Biology subjects

Kim, S.-H.

Publications and source records attributed to Kim, S.-H..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

A new tuna specimen (Genus Auxis) from the Duho Formation (middle Miocene) of South Korea

A partially preserved caudal vertebrae imprint of a tuna was discovered from the Duho Formation (Miocene) of South Korea. This specimen was assigned to the genus Auxis and represents the second record of fossil Auxis found in South Korea and in the world. We compared the vertebral morphology of the studied specimen to that of currently known species of Auxis, including extinct taxa. However, the specimen could not be assigned to any extant or new species of Auxis due to anatomical differences and a lack of comparability. The discovery of a new specimen of Auxis aligns with theories of high marine biodiversity in the East Sea (Sea of Japan) and its opening in the Early to Middle Miocene. A widely opened East Sea and upwelling activities might have increased the abundance and diversity of large oceanic fishes such as tunas during the deposition of the Duho Formation. The specimen supports paleoenvironmental interpretations of the Duho Formation as pelagic and subtropical. A taphonomic scenario of the specimen was inferred based on the lack of anal pterygiophores and the leaf imprint on the matrix. The specimen would have been exposed for at least a month in a low-energy sedimentary environment at the deep-sea bottom and would have undergone disintegration before being buried.

paleontology↗

bioRxiv2024

Matrix-rigidity cooperates with biochemical cues in M2 macrophage activation through increased nuclear deformation and chromatin accessibility

Macrophages encounter a myriad of biochemical and mechanical stimuli across various tissues and pathological contexts. Notably, matrix rigidity has emerged as a pivotal regulator of macrophage activation through mechanotransduction. However, the precise mechanisms underlying the interplay between mechanical and biochemical cues within the nuclear milieu remain elusive. Here we elucidate how the increased matrix rigidity drives macrophages to amplify alternatively-activated (M2 phenotype) signalings cooperatively with biochemical cues (e.g., IL4/13) through altered nuclear mechanics. Notably, we found that reconstructed podosome-like F-actins and contractility induced nucleus deformation, opening nuclear pores, which facilitates nuclear translocation of the key transcription factor STAT6. Furthermore, the altered nuclear mechanics increased chromatin accessibility induced by H3K9 methylation, particularly of M2-associated gene promoters. These cooperative events of the mechano-chemical signaling at the cytoskeletal-to-nuclear domains facilitated M2 transcriptional activation and cellular functions. We further evidenced the rigidity-primed M2 macrophages were immunosuppressive and accumulated in stiffened tumor tissues. This study proposes a mechanism by which matrix mechanics crosstalks with biochemical signals to potentiate macrophage activation through nuclear mechanosensing and chromatin modifications, offering insights into macrophage mechanobiology and its therapeutic modulations.

bioengineering↗

bioRxiv2024

Detailed mechanisms for unintended large DNA deletions with CRISPR, base editors, and prime editors

CRISPR-Cas9 nucleases are versatile tools for genetic engineering cells and function by producing targeted double-strand breaks (DSBs) in the DNA sequence. However, the unintended production of large deletions (>100 bp) represents a challenge to the effective application of this genome-editing system. We optimized a long-range amplicon sequencing system and developed a k-mer sequence-alignment algorithm to simultaneously detect small DNA alteration events and large DNA deletions. With this workflow, we determined that CRISPR-Cas9 induced large deletions at varying frequencies in cancer cell lines, stem cells, and primary T cells. With CRISPR interference screening, we determined that end resection and the subsequent TMEJ [DNA polymerase theta-mediated end joining] repair process produce most large deletions. Furthermore, base editors and prime editors also generated large deletions despite employing mutated Cas9 "nickases" that produce single-strand breaks. Our findings reveal an important limitation of current genome-editing tools and identify strategies for mitigating unwanted large deletion events.

genetics↗

bioRxiv2023

Development of novel high-resolution melting markers for the assessment of hybridization between Mauremys sinensis and Mauremys reevesii in South Korea

The Chinese striped-necked turtle Mauremys sinensis was first reported in the wild in South Korea in 2012. Owing to its potential to hybridize with the native and endangered Mauremys reevesii in South Korea, leading to ecosystem disturbance, M. sinensis was designated as an ecosystem-disturbing species (EDS; hereafter) in 2020. Such hybridization between M. sinensis and M. reevesii has previously been reported in Taiwan. To protect and conserve the native South Korean M. reevesii population, the extent of its hybridization needed to be examined. Therefore, we developed novel high-resolution melting markers to elucidate the status of hybridization between Mauremys sinensis and Mauremys reevesii in South Korea. We identified the presence of M. sinensis, M. reevesii, and their hybrid across 47 sites in South Korea. Among these sites, five locations were confirmed as areas of sympatry for both M. sinensis and M. reevesii, with one hybrid individual identified at the Jeonju-si site. In total, hybrids were identified at four different sites. For more definitive species identification, blood samples were collected from the specimens and subjected to mitochondrial DNA (mtDNA) cytochrome c oxidase subunit I (COI) gene and nuclear DNA (nDNA) R35 gene analysis, leading to the identification of two more hybrids from two other sites. To date, no hybrids of M. sinensis have been confirmed to reproduce in the wild, yet this requires further research for validation. The high-resolution melting (HRM) marker in the R35 gene developed in this study yielded three distinct curves that were designated as M. sinensis, M. reevesii, and M. sinensis x M. reevesii, aligning with those of the R35 gene sequencing. The novel markers developed in this study serve as a valuable tool that can be used in future research on rapid detection of hybridization.

zoology↗

bioRxiv2023

Subchronic exposure to ambient PM2.5 impairs novelty recognition and spatial memory

Air pollution remains a great challenge for public health, with the detrimental effects of air pollution on cardiovascular, rhinosinusitis, and pulmonary health increasingly well understood. Recent epidemiological associations point to the adverse effects of air pollution on cognitive decline and neurodegenerative diseases. Mouse models of subchronic exposure to PM2.5 (ambient air particulate matter < 2.5 {micro}m) provide an opportunity to demonstrate the causality of target diseases. Here, we subchronically exposed mice to concentrated ambient PM2.5 for 7 weeks (5 days/week; 8h/day) and assessed its effect on behavior using standard tests measuring cognition or anxiety-like behaviors. Average daily PM2.5 concentration was 200 {micro}g/m3 in the PM2.5 group and 10 {micro}g/m3 in the filtered air group. The novel object recognition (NOR) test was used to assess the effect of PM2.5 exposure on recognition memory. The increase in exploration time for a novel object versus a familiarized object was lower for PM2.5-exposed mice (42% increase) compared to the filtered air (FA) control group (110% increase). In addition, the calculated discrimination index for novel object recognition was significantly higher in FA mice (67 %) compared to PM2.5 exposed mice (57.3%). The object location test (OLT) was used to examine the effect of PM2.5 exposure on spatial memory. In contrast to the FA-exposed control mice, the PM2.5 exposed mice exhibited no significant increase in their exploration time between novel location versus familiarized location indicating their deficit in spatial memory. Furthermore, the discrimination index for novel location was significantly higher in FA mice (62.6%) compared to PM2.5 exposed mice (51%). Overall, our results demonstrate that subchronic exposure to higher levels of PM2.5 in mice causes impairment of novelty recognition and spatial memory.

pharmacology and toxicology↗

bioRxiv2023

`Mind in Vitro' platforms: Versatile, scalable, robust and open solutions to interfacing with living neurons

Motivated by the unexplored potential of in vitro neural systems for computing, and by the corresponding need of versatile, scalable interfaces for multimodal interaction, we present an accurate, modular, fully customizable and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated. A reconfigurable platform that works across multiple industry standards enables a complete signal chain, from neural substrates sampled through high-density Micro-Electrode Arrays (MEAs) to data acquisition, downstream analysis and cloud storage. Built-in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations and spatial topologies. Through a native analysis and management software suite, the utility and robustness of our system is demonstrated across neural cultures and applications, including embryonic stem cell-derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging and long-term recording. Overall, our technology, termed Mind in Vitro to underscore the computing inspiration, provides an end-to-end solution that can be widely deployed due to its affordable (>10X cost-reduction) and open-source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.

neuroscience↗

bioRxiv2023

TrkB-dependent regulation of molecular signaling across septal cell types

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimers.

neuroscience↗

bioRxiv2023

AMLs harboring DNMT3A-destabilizing variants show increased intratumor DNA methylation heterogeneity at bivalent chromatin domains

The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. A recent discovery on the catalogue of DNMT3A-destabilizing mutations throughout the DNMT3A gene as well as the oligomerization-dependent catalytic property of DNMT3A prompted us to investigate the common effect of DNMT3A-destabilizing mutations (DNMT3AINS) on the genomewide methylation patterns of AML cells. In this study, we describe the characteristics of DNMT3AINS AML methylomes through the comprehensive computational analyses on three independent AML cohorts. As a result, we show that methylomes of DNMT3AINS AMLs are considerably different from those of DNMT3AR882 AMLs in that they exhibit both locally disordered DNA methylation states and increased across-cell DNA methylation heterogeneity in bivalent chromatin domains. This increased epigenetic heterogeneity was functionally associated with heterogeneous expression of membrane-associated factors shaping stem cell niche, implying the diversification of the modes of leukemic stem cell-niche interactions. We also present that the level of methylation disorder at bivalent domains predicts the response of AML cells to hypomethylating agents through cell line- and patient-level analyses, which supports that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.

cancer biology↗

bioRxiv2022

Cropbox: a declarative crop modeling framework

Crop models mirror our knowledge on crops in silico. Therefore, crop modeling inherits common issues of software engineering and often suffers from technical debts. We introduce a new crop modeling framework: Cropbox as a declarative domain-specific language. Recognizing that a crop model is fundamentally an integrated network of generalized state variables, we developed the framework to encapsulate abstract primitives for representing variables, systems, and functions that are essential to crop modeling workflows. With a constrained syntax, high-level model specifications are automatically translated into low-level host code written in Julia programming language. This allows complex crop models to become more accessible and transparent for modelers to build and use. We highlight key capabilities of the Cropbox framework through specific case studies featuring a coupled leaf gas-exchange model and a process-based crop simulation model. We also illustrate potential extensions of the framework to support functional-structural plant modeling (FSPM) using a 3D root architectural model as an example.

plant biology↗

bioRxiv2022

Genomic demography of world's ethnic groups and their genomic identity between two individuals

All current categorizations of human population, such as ethnicity, ancestry and race, are based on various selections and combinations of subjectively- and/or qualitatively-defined characteristics, such as ancestral lineage/location, cultural/societal norm, language, skin color and other phenotypes and traits perceived by the members within or from outside of the categorized group. Yet, such categorization has been broadly used also in the fields of human genetics, health sciences and medical practices (e.g., 1,2,3), where the observed health characteristics are objectively and quantitatively definable, but the population categorization is not yet available. Here we show the feasibility of deriving a whole-genome-based categorization that is objectively definable and quantitatively measurable. We observe that: (a) the worlds ethnic populations form about 14 genomic groups (GGs); (b) each GG consists of multiple ethnic groups (EGs); and (c) at an individual level, approximately 99.8%, on average, of the whole genome contents are identical between any two individuals regardless of their GGs or EGs.

evolutionary biology↗

bioRxiv2021

COP1 promotes seed germination by destabilizing RGA-LIKE2 (RGL2) in Arabidopsis

Under favorable moisture, temperature and light conditions, gibberellin (GA) biosynthesis is induced and triggers seed germination. A major mechanism by which GA promotes seed germination is by promoting the degradation of the DELLA protein RGL2, a major repressor of germination in Arabidopsis seeds. Analysis of seed germination phenotypes of constitutively photomorphogenic 1 (cop1) mutants and complemented COP1-OX/cop1-4 lines in response to GA and paclobutrazol (PAC) suggested a positive role for COP1 in seed germination and a relation with GA signaling. cop1-4 mutant seeds showed PAC hypersensitivity, but transformation with a COP1 overexpression construct rendered them PAC insensitive, with a phenotype similar to that of rgl2 mutant (rgl2-SK54) seeds. Furthermore, cop1-4 rgl2-SK54 double mutants showed a PAC-insensitive germination phenotype like that of rgl2-SK54, identifying COP1 as an upstream negative regulator of RGL2. COP1 interacts directly with RGL2 and in vivo this interaction is strongly enhanced by SPA1. COP1 directly ubiquitinates RGL2 to promote its degradation. Moreover, GA stabilizes COP1 with consequent RGL2 destabilization. By uncovering this COP1-RGL2 regulatory module, we reveal a novel mechanism whereby COP1 positively regulates seed germination and controls the expression of germination-promoting genes.

plant biology↗

bioRxiv2021

An integrative process-driven model for biomass and yield estimation of hardneck garlic (Allium sativum)

We introduce an integrative process-driven crop model for garlic (Allium sativum). Building on our previous model that simulated key phenological, morphological, and physiological features of a garlic plant, the new garlic model provides comprehensive and integrative estimations of biomass accumulation and yield formation under diverse environmental conditions. This model also showcases an application of Cropbox to develop a comprehensive crop model. Cropbox is a crop modeling framework featuring declarative modeling language and unified simulation interface for building and improving crop models. Using Cropbox, we first evaluated the model performance against three datasets with an emphasis on biomass and yield measured under different environmental conditions and growing seasons. We then applied the model to simulate optimal planting dates under future climate conditions for assessing climate adaptation strategies between two contrasting locations in South Korea: the current growing region (Gosan) and an unfavorable cold winter region (Chuncheon, Gangwon-do). The model simulated the growth and development of a southern-type cultivar (Namdo, Jeju-do) reasonably well. Under RCP (Representative Concentration Pathway) scenarios, an overall delay in optimal planting date from a week to a month and a slight increase in potential yield were expected in Gosan. Expansion of growing region to northern area including Chuncheon was expected due to mild winter temperatures in the future and may allow Namdo cultivar production in more regions. The predicted optimal planting date in the new region was similar to the current growing region that favors early fall planting. Our new integrative garlic model provides mechanistic, process-driven crop responses to environmental cues and can be useful for assessing climate impacts and identifying crop specific climate adaptation strategies for the future.

plant biology↗

bioRxiv2021

Expression of brain-derived neurotrophic factor in basolateral amygdala inputs to lateral septum is necessary for mice to identify socially novel individuals

The lateral septum (LS) is a GABAergic region in the basal forebrain that is implicated in sociability. However, the neural circuits and cell signaling pathways that converge on the LS to mediate social behaviors arent well understood. Multiple lines of evidence suggest that brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays important roles in social behavior. While BDNF is not locally produced in LS, we demonstrate that nearly all GABAergic neurons in LS express TrkB. Local knock-down of TrkB expression from LS neurons decreased sociability and reduced recruitment of social novelty-induced neural activity. Since BDNF is not synthesized in LS, we evaluated which inputs to the LS could serve as potential BDNF sources for controlling sociability. By selectively ablating inputs to LS, we demonstrated that inputs from the basolateral amygdala (BLA), but not ventral CA1 (vCA1), regulate sociability. Moreover, depleting BDNF selectively in BLA-LS projection neurons phenocopied the decreased sociability observed following either local LS TrkB knockdown or ablation of BLA-LS inputs. These data support the hypothesis that BLA-LS projection neurons could serve as a critical source of BDNF for activating TrkB signaling in LS neurons to control sociability.

neuroscience↗

bioRxiv2021

JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

molecular biology↗

bioRxiv2021

An mRNA vaccine against SARS-CoV-2: Lyophilized, liposome-based vaccine candidate EG-COVID induces high levels of virus neutralizing antibodies

In addition to the traditional method of vaccine development, the mRNA coronavirus vaccine, which is attractive as a challenging vaccination, recently opened a new era in vaccinology. Here we describe the EG-COVID which is a novel liposome-based mRNA candidate vaccine that encodes the spike (S) protein of SARS-CoV-2 with 2P-3Q substitution in European variant. We developed the mRNA vaccine platform that can be lyophilized using liposome-based technology. Intramuscular injection of the EG-COVID elicited robust humoral and cellular immune response to SARS-CoV-2. Furthermore, sera obtained from mice successfully inhibited SARS-CoV-2 viral infection into Vero cells. We developed EG-COVID and found it to be effective based on in vitro data, and we plan to initiate a clinical trial soon. Since EG-COVID is a lyophilized mRNA vaccine that is convenient for transportation and storage, accessibility to vaccines will be significantly improved.

molecular biology↗

bioRxiv2021

A novel vascular endothelial growth factor-trap KP-VR2 with enhanced ligand blocking

Antiangiogenic therapies targeting vascular endothelial growth factor (VEGF)-A have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including the acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGF-B and placental growth factor (PlGF) levels. Thus, we developed a novel VEGF-Trap, KP-VR2, which can neutralize VEGF-A, VEGF-B, and PlGF to mediate these problems. KP-VR2 consists of two consecutive second Ig-like domains (D2s) of VEGF receptor 1 (VEGFR-1) fused to human IgG1 Fc. KP-VR2 showed more potent decoy activity than the current VEGF-Trap against VEGF and PlGF. Most importantly, two consecutive D2s of VEGFR-1 can generate two putative binding sites, resulting in a significant improvement in binding capacity. These advances resulted in stronger antitumor efficacy in implanted tumor models than aflibercept and bevacizumab. Overall, the results of this study highlight KP-VR2 as a promising therapeutic candidate for further clinical drug development.

cancer biology↗

bioRxiv2021

Anterior insula-associated social novelty recognition: orchestrated regulation by a local retinoic acid cascade and oxytocin signaling

BackgroundDeficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a common core brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. MethodsTo determine the role of anterior insula in social cognition, we manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. We conducted multimodal analyses at the molecular, cellular, circuitry, and behavioral levels. ResultsAt the molecular/cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. We also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus where serotonergic neurons are projected to the anterior insula. Furthermore, we show that serotonin 5HT2C receptor expressed in the anterior insula influences social novelty recognition. ConclusionsAnterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade, but also remotely regulated by oxytocin via a non-classic mechanism.

animal behavior and cognition↗

bioRxiv2021

The Flowering Time Regulator FLK Controls Pathogen Defense in Arabidopsis thaliana

Plant disease resistance is a complex process that is maintained in an intricate balance with development. Increasing evidence indicates the importance of post-transcriptional regulation of plant defense by RNA binding proteins. The K homology (KH) repeat is an ancient RNA binding motif found in proteins from diverse organisms. The role of KH domain proteins in pathogen resistance is not well known. From a genetic screen aimed to uncover novel defense genes in Arabidopsis, we identified a new allele of the canonical flowering regulatory gene, FLOWERING LOCUS KH Domain (FLK), encoding a putative triple KH-repeat protein. In addition to late flowering, the flk mutants exhibited decreased resistance to the bacterial pathogen Pseudomonas syringae and increased resistance to the necrotrophic fungal pathogen Botrytis cinerea. We found that the flk mutations compromised basal defense and defense signaling mediated by salicylic acid and led to increased reactive oxygen species (ROS) scavenging, likely through FLKs regulation of the ROS scavenging enzyme catalases. RNA-seq data revealed that major defense signaling genes are regulated by FLK, providing a molecular basis for FLKs contribution to pathogen defense. Together our data support that FLK is a multifunctional protein regulating pathogen defense and development of plants.

plant biology↗