Biology subjects

Shin, M. K.

Publications and source records attributed to Shin, M. K..

8 recordsLinked to original sources

bioRxiv2026

Leptin alleviates obesity hypoventilation via serotonergic pathways

RationaleThere is no effective pharmacotherapy for obesity hypoventilation syndrome (OHS). Intranasal leptin augments the hypercapnic ventilatory response (HCVR), attenuates upper airway obstruction, and increases ventilation during sleep in diet-induced obese (DIO) mice. Respiratory effects of leptin can be attenuated by serotonergic antagonists. ObjectivesTo establish if serotonergic innervation of the hypoglossal motoneurons (XII MN) mediates effects of leptin on OHS. MethodsWe examined effects of intranasal leptin on the HCVR, sleep architecture, arousal latency, flow limited (obstructed) and non-flow limited breathing, genioglossus muscle (GG) activity and metabolic rate across sleep/wake states in the presence and absence of serotonergic neurons innervating XII MN in DIO Sert-flp mice expressing FlpO recombinase in the serotonergic neurons. These mice were transfected into the XII MN with retrograde adeno-associated virus carrying either FlpO-dependent caspase or control yellow fluorescent protein (YFP). Measurements and Main ResultsControl YFP virus was densely localized to the serotonergic neurons of the medullary raphe (MR), but not the dorsal raphe (DR), and these neurons were ablated by caspase. Leptin enhanced the HCVR, increased arousal latency in males, but not in females, and these effects were abolished by caspase. Neither leptin nor caspase affected sleep architecture or metabolic rate. Leptin increased GG activity awake and during NREM sleep, attenuated pharyngeal obstruction and increased minute ventilation in NREM and REM sleep. All effects of leptin were abolished by the FlpO-dependent caspase. ConclusionsLeptin treats OHS by stimulating MR serotonergic neurons, which project to XII MN and stimulate pharyngeal muscles during sleep.

physiology↗

bioRxiv2026

Retrosplenial cortex vulnerability links severe hypoglycemia to cognitive impairment through neuron-microglia crosstalk

Severe hypoglycemia remains a serious adverse effect of insulin therapy in individuals with diabetes and is linked to cognitive decline, yet the mechanisms by which transient metabolic stress leads to persistent neuronal dysfunction remain poorly defined. Using mouse models of acute severe hypoglycemia and integrated screening, we identified the retrosplenial cortex as a previously unrecognized brain region that is particularly vulnerable to hypoglycemia-induced neuronal damage. This injury is driven by a feedforward interaction between neuron-specific Drp1-dependent mitochondrial fission and microglial IL-1 signaling, as pharmacological or genetic targeting of either pathway suppressed the other, rescued neuronal damage, and reversed cognitive impairment. These findings identify a region-specific neuron-microglia injury circuit that links severe hypoglycemia to cognitive dysfunction and suggest a therapeutic strategy to protect brain function without compromising diabetes management.

neuroscience↗

bioRxiv2026

Epigenetic Silencing of Carotid Body TRPM7 Attenuates Hypertension in Obese Mice

Obesity is the most common cause of hypertension. We have previously shown that high levels of circulating leptin in diet-induced obese (DIO) mice induced hypertension by increasing expression of Transient Receptor Potential Melastatin-subfamily member 7 (TRPM7) in the carotid bodies (CB). In addition, we demonstrated in rat PC12 cells that leptin increases Trpm7 gene expression by inducing CpG site-specific demethylation within the 5 regulatory region containing a signal transducer and activator of transcription 3 (STAT3) binding site. This leptin-induced Trpm7 upregulation was prevented by inhibition of JAK-STAT3 signaling. Based on these findings, we hypothesized that reversing region-specific methylation at the Trpm7 promoter in the CB could attenuate obesity-associated hypertension. Compared with lean controls, DIO mice exhibited increased Trpm7 expression and the STAT3- binding site-specific promoter demethylation in the CB. Administration of methylated DNA oligonucleotides targeting the STAT3 binding site attenuated CpG site-specific DNA demethylation and reduced Trpm7 transcription in the CB of DIO mice. This intervention resulted in decreased carotid sinus nerve activity and reduced arterial blood pressure, especially during the light phase. Our results suggest that targeted modulation of CpG site-specific DNA methylation at the Trpm7 promoter using DNA oligonucleotide may represent a novel therapeutic strategy for obesity-induced hypertension.

physiology↗

bioRxiv2025

The phylogenetic context for the origin of a unique purple-green photosymbiosis

Symbioses are widespread in nature and have been the source of much evolutionary innovation. While some types of symbioses evolved multiple times across space and time (e.g., oxygenic photosymbioses or chemosymbioses), others are extremely rare. Purple photosymbioses are an example of such rare associations. Only two purple photosymbioses between heterotrophic eukaryotes and intracellular purple bacteria have been documented. This is in stark contrast to very common oxygenic photosymbioses and poses the question of what factors prevent the more frequent establishment of purple photosymbioses. To shed light on this question, we investigated the evolutionary history of the purple-green ciliate Pseudoblepharisma tenue (Spirostomidae) using a phylogenetic and comparative approach. We sampled about 30 new isolates of spirostomid ciliates, inferred a comprehensive and well-supported phylogenomic tree, and resolved the sister relationship between Pseudoblepharisma and Spirostomum. Furthermore, we characterized P. tenues sister species, here renamed Pseudoblepharisma chlorelligera, and revealed that it constitutes a quadripartite symbiosis between a ciliate, a green alga, and two different non-photosynthetic bacteria. In addition, we discovered three colorless, non-photosymbiotic Pseudoblepharisma species, which branch as sister to the photosymbiotic P. tenue and P. chlorelligera. Our phylogenetic and comparative genomic analyses suggest that the green algal symbionts of P. tenue predated the acquisition of purple bacterial symbionts, and that the ancestor of the extant Pseudoblepharisma species was non-photosymbiotic and facultatively anaerobic. These data allowed us to hypothesize on the evolutionary steps that led to the origin of P. tenue and thus bring us closer to explaining the conditions that led to the evolutionary emergence of a unique purple-green symbiosis.

evolutionary biology↗

bioRxiv2024

Phylogeny and species delimitation of ciliates in the genus Spirostomum (Class, Heterotrichea) using single-cell transcriptomes

Ciliates are single-celled microbial eukaryotes that diverged from other eukaryotic lineages over a billion years ago. The extensive evolutionary timespan of ciliate has led to enormous genetic and phenotypic changes, contributing significantly to their high level of diversity. Recent analyses based on molecular data have revealed numerous cases of cryptic species complexes in different ciliate lineages, demonstrating the need for a robust approach to delimit species boundaries and elucidate phylogenetic relationships. Heterotrich ciliate species of the genus Spirostomum are abundant in freshwater and brackish environments and are commonly used as biological indicators for assessing water quality. However, some Spirostomum species are difficult to identify due to a lack of distinguishable morphological characteristics, and the existence of cryptic species in this genus remains largely unexplored. Previous phylogenetic studies have focused on only a few loci, namely the ribosomal RNA genes, alpha-tubulin, and mitochondrial CO1. In this study, we obtained single-cell transcriptome of 25 Spirostomum species populations (representing six morphospecies) sampled from South Korea and the USA, and used concatenation- and coalescent-based methods for species tree inference and delimitation. Phylogenomic analysis of 37 Spirostomum populations and 265 protein-coding genes provided a robustious insight into the evolutionary relationships among Spirostomum species and confirmed that species with moniliform and compact macronucleus each form a distinct monophyletic lineage. Furthermore, the multispecies coalescent (MSC) model suggests that there are at least nine cryptic species in the Spirostomum genus, three in S. minus, two in S. ambiguum, S. subtilis, and S. teres each. Overall, our fine sampling of closely related Spirostomum populations and wide scRNA-seq allowed us to demonstrate the hidden crypticity of species within the genus Spirostomum, and to resolve and provide much stronger support than hitherto to the phylogeny of this important ciliate genus.

evolutionary biology↗

bioRxiv2023

CoPheScan: phenome-wide association studies accounting for linkage disequilibrium

Phenome-wide association studies (PheWAS) facilitate the discovery of associations between a single genetic variant with multiple phenotypes. For variants which impact a specific protein, this can help identify additional therapeutic indications or on-target side effects of intervening on that protein. However, PheWAS is restricted by an inability to distinguish confounding due to linkage disequilibrium (LD) from true pleiotropy. Here we describe CoPheScan (Coloc adapted Phenome-wide Scan), a Bayesian approach that enables an intuitive and systematic exploration of causal associations while simultaneously addressing LD confounding. We demonstrate its performance through simulation, showing considerably better control of false positive rates than a conventional approach not accounting for LD. We used CoPheScan to perform PheWAS of protein-truncating variants and fine-mapped variants from disease and pQTL studies, in 2275 disease phenotypes from the UK Biobank. Our results identify the complexity of known pleiotropic genes such as APOE, and suggest a new causal role for TGM3 in skin cancer.

genetics↗

bioRxiv2020

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

The functional interpretation of GWAS remains challenging due to cell-type dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTL) for 659 microdissected human kidney samples and identified cell-type eQTLs by mapping interactions between cell type abundance and genotype. Separately, we generated single cell open chromatin maps (by snATAC-seq) for human kidney samples. We highlight critical enrichment of proximal tubules in kidney function and endothelial cells and distal tubule segments in blood pressure by partitioning heritability using stratified LD-score regression to integrate GWAS with scRNA-seq and snATAC-seq data. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of the most commonly used antihypertensive and renal protective drugs and identifies drug repurposing opportunities for kidney disease. One Sentence SummaryWe define causal cell types, genes and mechanism for kidney dysfunction.

genetics↗

bioRxiv2019

APOL1 is not expressed in proximal tubules and is not filtered

The kidney expression pattern of APOL1 was examined using both protein and mRNA in situ methods on APOL1 bacterial artificial chromosome transgenic mice, with and without proteinuria. APOL1 was detected in podocytes and endothelial cells of the kidney, but was not expressed in tubular epithelia, nor was plasma APOL1 protein filtered and reabsorbed by the proximal tubule. APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies of APOL1-mediated pathogenesis.

pathology↗