Biology subjects

Ahn, I.

Publications and source records attributed to Ahn, I..

8 recordsLinked to original sources

bioRxiv2025

AGO1 in neural progenitor cells orchestrates brain development and sociability via LIN28A-REELIN axis

AGO1, an essential RNA binding protein (RBP) in RNA interference, is associated with autism spectrum disorder (ASD). However, the precise functions of AGO1 in brain development and related disorders remain largely unexplored. Here, we report the critical roles of AGO1 in neural progenitor cells (NPCs) in promoting sociability and shaping the structure of the developing brain. Ago1 knockout (KO) in the mouse brain leads to hyposociability, a characteristic symptom of ASD. In human forebrain organoids, AGO1 KO disrupts the formation of ventricle-like structures and delays cortical layer development. We discovered that AGO1 KO results in a loss of polarity in NPCs, which subsequently reduces neuronal development. These AGO1 KO phenotypes originate from the failure to suppress LIN28A in NPCs. AGO1 is primarily localized in the nucleus within NPCs and binds to the LIN28A promoter region, thereby inhibiting LIN28A transcription. We found that increased LIN28A in AGO1 KO NPCs reduces REELIN expression, a key regulator of brain development, by binding directly to the REELIN mRNA. The aberrant polarity phenotype in AGO1 KO NPCs was successfully ameliorated by either LIN28A knockdown or recombinant REELIN treatment. Collectively, our findings elucidate the intricate molecular mechanisms orchestrated by nuclear AGO1 in NPCs and underscores its pivotal roles in brain development, providing significant insights into ASD.

neuroscience↗

bioRxiv2025

Exploration of Novel Biomarkers through a Precision Medicine Approach Using Multi-omics and Brain Organoids in Patients with Atypical Depression and Psychotic Symptoms

Major depressive disorder (MDD) with atypical features accompanied by psychotic symptoms represents a severe and under-researched subtype of depression and severe mental illness, characterized by significant personal and social impact. This study aims to explore novel biomarkers through a precision medicine approach by integrating clinical data, white blood cell (WBC) single-cell RNA sequencing (scRNA-seq), plasma proteomics, and brain organoid models to uncover immunological and neurological alterations in patients with this condition. Patients exhibited elevated stress, anxiety, and depression levels, with increased WBC counts. Plasma proteomic profiling identified an upregulation of proteins implicated in synaptic formation, including Doublecortin-Like Kinase 3 (DCLK3) and Calcyon (CALY), as well as immune-related proteins such as Complement Component 5 (C5). WBC scRNA-seq revealed significant neutrophil and monocyte transcriptomic alterations, suggesting increased inflammation and immune dysregulation. Patient-derived brain organoids display reduced growth and distinct gene expression patterns compared to controls, particularly under dexamethasone-induced stress conditions. Integrating multi-omics data and brain organoid models offers a novel framework for understanding the pathophysiology of psychiatric disorder, which is one of the most complex disorders.

neuroscience↗

bioRxiv2025

Glo1 reduction in mice results in age- and sex-dependent metabolic dysfunction

ObjectivesAdvanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. MethodsWe performed a longitudinal study of female and male Glo1 heterozygous knockdown (Glo1+/-) mice with [~]50% gene expression and screened metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipids. We also evaluated atherosclerotic burden, AGE levels, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle, kidney and aorta) to identify pathway perturbations and potential regulatory genes of Glo1 actions. ResultsPartial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia, and alterations in lipid metabolism in metabolic tissues in an age- and sex-dependent manner. Glo1+/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg, insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1+/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes manifested after 14 weeks of age. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, which cannot explain the broad metabolic changes observed in Glo1+/-mice. Transcriptional profiles suggest that altered glucose and lipid metabolism may be partially explained by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Moreover, transcription factor (TF) analysis of the tissue-specific gene expression data identified TFs involved in cardiometabolic diseases such as Hnf4a (all tissues) and Arntl (aorta, liver, and kidney) which are female-biased regulators and whose targets are altered in response to Glo1+/-. ConclusionsOur results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in Glo1+/- mice.

molecular biology↗

bioRxiv2022

Thyroid Hormone T4 Mitigates Traumatic Brain Injury via Dynamically Remodeling Cell Type Specific Genes and Pathways

BackgroundThe complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice. MethodTo understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages. FindingsOur multi-tissue multi-stage results showed that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks recapitulated the roles of App, Hmgb1, Fn1, and Tnf in mTBI, the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI, supporting T4 as a potential mTBI treatment. InterpretationOur systems-level approach elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications through which T4 mitigates cognitive dysfunction induced by mTBI. FundingThis work was funded by NIHR01NS117148 to X.Y. and F.G.P. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDysfunction in the brain resulting from traumatic brain injury can display immediately as well as several years post-injury. It also impacts various brain regions, including the hippocampus and frontal cortex, which are linked to distinct disease pathologies. The complexity of spatiotemporal and molecular dynamics of perturbation caused by TBI hinder our ability to establish an effective therapeutic approach. Recently, thyroid hormone poses promise as a potential therapeutic target based on our previous scRNA-seq studies. Yet, the mechanisms by which T4 alleviates mTBI, specifically those related to spatial, temporal, and cell-type specificity, remain unexplored. Added value of this studyWe examined the impact of T4 intervention in mitigating mTBI by investigating the transcriptome and functional pathways across two affected brain regions, the frontal cortex and hippocampus, in different stages of injury. Utilizing a systems biology approach, we conducted within- and between-cell-type network modeling, cell-cell communication and integrating human genome-wide association studies (GWAS) analysis. This comprehensive strategy aimed to elucidate the cellular and molecular mechanisms through which T4 averts cognitive impairments induced by mTBI. Implications of all the available evidenceOur findings offer molecular evidence that the administration of T4 impacts a wide range of genes, biological processes, and networks, thereby preventing the advancement of mTBI-induced brain dysfunction and associated diseases. This comprehensive impact of T4 suggests potential advantages in efficacy compared to other therapeutic options that concentrate on specific pathways and targets.

neuroscience↗

bioRxiv2020

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ER), as conditional knockout of ER in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ER-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ER mediates several key side effects of tamoxifen therapy.

neuroscience↗

bioRxiv2020

Functional maturation of the gut microbiota at weaning is influenced by maternal environment in piglets

The objective of this study was to analyze in piglets the impact of weaning on the production of metabolites by gut bacteria and to determine whether early life environment influences the functional maturation of the gut microbiota. Fecal metabolome and microbiome were analyzed in piglets raised in two separate maternity farms and mixed at weaning. In piglets from both maternity farms, the relative abundance of Lactobacillus and of the predicted function "Fucose degradation" decreased after weaning while the relative abundance of Ruminococcus 2 and of the predicted function "Starch degradation" increased. In piglets from the first maternity farm, the relative concentration of biogenic amines and the relative abundance of Escherichi-Shigella decreased after weaning while the relative concentration of short chain fatty acids and the relative abundance of Christensenellaceae R-7 group and Ruminococcaceae UCG-002 increased. These changes were not observed at weaning in piglets from the second maternity farm probably because they already had high relative concentration of short chain fatty acids and higher relative abundance of Christensenellaceae R-7 group and Ruminococcaceae UCG-002 during the suckling period. In conclusion, the functional maturation of the microbiota at weaning is highly dependent on the maternal environment in piglets. ORIGINALITY - SIGNIFICANCE STATEMENTBacterial metabolites are key molecular intermediates between the gut microbiota and host cells. Our study in piglets reveals that the metabolic activity of the gut microbiota shifts at weaning, a key developmental period for intestinal and immune health. We also show that this functional maturation of the gut microbiota is strongly influenced by maternal environment. Thus, targeting early life environmental factors is a promising strategy to program health trough the production of beneficial bacterial metabolites at the suckling-to-weaning transition.

microbiology↗

bioRxiv2019

Forecasting type-specific seasonal influenza after 26 weeks in the United States using influenza activities in other countries

To identify countries that have seasonal patterns similar to the time series of influenza surveillance data in the United States and other countries, and to forecast the 2018-2019 seasonal influenza outbreak in the U.S. using linear regression, auto regressive integrated moving average, and deep learning. We collected the surveillance data of 164 countries from 2010 to 2018 using the FluNet database. Data for influenza-like illness (ILI) in the U.S. were collected from the Fluview database. This cross-correlation study identified the time lag between the two time-series. Deep learning was performed to forecast ILI, total influenza, A, and B viruses after 26 weeks in the U.S. The seasonal influenza patterns in Australia and Chile showed a high correlation with those of the U.S. 22 weeks and 28 weeks earlier, respectively. The R2 score of DNN models for ILI for validation set in 2015-2019 was 0.722 despite how hard it is to forecast 26 weeks ahead. Our prediction models forecast that the ILI for the U.S. in 2018-2019 may be later and less severe than those in 2017-2018, judging from the influenza activity for Australia and Chile in 2018. It allows to estimate peak timing, peak intensity, and type-specific influenza activities for next season at 40th week. The correlation for seasonal influenza among Australia, Chile, and the U.S. could be used to decide on influenza vaccine strategy six months ahead in the U.S.

bioinformatics↗

bioRxiv2018

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to High Fructose Consumption in Mice

BackgroundIt is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. ObjectiveWe aim to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. MethodsEight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 weeks. The gut microbiota composition in cecum and feces was analyzed using 16S rDNA sequencing, and PERMANOVA was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 weeks, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 weeks, accompanied with or without fructose treatment. ResultsCompared to B6 and FVB, DBA mice had significantly higher Firmicutes/Bacteroidetes ratio and lower baseline levels of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (FDR < 5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P <0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. ConclusionsOur findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

systems biology↗