial sub-populations in SAH. Receptor-ligand pair analysis revealed that complex inter-cellular interactions exist between the microglia subsets and other cell types, and indicated that microglia are important mediators of neuroinflammation after SAH. Integrated analysis with normal microglia further proved the existence of these microglia subpopulations and different gene markers associated with SAH were clarified. ConclusionsCollectively, we first report the single-cell transcriptome of post-SAH microglia and found specific biomarkers related to the neuroinflammation in SAH. These results enhanced our understanding of the pathological mechanisms of microglial response to SAH, and may guide future development of SAH monitoring methods and therapeutics.

neuroscience↗

bioRxiv2021

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

Pathologic -synuclein (-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid {beta} precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by -syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of -syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by -syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for -syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic -syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinsons disease and related -synucleinopathies. One Sentence SummaryAplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -synuclein. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/442157v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1d746bforg.highwire.dtl.DTLVardef@65acb2org.highwire.dtl.DTLVardef@12cf2f0org.highwire.dtl.DTLVardef@19d6e_HPS_FORMAT_FIGEXP M_FIG Aplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic -synuclein. Aplp1 is a receptor that drives pathologic -syn transmission, and genetic depletion of Aplp1 can significantly reduce the -synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic -syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic -syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks -syn PFF-induced neurodegeneration. C_FIG

neuroscience↗

bioRxiv2021

A neural circuit basis for bilateral olfactory input-enhanced chemosensory avoidance navigation

Our understanding of how bilaterian animals utilize parallel input channels from paired sensory organs to optimize chemosensory behavior and the underlying neural circuit mechanisms are limited. Here we developed microfluidics-based behavioral and brainwide imaging platforms to study the neural integration of binasal inputs and chemosensory avoidance in larval zebrafish. We show that larval zebrafish efficiently escape from cadaverine-carrying streams by making more frequent swim bouts and larger undirected turns. Binasal inputs are strictly required for the nasal input-dependent component of klinokinesis, while each nasal input additively enhances angular orthokinesis. Throughout brain regions, including those along the olfactory processing pathways, a distributed neural representation with a wide spectrum of ipsilateral-contralateral nasal stimulus selectivity is maintained. Nonlinear sensory information gain with bilateral signal convergence is especially prominent in neurons weakly encoding unilateral cadaverine stimulus, and associated with stronger activation of sensorimotor neurons in the downstream brain regions. Collectively, these results provide insights into how the vertebrate model sums parallel input signals to guide chemosensory avoidance behavior.

neuroscience↗

bioRxiv2020

Genome-wide reversal of glial and neurovascular cell transcriptomic aging signatures by GLP-1R agonism

Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimers disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.

neuroscience↗

bioRxiv2020

Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp). Our results thus reveal the viral protein targets of simeprevir, and provide preclinical rationale for the combination of simeprevir and remdesivir for the pharmacological management of COVID-19 patients. One Sentence SummaryDiscovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes with remdesivir.

microbiology↗

bioRxiv2019

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail1,2, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed - the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions8-17. Furthermore, an overrepresentation of Alzheimers disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

neuroscience↗

bioRxiv2019

Caenorhabditis elegans Exhibits Positive Gravitaxis

Whether or not the micro swimmer Caenorhabditis elegans senses and respond to gravity is unknown. We find that C. elegans aligns its swimming direction with that of the gravity vector (positive gravitaxis). When placed in an aqueous solution that is denser than the animals, they still orient downwards, indicating that non-uniform mass distribution and/or hydrodynamic effects are not responsible for animals downward orientation. Paralyzed worms and worms with globally disrupted sensory cilia do not change orientation as they settle in solution, indicating that gravitaxis is an active behavior that requires gravisensation. Other types of sensory driven orientation behaviors cannot explain our observed downward orientation. Like other neural behaviors, the ability to respond to gravity declines with age. Our study establishes gravitaxis in the micro swimmer C. elegans and suggests that C. elegans can be used as a genetically tractable system to study molecular and neural mechanisms of gravity sensing and orientation.\n\nSignificance StatementUnderstanding how animals respond to gravity is not only of fundamental scientific interest, but has clinical relevance, given the prevalence of postural instability in aged individuals. Determining whether C. elegans responds to gravity is important for mechanistic studies of gravity sensing in an experimentally tractable animal, for a better understanding of nematode ecology and evolution, and for studying biological effects of microgravity. Our experiments, which indicate that C. elegans senses and responds to gravity, set the stage for mechanistic studies on molecular mechanisms of gravity sensing.

neuroscience↗