Biology subjects

Park, K. S.

Publications and source records attributed to Park, K. S..

9 recordsLinked to original sources

bioRxiv2025

Clonal Hematopoiesis Mutations Increase Risk of Alzheimer's Disease with APOE ϵ3/ϵ3 Genotype

Clonal hematopoiesis of indeterminate potential (CHIP) represents clonal expansion of blood cells, and increases the risk of hematological malignancies and cardiovascular disorders. Recent studies have studied CHIP mutations in individuals with Alzheimers disease (AD), but it is unclear whether their role in AD pathogenesis is protective, detrimental, or neutral. In this study, we used molecular-barcoded deep gene panel sequencing ([~]400X) to examine CHIP mutations in 298 blood samples from AD and neurotypical individuals 60 years and older. The AD patients exhibited a significantly higher burden of CHIP mutations compared to the age-matched controls (p < 2e-7, odds ratio (OR) = 2.89), particularly in low-frequency variants often not captured by standard whole exome or whole genome sequencing (WGS). This increase was driven by individuals with the APOE {varepsilon}3/{varepsilon}3 genotype and absent in {varepsilon}4 carriers. Analysis of an independent dataset from the Alzheimers Disease Sequencing Project (ADSP), comprised of WGS data from [~]30,000 individuals, confirmed increased CHIP mutations in AD versus control (p < 0.02, OR = 1.32), again driven by individuals with APOE {varepsilon}3/{varepsilon}3 genotype. CHIP mutations in AD patients also showed stronger positive selection than in controls. Our results indicate that AD patients show significantly more CHIP mutations in their blood than controls, involving more than one third of AD patients, and contributing to AD risk through a mechanism independent of APOE {varepsilon}4.

genetics↗

bioRxiv2024

Extracellular vesicles isolated from frozen and fresh human melanoma tissue are similar in purity and protein composition

Extracellular vesicles (EVs) isolated from tumor tissues represent a precious source of EVs because they are enriched in disease-associated biomarkers and are highly concentrated. However, a fundamental question is whether freezing of tissues influences the EVs integrity and function and whether non-EVs are co-isolated with the EVs. In this work, we isolated EVs from metastatic melanoma tissue both immediately after tissue resection and after being frozen for at least two weeks. Specifically, the samples were divided into two parts: one was immediately processed for EV isolation (hereafter called fresh), and the other was frozen on dry ice and stored for two weeks before being processed for EV isolation (hereafter called frozen). Large and small EVs were isolated through ultracentrifugation, pooled, and further purified on an iodixanol density cushion. The EVs were analyzed by transmission electron microscopy, nanoparticle tracking analysis, and protein quantification as well as by quantitative mass spectrometry. The results did not show any significant difference between EVs isolated from fresh and frozen tissue. Importantly, there was no enrichment of either intracellular proteins or mitochondrial proteins in EVs isolated from frozen tissues vs. fresh tissues. Moreover, there were no significant differences in the quantity of proteins like MT-CO2, Cox6, SLC24A22, HLA-DR, and Erlin2, which were previously identified as potential markers of melanoma, ovarian cancer, and breast cancer. Overall, this study supports the use of frozen tissues as a source of EVs for research purposes because frozen tissue-derived EVs do not differ in purity or protein composition compared to their fresh counterparts.

cell biology↗

bioRxiv2020

SUMO-specific protease 2 (SENP2) suppresses browning of white adipose tissue through C/EBPβ modulation

SUMO-specific protease 2 (SENP2) is highly expressed in white adipose tissue (WAT) and plays an important role in the early stages of adipogenesis. To investigate the function of SENP2 in adipocytes, we generated adipocyte-specific Senp2 knock-out (Senp2-aKO) mice. Compared to wild-type mice, Senp2-aKO mice had reduced adipose tissue mass and smaller multi-locular adipocytes in inguinal WAT (iWAT). Body temperatures of Senp2-aKO mice were effectively regulated during cold exposure. Additionally, Senp2-aKO mice were resistant to high-fat-diet-induced obesity and insulin resistance and exhibited an increase in energy expenditure rates. Expression of thermogenic genes, including Ucp1, was significantly increased in iWAT (and less efficiently in epidydimal WAT [eWAT]) of Senp2-aKO mice, suggesting that SENP2 depletion accelerates browning of WAT. Further, suppression of HOXC10 was essential for beige adipocyte formation in SENP2-deficient cells of iWAT, and Hoxc10 transcriptional suppression was mediated by C/EBP{beta}, a direct target of SENP2. Sumoylated C/EBP{beta} efficiently inhibited Hoxc10 transcription through recruitment of the transcriptional co-repressor DAXX. Similarly, Senp2 knockdown using siRNAs during adipogenesis promoted thermogenic adipocyte differentiation of precursor cells in both iWAT and eWAT, and C/EBP{beta} was a common mediator. Together these results suggest that SENP2 plays critical role in white adipocyte differentiation by suppressing differentiation toward thermogenic adipocytes through modulation of C/EBP{beta} in both iWAT and eWAT.

cell biology↗

bioRxiv2020

Gradual segregation of Adult Stem Cells and Niche cells during development from common precursors under the guidance of graded extracellular signals

Adult stem cell function relies on the prior development of appropriate numbers and spatial organization of stem cells and supportive niche cells. Drosophila Follicle Stem Cells (FSCs) present a favorable paradigm for understanding those developmental processes. About sixteen FSCs in an adult germarium produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. Both ECs and FCs also act as niche cells. Here we show that adult ECs, FSCs and FCs derive from common precursors intermingled with germline cells during pupal development, with progeny of a single precursor commonly including ECs and FSCs, FSCs and FCs, or all three adult cell types. Precursors posterior to germline cells become the first FCs and engulf a largely naked germline cyst projected out of the germarium to form the first egg chamber and set up a key posterior signaling center for regulating adult FSC behavior.

developmental biology↗

bioRxiv2019

High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss

Phosphate overload contributes to mineral bone disorders associated with crystal nephropathies. Phytate, the major form of phosphorus in plant seeds, is known as an indigestible and negligible in humans. However, the mechanism and adverse effects of high-phytate intake on Ca2+ and phosphate absorption and homeostasis are unknown. Here we show that excessive intake of phytate with a low-Ca2+ diet fed to rats contributed to the development of crystal nephropathies, renal phosphate wasting, and bone loss through tubular dysfunction secondary to dysregulation of intestinal calcium and phosphate absorption. Moreover, Ca2+ supplementation alleviated the detrimental effects of excess dietary phytate on bone and kidney through excretion of undigested Ca2+-phytate, which prevented a vicious cycle of intestinal phosphate overload and renal phosphate wasting while improving intestinal Ca2+ bioavailability. Thus, we demonstrate that phytate is digestible without a high-Ca2+ diet and a risk factor for phosphate overloading and developing crystal nephropathies and bone disease.

physiology↗

bioRxiv2019

Rho-kinase mediates the anorexigenic action of melanocortin by suppressing AMPK

ObjectiveMelanocortin action is essential for the maintenance of energy homeostasis. However, knowledge of the signaling mechanism(s) that mediates the effect of melanocortin remains incomplete.\n\nMethodsROCK1 is a key regulator of energy balance in the hypothalamus. To explore the role of ROCK1 in the anorexigenic action of melanocortin, we deleted ROCK1 in MC4R neurons in mice. Next, we studied the metabolic effects of MC4R neuron-specific ROCK1-deficiency and following treatment with -melanocyte-stimulating hormone (MSH).\n\nResultsHere we show that -MSH increases Rho-kinase 1 (ROCK1) activity in the hypothalamus. Deficiency of ROCK1 in MC4R-expressing neurons results in increased body weight in mice fed normal chow diet. This is likely due to increased food intake and decreased energy expenditure. Importantly, we find that ROCK1 activation in MC4R expressing neurons is required for melanocortin action, as evidenced by the fact that - MSHs ability to suppress food intake is impaired in MC4R neuron-specific ROCK1-deficient mice. To elucidate the mechanism by which ROCK1 mediates melanocortin action, we performed in vitro studies in hypothalamic cells expressing MC4R. We demonstrate that -MSH promotes the physical interaction of ROCK1 and G12, and this results in suppression of AMPK activity.\n\nConclusionsOur study identifies ROCK1 as a novel mediator of melanocortins anorexigenic action and uncover a new MC4R[->]G12[->]ROCK1[->]AMPK signaling pathway. Targeting Rho-kinase in MC4R-expressing neurons could provide a new strategy to combat obesity and its related complications.

neuroscience↗

bioRxiv2019

Data Resource Profile:The Dementias Platform UK (DPUK) Data Portal

The Dementias Platform UK (DPUK) Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform (UKSeRP) infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure lab using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Project are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

neuroscience↗

bioRxiv2019

Dual activity of PNGM-1, a metallo-β-lactamase and tRNase Z, pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases

Antibiotic resistance is a steadily increasing global problem which could lead to a fundamental upheaval in clinical care with the potential to return us to the pre-antibiotic era1-4. The production of {beta}-lactamases, a group of enzymes that confer antibiotic resistance in Gram-negative bacteria, is now one of the major barriers in treating Gram-negative infections5. {beta}-Lactamases are classified according to their catalytic mechanisms into serine {beta}-lactamases and metallo-{beta}-lactamases6,7. There are functional and structural similarities between serine {beta}-lactamases and penicillin-binding proteins, and so serine {beta}-lactamases are thought to have evolved from a penicillin-binding protein7,8. Given the functional and structural differences between serine {beta}-lactamases and metallo-{beta}-lactamases, metallo-{beta}-lactamases are thought to have evolved from a protein other than a penicillin-binding protein, but to date this ancestor remains unknown8-11. We discovered PNGM-1, the first subclass B3 metallo-{beta}-lactamase, in deep-sea sediments that predate the antibiotic era12. Here we discover the dual activity of PNGM-1, pinpointing the evolutionary origin of subclass B3 metallo-{beta}-lactamases. Phylogenetic analysis suggested that PNGM-1 could yield insights into the evolutionary origin of subclass B3 metallo-{beta}-lactamases. We reveal the structural similarities between tRNase Zs and PNGM-1, which prompted us to investigate their evolutionary relationship and the possibility of them possessing dual enzymatic activities. We demonstrate that PNGM-1 has dual activity with both true metallo-{beta}-lactamase and tRNase Z activity, suggesting that PNGM-1 is thought to have evolved from a tRNase Z. We also show kinetic and structural comparisons between PNGM-1 and other proteins including subclass B3 metallo-{beta}-lactamases and tRNase Zs. These comparisons revealed that the B3 metallo-{beta}-lactamase activity of PNGM-1 is a promiscuous activity and subclass B3 metallo-{beta}-lactamases are thought to have evolved through PNGM-1 activity. Our work provides a foundation for the evolution of tRNase Z into subclass B3 metallo-{beta}-lactamases through the dual activity of PNGM-1.

microbiology↗

bioRxiv2017

Functional Difference of Mitochondrial Genome and Its Association with Traits of Common Complex Diseases in Humans

Recent evidence suggests that mitochondrial genomes harboring common mitochondrial DNA polymorphisms might have functional difference and could be associated with common complex human diseases such as metabolic syndrome and cancer that are related to mitochondrial dysfunction. However, there has been no report examining the functional difference of mitochondrial genome in the pathogenesis of such diseases at the cellular or molecular level. In order to examine the effect of mitochondrial genome on metabolic syndrome or cancer without interference from nuclear genes, we analyzed trans-mitochondrial cytoplasmic hybrid cells (cybrids) with common Asian mtDNA haplogroups A, B, D, and F from healthy volunteers. The mitochondrial oxygen consumption rates of cybrids were associated with multiple components of metabolic syndrome such as body mass index, waist circumference, serum triglyceride levels and high-density lipoprotein cholesterol levels. In addition, the cybrids showed varying degree of tumorigenicity both in vitro and in vivo. Especially, the cybrids harboring mtDNA haplogroup D had a significantly slower growth rate. These findings suggest that the phenotypes of common complex diseases in humans can be determined by their mitochondrial genomes. Therefore, not only nuclear genome but also mitochondrial genome should be considered in explaining the genetic pathogenesis of common complex human diseases.

genetics↗