Biology subjects

Park, B.

Publications and source records attributed to Park, B..

31 records · Page 2Linked to original sources

bioRxiv2023

A mouse model of ZTTK syndrome reveals indispensable SON functions in organ development and hematopoiesis

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hamper our understanding of both SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency inclines cell fate toward the myeloid lineage but compromises lymphoid lineage development by reducing key genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythroid maturation. These findings highlight the importance of the full gene dosage of Son in organ development and hematopoiesis. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

genetics↗

bioRxiv2022

Rat leukocyte population dynamics predicts a window for intervention in aging.

Age-associated changes in human hematopoiesis have been mostly recapitulated in mouse models; but not much has been explored in rats, a physiologically closer model to humans. To establish whether rat hematopoiesis closely mirrors humans, we examined the peripheral blood of rats throughout their lifespan. Significant age-associated changes showed distinctive population shifts predictive of age. A divergence between predicted versus chronological age changes was indicative of fragility; thus, these data may be a valuable tool to identify underlying diseases or as a surrogate predictor for intervention efficacy. Notably, several blood parameters and DNA methylation alterations defined specific leverage points during aging, supporting non-linear aging effects and highlighting a roadmap for interventions at these junctures. Overall, we present a simple set of rat blood metrics that can provide a window into their health and inform the implementation of interventions in a model system physiologically relevant for humans.

evolutionary biology↗

bioRxiv2021

ChexMix: A Literature Content Extraction Tool for Bioentities

Biomedical databases grow by more than a thousand new publications every day. The large volume of biomedical literature that is being published at an unprecedented rate hinders the discovery of relevant knowledge from keywords of interest to gather new insights and form hypotheses. A text-mining tool, PubTator, helps to automatically annotate bioentities, such as species, chemicals, genes, and diseases, from PubMed abstracts and full-text articles. However, the manual re-organization and analysis of bioentities is a non-trivial and highly time-consuming task. ChexMix was designed to extract the unique identifiers of bioentities from query results. Herein, ChexMix was used to construct a taxonomic tree with allied species among Korean native plants and to extract the medical subject headings unique identifier of the bioentities, which co-occurred with the keywords in the same literature. ChexMix discovered the allied species related to a keyword of interest and experimentally proved its usefulness for multi-species analysis.

bioinformatics↗

bioRxiv2021

Universal gene co-expression network reveals receptor-like protein genes conferring broad-spectrum resistance in pepper (Capsicum annuum L.)

Receptor-like proteins (RLPs) on the plant cell surface have been implicated in immune responses and developmental processes. Although hundreds of RLP genes have been identified in plants, only a few RLPs have been functionally characterized in a limited number of plant species. Here, we identified RLPs in the pepper (Capsicum annuum) genome, and performed comparative transcriptomics coupled with the analysis of conserved gene co-expression networks (GCNs) to reveal the role of core RLP regulators in pepper-pathogen interactions. A total of 102 RNA-seq datasets of pepper plants infected with four pathogens were used to construct CaRLP-targeted GCNs (CaRLP-GCN). All resistance-responsive CaRLP-GCNs were merged to construct a universal GCN. Fourteen hub CaRLPs, tightly connected with defense related gene clusters, were identified in eight modules. Based on the CaRLP-GCNs, we experimentally tested whether hub CaRLPs in the universal GCN are involved in biotic stress response. Of the nine hub CaRLPs tested by virus-induced gene silencing (VIGS), three genes (CaRLP264, CaRLP277, and CaRLP351) showed defense suppression with less hypersensitive response (HR)-like cell death in race-specific and non-host resistance response to viruses and bacteria, respectively, and consistently enhanced susceptibility to Ralstonia solanacearum and/or Phytophthora capsici. These data suggest that key CaRLPs exhibit conserved functions in response to multiple biotic stresses and can be used for engineering of a plant with broad-spectrum resistance. Altogether, we show that generation of a universal GCN using comprehensive transcriptome datasets could provide important clues for uncovering genes involved in various biological processes.

plant biology↗

bioRxiv2020

Deep Metric Learning Network using Proxies for Chromosome Classification and Retrieval in Karyotyping Test

In karyotyping, the classification of chromosomes is a tedious, complicated, and time-consuming process. It requires extremely careful analysis of chromosomes by well-trained cytogeneticists. To assist cytogeneticists in karyotyping, we introduce Proxy-ResNeXt-CBAM which is a metric learning based network using proxies with a convolutional block attention module (CBAM) designed for chromosome classification. RexNeXt-50 is used as a backbone network. To apply metric learning, the fully connected linear layer of the backbone network (ResNeXt-50) is removed and is replaced with CBAM. The similarity between embeddings, which are the outputs of the metric learning network, and proxies are measured for network training. Proxy-ResNeXt-CBAM is validated on a public chromosome image dataset, and it achieves an accuracy of 95.86%, a precision of 95.87%, a recall of 95.9%, and an F-1 score of 95.79%. Proxy-ResNeXt-CBAM which is the metric learning network using proxies outperforms the baseline networks. In addition, the results of our embedding analysis demonstrate the effectiveness of using proxies in metric learning for optimizing deep convolutional neural networks. As the embedding analysis results show, Proxy-ResNeXt-CBAM obtains a 94.78% Recall@1 in image retrieval, and the embeddings of each chromosome are well clustered according to their similarity.

bioengineering↗

bioRxiv2019

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/836304v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1820147org.highwire.dtl.DTLVardef@21fad6org.highwire.dtl.DTLVardef@db22c1org.highwire.dtl.DTLVardef@c6ae5e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHeme synthesis inhibition changes mitochondrial morphology in endothelial cells C_LIO_LILoss of heme causes a buildup of mitochondrial ROS and depolarized membrane potential C_LIO_LIEndothelial cells have defective oxidative phosphorylation and glycolysis on loss of heme C_LIO_LIMitochondrial damage is caused by loss of functional heme-containing Complex IV and partially restored by exogenous heme C_LI

cell biology↗

bioRxiv2019

Joint phylogenetic estimation of geographic movements and biome shifts during the global diversification of Viburnum

Phylogeny, fossils, biogeography, and biome occupancy provide evidence that reflects the singular evolutionary history of a clade. Despite the connections that bind them together, these lines of evidence are most often studied separately, by first inferring a fossil-dated molecular phylogeny, then mapping on ancestral ranges and biomes inferred from extant species. Here we jointly model the evolution of biogeographic ranges, biome affinities, and molecular sequences, incorporating fossils to estimate a dated phylogeny for all of the 163 extant species of the woody plant clade Viburnum (Adoxaceae) that we currently recognize. Our analyses indicate that while the major Viburnum lineages evolved in the Eocene, the majority of extant species originated since the Miocene. Viburnum radiated first in Asia, in warm, broad-leaved evergreen (lucidophyllous) forests. Within Asia we infer several early shifts into more tropical forests, and multiple shifts into forests that experience prolonged freezing. From Asia we infer two early movements into the New World. These two lineages probably first occupied warm temperate forests and adapted later to spreading cold climates. One of these lineages (Porphyrotinus) occupied cloud forests and moved south through the mountains of the Neotropics. Several other movements into North America took place more recently, facilitated by prior adaptations to freezing in the Old World. We also infer four disjunctions between Asia and Europe: the Tinus lineage is the oldest and probably occupied warm forests when it spread, while the other three were more recent and in cold-adapted lineages. These results variously contradict published accounts, especially the view that Viburnum radiated initially in cold forests and, accordingly, maintained vessel elements with scalariform perforations. We explored how the location and biome assignments of fossils affected our inference of ancestral areas and biome states. Our results are sensitive to, but not entirely dependent upon, the inclusion of fossil biome data. We argue that it will be critical to take advantage of all available lines of evidence to decipher events in the distant past, and the joint estimation approach developed here provides cautious hope even when fossil evidence is limited.

evolutionary biology↗

bioRxiv2019

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Given that small-conductance Ca2+-activated K+ (KCa2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a crucial target that contributes to heavy drinking and alcohol-induced functional neuroadaptations, we performed a cross-species analysis of KCNN3 methylation, gene expression, and polymorphisms of alcohol-drinking monkeys and alcohol dependent mice. Because of the alternative promoters in KCNN3, we analyzed expression of the different transcript variants that when translated influence surface trafficking and function of KCa2 channels. In heavy drinking rhesus macaques and alcohol dependent C57BL/6J mice, bisulfite sequencing analysis of the nucleus accumbens revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in monkey and mouse accumbens paralleled an increase in expression of alternative transcript variants that encode apamin-insensitive and dominant-negative KCa2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, KCa2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 by heavy alcohol drinking and dependence represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 by excessive alcohol drinking as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.

neuroscience↗

bioRxiv2019

Use of latent class analysis to identify multimorbidity patterns and associated factors in Korean adults aged 50 years and older

IntroductionMultimorbidity associated with significant disease and economic burdens is common among the aged. We identified chronic disease multimorbidity patterns in Koreans 50 years of age or older, and explored whether such patterns were associated with particular sociodemographic factors and health-related quality-of-life.\n\nMethodsThe multimorbidity patterns of 10 chronic diseases (hypertension, dyslipidemia, stroke, osteoarthritis, tuberculosis, asthma, allergic rhinitis, depression, diabetes mellitus, and thyroid disease) were identified via latent class analysis of data on 8,370 Korean adults aged 50+ years who participated in the sixth Korean National Health and Nutrition Examination Survey (2013-2015). The associations between multimorbidity patterns, and sociodemographic factors and health-related quality of life, were subjected to regression analysis.\n\nResultsThree patterns of multimorbidity were identified: 1) a relatively healthy group (60.4% of the population); 2) a cardiometabolic conditions group (27.8%); and, 3) an arthritis, asthma, allergic rhinitis, depression, and thyroid disease group (11.8%). The female (compared to male) gender was associated with an increased likelihood of membership of the cardiometabolic conditions group (odds ratio [OR]=1.32, 95% confidence interval [CI]=1.15-1.51) and (to a much greater extent) the arthritis, asthma, allergy, depression, and thyroid disease group (OR=4.32, 95% CI=3.30-5.66). Low socioeconomic status was associated with membership of the two multimorbidity classes. Membership of the arthritis, asthma, allergy, depression, and thyroid disease group was associated with a significantly poorer health-related quality-of-life than was membership of the other two groups.\n\nConclusionThe co-occurrence of chronic diseases was not attributable to chance. Multimorbidity patterns were associated with sociodemographic factors and quality-of-life. Our results suggest that targeted, integrated public health and clinical strategies dealing with chronic diseases should be based on an understanding of multimorbidity patterns; this would improve the quality-of-life of vulnerable multimorbid adults.

epidemiology↗

bioRxiv2019

Calcitriol and Non-Calcemic Vitamin D Analogue, 22 Oxacalcitriol, Attenuate Developmental and Pathological Ocular Angiogenesis Ex Vivo and In Vivo

Aberrant ocular blood vessel growth can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration, retinopathy of prematurity and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, lack efficacy in some patients and are associated with poor patient compliance and tachyphylaxis. Small molecule vitamin D has de novo pro-differentiative, anti-proliferative, immunomodulatory, pro-apoptotic and anti-angiogenic properties. Here, our aim was to validate the anti-angiogenic activity of the biologically active form of vitamin D, calcitriol, and a selected vitamin D analogue, 22-oxacalcitriol, across a range of ocular angiogenesis models.\n\nFirst, we validated the anti-angiogenic activity of calcitriol, showing calcitriol to significantly inhibit choroidal sprouting in an ex vivo mouse choroidal fragment sprouting assay. Viability studies in human RPE cell line, ARPE-19, suggested non-calcemic vitamin D analogues have the least off-target anti-proliferative activity compared to calcitriol and additional analogues. Thereafter, the ocular anti-angiogenic activity of non-calcemic vitamin D analogue, 22-oxacalcitriol, was demonstrated in the ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was anti-angiogenic, inducing a dose-dependent reduction in choriocapillary angiogenesis. Inhibition of mouse retinal vasculature development was not induced by systemically delivered calcitriol. However, both calcitriol and 22-oxacalcitriol administered intraperitoneally significantly attenuate choroidal neovascularisation lesion volume in the laser-induced CNV mouse model. 22-oxacalcitriol presented with a more favourable safety profile than calcitriol.\n\nIn summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Vitamin D has potential as a preventative or interventional treatment for ophthalmic neovascular indications.

pharmacology and toxicology↗

bioRxiv2018

Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis

BackgroundPreviously reported observational associations between risk factors and epithelial ovarian cancer (EOC) could reflect residual confounding, reverse causation, or measurement error. Mendelian randomization (MR) uses genetic variants as proxies for modifiable risk factors to strengthen causal inference in observational studies.\n\nMethodsWe used MR to evaluate the causal role of 13 previously reported risk factors in overall and histotype-specific EOC in up to 25,509 case subjects and 40,941 controls in the Ovarian Cancer Association Consortium. Inverse-variance weighted models were employed to generate effect estimates and MR-Egger, weighted median, and weighted mode were performed to examine evidence of horizontal pleiotropy. A Bonferroni-corrected P-value threshold was used to establish \"strong evidence\" (P<0.0038) and \"suggestive evidence\" (0.0038<P<0.05) for associations.\n\nResultsThere was strong or suggestive evidence that 9 of 13 risk factors were causally associated with overall or histotype-specific EOC. Genetic liability to endometriosis was strongly associated with EOC (OR per log odds higher liability: 1.27,95%CI:1.16-1.40;P=6.94x10-7) and lifetime smoking exposure was suggestively associated with EOC (OR per unit increase in smoking score:1.36,95%CI:1.04-1.78;P=0.02). In histotype-stratified analyses, the strongest associations found were between: height and clear cell carcinoma (OR per SD increase:1.36,95%CI:1.15-1.61;P=0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset:1.09,95% CI:1.02-1.16;P=0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per log odds higher liability:0.74,95% CI:0.62-0.90;P=0.002). There was little evidence that genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone-binding globulin were associated with ovarian cancer or its subtypes.\n\nConclusionsOur comprehensive examination of possible etiological drivers of ovarian carcinogenesis supports a causal role for few of these factors in epithelial ovarian cancer and suggests distinct etiologies across histotypes.

epidemiology↗

bioRxiv2018

Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-{kappa}B and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 M, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a GI50 APX2009: 26 M, APX2014: 5.0 M). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-{kappa}B activation and downstream targets. Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p < 0.0001, ANOVA with Dunnetts post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for CNV in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

pharmacology and toxicology↗

bioRxiv2018

Chromosome Removal Via Cellular Fragmentation and Aneuploid Blastomere Exclusion in Primate Embryos

Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously demonstrated that human preimplantation embryos encapsulate mis-segregated chromosomes into micronuclei while undergoing cellular fragmentation and that fragments can contain chromosomal material, but the source of this DNA was unknown. Here, we leveraged the use of a non-human primate model and single-cell DNA-sequencing (scDNA-seq) to examine the chromosomal content of 471 individual samples comprising 254 blastomeres, 42 polar bodies, and 175 cellular fragments from a large number (N=50) of disassembled rhesus cleavage-stage embryos. Our analysis revealed that the frequency of aneuploidy and micronucleation is conserved between humans and macaques and that cellular fragments encapsulate whole and/or partial chromosomes lost from blastomeres. Single-cell/fragment genotyping demonstrated that these chromosome-containing cellular fragments (CCFs) can be either maternal or paternal in origin and display DNA damage via double-stranded breaks. Chromosome breakage and abnormal cytokinesis resulted in reciprocal losses/gains at the terminal ends of chromosome arms, uniparental genome segregation, and mixoploidy between blastomeres. Combining time-lapse imaging with scDNA-seq, we also determined that multipolar divisions at the zygote or 2-cell stage generated chaotic aneuploidy encompassing a complex mixture of maternal and paternal chromosomes. Despite frequent chromosomal mis-segregation at the cleavage-stage, we show that CCFs and non-dividing aneuploid blastomeres exhibiting extensive DNA damage are prevented from incorporation at the blastocyst stage. These findings suggest that embryos respond to chromosomal errors by encapsulation into micronuclei, elimination by cellular fragmentation, and selection against highly aneuploid blastomeres to overcome chromosome instability during preimplantation development.

developmental biology↗