Biology subjects

Kim, H. A.

Publications and source records attributed to Kim, H. A..

4 recordsLinked to original sources

bioRxiv2026

CTL1 (SLC44A1) regulates myelin lipid composition and architecture in Schwann cells

Myelin formation requires extensive membrane lipid synthesis, yet how myelinating glia acquire the choline needed for this process remains incompletely understood. Choline transporter-like protein 1 (CTL1; SLC44A1) is highly expressed in Schwann cells, and CTL1 deficiency in oligodendrocytes impairs CNS myelination. Here, we examined the role of CTL1 in peripheral nerve myelination using Schwann cell-specific Ctl1 knockout mice. Unexpectedly, loss of Ctl1 did not alter Schwann cell differentiation, the number of myelinated axons, or myelin thickness, but increased myelin abnormalities, including in-foldings and out-foldings. Lipidomic analysis revealed selective alterations in myelin lipid composition, particularly among long-chain lipid species, together with triglyceride accumulation in whole nerves. CTL1 deficiency also increased mTORC1-associated S6 and mTORC2-associated AKT S473 phosphorylation. Transcriptomic analysis revealed downregulation of gene programs associated with fatty acid {beta}-oxidation, triglyceride catabolism, and oxidative phosphorylation. Following peripheral nerve injury, Ctl1-deficient Schwann cells generated a normal repair response and efficiently remyelinated regenerated axons despite altered mTOR signaling. Together, these findings demonstrate that CTL1 is not required for overall peripheral myelin production but contributes to maintaining normal myelin lipid composition and architecture, revealing an unexpected ability of Schwann cells to sustain myelination despite disruption of CTL1-dependent choline metabolism

neuroscience↗

bioRxiv2025

S100A8/A9 Inhibition Reduces Splenic Myelopoiesis and Improves Outcomes After Stroke

BackgroundNeutrophils are among the earliest immune cells to infiltrate the ischemic brain and contribute to secondary neuronal damage. The alarmin S100 calcium-binding protein A8/A9 (S100A8/A9), predominantly released by neutrophils, is upregulated during this process. Although the bone marrow is recognised as the principal site of neutrophil production via myelopoiesis, the role of the spleen as an immune-responsive organ remains incompletely understood. MethodsIn this study, we employed a transient middle cerebral artery occlusion (MCAO) model in male C57Bl/6 mice and examined immune responses 24 hours post-stroke in the blood, bone marrow and spleen using flow cytometry. To understand the role of S100A8/A9 in modulating stroke-induced myelopoiesis, we administered a small molecule inhibitor of S100A8/A9, ABR-215757, before and after stroke. ResultsNeutrophils and S100A8/A9 were found in the infarcted brain tissue. Interestingly, we observed a marked increase in splenic neutrophils, accompanied by an expansion of myeloid progenitors, indicating activation of extramedullary myelopoiesis. Given our previous work showing that S100A8/A9 promotes myelopoiesis, we pharmacologically inhibited S100A8/A9 to determine if this would modulate stroke-induced myelopoiesis. Treatment with ABR-215757 at 24 hours post-stroke led to reduced splenic myelopoiesis, reversed neutrophilia, enhanced forelimb grip strength, and a one-third reduction in infarct size. ConclusionThese findings identify the spleen as a key contributor to neutrophil production following stroke and suggest that targeting S100A8/A9 may attenuate post-stroke inflammation and improve neurological recovery. HighlightsO_LIStroke induces extramedullary myelopoiesis in the spleen, not femoral bone marrow. C_LIO_LINeutrophil-derived S100A8/A9 drives splenic myelopoiesis after ischemic stroke. C_LIO_LIPharmacological blockade of S100A8/A9 with ABR-215757 reduces neutrophilia. C_LIO_LIInhibition of S100A8/A9 lessens infarct size and improves neurological recovery. C_LIO_LIHuman stroke tissue confirms S100A8/A9 accumulation with neutrophil infiltration. C_LI

neuroscience↗

bioRxiv2023

A harmonized public resource of deeply sequenced diverse human genomes

Underrepresented populations are often excluded from genomic studies due in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high quality set of 4,094 whole genomes from HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also demonstrate substantial added value from this dataset compared to the prior versions of the component resources, typically combined via liftover and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared to previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations.

genomics↗

bioRxiv2022

Intermittent Fasting Mitigates Vascular and Neuronal Pathologies in a Mouse Model of Vascular Dementia

Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism of vascular cognitive impairment (VCI). The heterogeneous effects of CCH complicate establishing single target therapies against VCI and its more severe form, vascular dementia (VaD). Intermittent fasting (IF) has multiple targets and is neuroprotective across a range of disease conditions including stroke, but its effects against CCH-induced neurovascular pathologies remain to be elucidated. We therefore assessed the effect of IF against CCH-associated neurovascular pathologies and investigated underlying mechanisms. Male C57BL/6 mice were subjected to either ad libitum feeding (AL) or IF (16 hours of fasting per day) for 4 months. In both groups, CCH was experimentally induced by the bilateral common carotid artery stenosis (BCAS) method. Sham operated groups were used as controls. Measures of leaky microvessels, blood brain barrier (BBB) permeability, protein expression of tight junctions, extracellular matrix components and white matter changes were determined to investigate the effect of IF against CCH-induced neurovascular pathologies. IF alleviated CCH-induced neurovascular pathologies by reducing the number of leaky microvessels, BBB breakdown, loss of tight junctional proteins and vascular endothelial growth factors. In addition, IF mitigated the severity of white matter lesions, maintained myelin basic protein levels, while concurrently reducing hippocampal neuronal cell death. Furthermore, IF reduced CCH-induced increase in levels of matrix metalloproteinase (MMP)-2 and its upstream activator MT1-MMP, which are involved in the breakdown of the extracellular matrix that is a core component of the BBB. Additionally, we observed that IF reduced CCH-induced increase in the oxidative stress marker malondialdehyde, and increased antioxidant markers glutathione and superoxide dismutase. Combined, our data suggests that IF attenuates neurovascular damage, metalloproteinase and oxidative stress-associated pathways, and cell death in the brain following CCH in a mouse model of VCI. Although IF has yet to be assessed in human patients with VaD, our data suggest that IF may be an effective means of preventing the onset or suppressing the development of neurovascular pathologies in VCI and VaD.

neuroscience↗