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The study evaluated different molt-inducing methods to achieve the main goal of molting in commercial layers during molting and post-molting periods. A total of 400 60-week-old Lohmann Brown layers were randomly divided into five groups (eight replicates of 10 birds for each group). Laying hens in the fasting control group received no diet from day 1 to day 10. The second group received a molt-inducing diet recommended by the breeding company. The third group received a wheat bran-based diet. The fourth group received a commercial layer diet with 8,000 ppm zinc (as zinc oxide, ZnO). The fifth group received an induced molting diet given to the second group with 8,000 ppm zinc, respectively. Egg production in the fasting control group and groups fed a diet with ZnO were significantly lower (p < 0.001) than those in groups fed the molt-inducing and wheat bran-based diets without ZnO during molting. Egg laying in the fasting control group was rapidly reduced and stopped on the 5.9th day of molting. In both groups having molt treatment with ZnO, egg production was similarly reduced and ceased on the 6.9th day and 7.0th day of molting, respectively, none of them differed significantly from the control. Layers fed molt-inducing diet or wheat bran-based diet did not reach the cessation of laying even on the 28th d of molting period. Relative weights of the ovary and growing oocytes of layers subjected to fasting or fed diets with ZnO were significantly lower than those of other groups. During the first two weeks of post molting, layers fed molt-inducing diet with ZnO showed higher egg production than the other two groups (p < 0.01). The eggshell strength in the group fed the commercial diet with ZnO was significantly higher than those fed the molt-inducing diet or wheat bran-based diets at 6 weeks of post molting (p < 0.05). These results suggest that the non-feed withdrawal molting using ZnO is more effective in inducing molting and increasing post-molt egg production and egg quality than other methods using a molt-inducing diet alone or wheat bran-based diet without ZnO.

Abstract Background and purpose Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS. Methods GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth. Results According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects. Conclusion This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS.

Osteoporosis is a medical condition of global concern, with increasing incidence in both sexes. Bone mineral density (BMD), a highly heritable trait, has been proven a useful diagnostic factor in predicting fracture. Because medical information is lacking about male osteoporotic genetics, we conducted a genome-wide association study of BMD in Korean men. With 1,176 participants, we analyzed 4,414,664 single nucleotide polymorphisms (SNPs) after genomic imputation, and identified five SNPs and three loci correlated with bone density and strength. Multivariate linear regression models were applied to adjust for age and body mass index interference. Rs17124500 (p = 6.42 × 10-7), rs34594869 (p = 6.53 × 10-7) and rs17124504 (p = 6.53 × 10-7) in 14q31.3 and rs140155614 (p = 8.64 × 10-7) in 15q25.1 were significantly associated with lumbar spine BMD (LS-BMD), while rs111822233 (p = 6.35 × 10-7) was linked with the femur total BMD (FT-BMD). Additionally, we analyzed the relationship between BMD and five genes previously identified in Korean men. Rs61382873 (p = 0.0009) in LRP5, rs9567003 (p = 0.0033) in TNFSF11 and rs9935828 (p = 0.0248) in FOXL1 were observed for LS-BMD. Furthermore, rs33997547 (p = 0.0057) in ZBTB and rs1664496 (p = 0.0012) in MEF2C were found to influence FT-BMD and rs61769193 (p = 0.0114) in ZBTB to influence femur neck BMD. We identified five SNPs and three genomic regions, associated with BMD. The significance of our results lies in the discovery of new loci, while also affirming a previously significant locus, as potential osteoporotic factors in the Korean male population.

Abstract We explored the genomic events underlying central neurocytoma (CN), a rare neoplasm of the central nervous system, via multiomics approaches, including whole-exome sequencing, bulk and single-nuclei RNA sequencing, and methylation sequencing. We identified FGFR3 hypomethylation leading to FGFR3 overexpression as a major event in the ontogeny of CN that affects crucial downstream events, such as aberrant PI3K-AKT activity and neuronal development pathways. Furthermore, we found similarities between CN and radial glial cells based on analyses of gene markers and CN tumor cells and postulate that CN tumorigenesis is due to dysregulation of radial glial cell differentiation into neurons. Our data demonstrate the potential role of FGFR3 as one of the leading drivers of tumorigenesis in CN.

Abstract Glaucoma, particularly primary open-angle glaucoma (POAG), poses a significant global health concern. Distinguished by intraocular pressure (IOP), POAG encompasses high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Apolipoprotein E (APOE) is a multifaceted protein with roles in lipid metabolism, neurobiology, and neurodegenerative diseases. However, controversies persist regarding the impact of APOE single-nucleotide polymorphisms (SNPs) on open-angle glaucoma and NTG. This study aimed to identify APOE-specific SNPs influencing NTG risk. A cohort of 178 patients with NTG recruited from Uijeongbu St. Mary’s Hospital and 32,858 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort were included in the analysis. Genotype and haplotype analyses were performed on three promoter SNPs (rs449647, rs769446, and rs405509) and two exonic SNPs (rs429358 and rs7412) located on chromosome 19. Among the five SNPs, rs769446 genotypes exhibited significant differences between cases and controls. The minor allele C of rs769446 emerged as a protective factor against NTG. Furthermore, haplotype analysis of the five SNPs revealed that the A-T-G-T-T haplotype was a statistically significant risk factor for NTG. This study indicated an association between APOE promoter SNPs and NTG in the Korean population. Further studies are required to understand how APOE promoter SNPs contribute to NTG pathogenesis.

Cancer of unknown primary (CUP) is a rare type of metastatic cancer in which the origin of the tumor is unknown. Since the treatment strategy for patients with metastatic tumors depends on knowing the primary site, accurate identification of the origin site is important. Here, we developed an image-based deep-learning model that utilizes a vision transformer algorithm for predicting the origin of CUP. Using DNA methylation dataset of 8,233 primary tumors from The Cancer Genome Atlas (TCGA), we categorized 29 cancer types into 18 organ classes and extracted 2,312 differentially methylated CpG sites (DMCs) from non-squamous cancer group and 420 DMCs from squamous cell cancer group. Using these DMCs, we created organ-specific DNA methylation images and used them for model training and testing. Model performance was evaluated using 394 metastatic cancer samples from TCGA (TCGA-meta) and 995 samples (693 primary and 302 metastatic cancers) obtained from 20 independent external studies. We identified that the DNA methylation image reveals a distinct pattern based on the origin of cancer. Our model achieved an overall accuracy of 96.95 % in the TCGA-meta dataset. In the external validation datasets, our classifier achieved overall accuracies of 96.39 % and 94.37 % in primary and metastatic tumors, respectively. Especially, the overall accuracies for both primary and metastatic samples of non-squamous cell cancer were exceptionally high, with 96.79 % and 96.85 %, respectively.

The percutaneous placement of a totally implantable vascular access port via the subclavian vein is commonly used in patients with a need for multiple intravenous infusions such as administration of chemotherapy. Unfortunately, the use of central venous ports have been associated with adverse events that are hazardous to patients. Here we report the case of a 5-year-old child who died of catastrophic hemothorax after several attempts at insertion of an implantable subclavian venous access device and removal of an infected port. Massive hemothorax occurred on the side contralateral to unsuccessful attempts at insertion of a new port and ipsilateral to the removal of an infected port. We could not confirm the cause of death and hemothorax without autopsy, but we discuss several possible causes of massive hemothorax.

Abstract Kidney fibrosis is a major mechanism underlying chronic kidney disease (CKD). N6-methyladenosine (m6A) RNA methylation is associated with organ fibrosis. We investigated m6A profile alterations and the inhibitory effect of RNA methylation in kidney fibrosis in vitro (TGF-β-treated HK-2 cells) and in vivo (unilateral ureteral obstruction [UUO] mouse model). METTL3-mediated signaling was inhibited using siRNA in vitro or the METTL3-specific inhibitor STM2457 in vivo and in vitro. In HK-2 cells, METTL3 protein levels increased in a dose- and time-dependent manner along with an increase in the cellular m6A levels. In the UUO model, METTL3 expression and m6A levels were significantly increased. Transcriptomic and m6A profiling demonstrated that epithelial-to-mesenchymal transition- and inflammation-related pathways were significantly associated with RNA m6A methylation. Genetic and pharmacologic inhibition of METTL3 in HK-2 cells decreased TGF-β-induced fibrotic marker expression. STM2457-induced inhibition of METTL3 attenuated the degree of kidney fibrosis in vivo. Furthermore, METTL3 protein expression was significantly increased in the tissues of CKD patients with diabetic or IgA nephropathy. Therefore, targeting alterations in RNA methylation could be a potential therapeutic strategy for treating kidney fibrosis.

Summary: Expression quantitative trait loci (eQTL) analysis measures the contribution of genetic variation in gene expression on complex traits. Although this methodology has been used to examine gene regulation in numerous human tissues, eQTL research in solid tissues is relatively lacking. We conducted eQTL analysis on placentas collected from an East Asian population in an effort to identify gene regulatory mechanisms in this tissue. Placentas (n = 102) were collected at the time of cesarean delivery. mRNA was extracted, sequenced with NGS, and compared with matched maternal and fetal DNA arrays performed using maternal and neonatal cord blood. Linear regression modeling was performed using tensorQTL. Fine-mapping along with epigenomic annotation was used to select putative functional variants. We identified 2,703 coding genes that contained at least one eQTL with statistical significance (false discovery rate 0.1. Of these, 19% were located in genomic regions with evidence from public placental epigenome suggesting that they may be functionally relevant. For example, variant rs28379289 located in the placenta-specific regulatory region changes the binding affinity of transcription factor leading to higher expression of LGALS3, which is known to affect placental function. This study expands the knowledge base of regulatory elements within the human placenta and identifies 108 previously unreported placenta eQTL signals, which are listed in our publicly available GMI eQTL database. Further studies are needed to identify and characterize genetic regulatory mechanisms that affect placental function in normal pregnancy and placenta-related diseases.

Abstract Background Fragmentomics, the investigation of fragmentation patterns of cell-free DNA (cfDNA), has emerged as a promising strategy for the early detection of multiple cancers in the field of liquid biopsy. However, the clinical application of this approach has been hindered by a limited understanding of cfDNA biology. Furthermore, the prevalence of hematopoietic cell-derived cfDNA in plasma complicates the in vivo investigation of tissue-specific cfDNA other than that of hematopoietic origin. While conventional two-dimensional cell lines have contributed to research on cfDNA biology, their limited representation of in vivo tissue contexts underscores the need for more robust models. In this study, we propose three-dimensional organoids as a novel in vitro model for studying cfDNA biology, focusing on multifaceted fragmentomic analyses. Results We established nine patient-derived organoid lines from normal lung airway, normal gastric, and gastric cancer tissues. We then extracted cfDNA from the culture medium of these organoids in both proliferative and apoptotic states. Using whole-genome sequencing data from cfDNA, we analyzed various fragmentomic features, including fragment size, footprints, end motifs, and repeat types at the end. The distribution of cfDNA fragment sizes in organoids, especially in apoptosis samples, was similar to that found in plasma, implying occupancy by mononucleosomes. The footprints determined by sequencing depth exhibited distinct patterns depending on fragment sizes, reflecting occupancy by a variety of DNA-binding proteins. Notably, we discovered that short fragments (

A post-menopausal patient with normal kidney function was referred to our hospital because of severe lumber pain. She had been treated by initially oral, and then by intravenous iron for longer than five years for the treatment of iron deficiency anemia due to recurrent GI bleeding. On admission, multiple lumber bone fracture with low bone mineral density was confirmed. Laboratory tests revealed severe hypophosphatemia (1.6 mg/dl) with slight decrease of calcium ion level. Serum levels of 25D and 1,25D were low normal, while increase of intact PTH (83.9 pg/ml) and FGF23 (60 pg/ml) were observed. After terminating intravenous iron supplement, her symptoms and hypophsophatemia were gradually normalized with oral active vitamin D treatment. Although we could not completely exclude the contribution of disturbed iron absorption from the intestine, damages of proximal tubular cells by iron, and osteomalacia caused by the deposition of iron, increased FGF23 level may have played critical roles in the development of severe hypophosphatemia in this patient. Such hypophosphatemia due to high FGF23 has recently been reported in patients treated by intravenous sacharated ferric oxide.

Abstract We present an in-depth single-cell atlas of in vitro multiculture systems on human primary airway epithelium derived from normal and diseased lungs of 27 individual donors. Our large-scale single-cell profiling identified new cell states and differentiation trajectories of rare airway epithelial cell types in human distal lungs. By integrating single-cell datasets of human lung tissues, we discovered immune-primed subsets enriched in lungs and organoids derived from patients with chronic respiratory disease. To demonstrate the full potential of our platform, we further illustrate transcriptomic responses to various respiratory virus infections in vitro airway models. Our work constitutes a single-cell roadmap for the cellular and molecular characteristics of human primary lung cells in vitro and their relevance to human tissues in vivo.

Abstract Blood pressure (BP) is a typical complex trait, and the genetic susceptibility of individuals to changes in BP induced by air pollution exposure is different. Although interactions of exposure to air pollutants with several candidate genes have been identified, genome-wide interaction studies (GWISs) are needed to understand the association between them with BP. Therefore, we aimed to discover the unique genetic loci for BP that interact with exposure to air pollutants in Korean adults. We ultimately included 1868 participants in the discovery step and classified them into groups of those with low-to-moderate exposure and high exposure to average annual concentration of particulate matter with an aerodynamic diameter ≤ 10 μm (PM10). Because none of the single nucleotide polymorphisms (SNPs) achieved a genome-wide level of significance of p int

Abstract Dysembryoplastic neuroepithelial tumor (DNET) is a low-grade brain tumor commonly associated with drug-resistant epilepsy. About half of DNETs are accompanied by tiny nodular lesions separated from the main mass. The existence of these satellite lesions (SLs) has shown a strong association with tumor recurrence, suggesting that they are true tumors. However, it is not known whether SLs represent multiple foci of progenitor tumor cell extension and migration or a multifocal development of the main DNET. This study was designed to elucidate the histopathology and pathogenesis of SLs in DNETs. Separate biopsies from the main masses and SLs with DNET were analyzed. We performed comparative lesion sequencing and phylogenetic analysis. FGFR1 K656E and K655I mutations or duplication of the tyrosine kinase domain was found in all 3 DNET patients and the main masses and their SLs shared the same FGFR1 alterations. The phylogenic analysis revealed that the SLs developed independently from their main masses. It is possible that the main mass and its SLs were separated at an early stage in oncogenesis with shared FGFR1 alterations, and then they further expanded in different places. SLs of DNET are true tumors sharing pathogenic mutations with the main masses. It is plausible that multifocal tumor development takes place in the dysplastic cortex containing cells with a pathogenic genetic alteration.

Insulin is a crucial signalling molecule that primarily functions to reduce blood glucose levels through cellular uptake of glucose. In addition to its role in glucose homeostasis, insulin has been shown to regulate cell proliferation. Specifically, insulin enhances the phosphorylation of pyruvate dehydrogenase E1α (PDHA1) at the Ser293 residue and promotes the proliferation of HepG2 hepatocellular carcinoma cells. Furthermore, we previously observed that p-Ser293 PDHA1 bound with pyruvate kinase M2 (PKM2) as confirmed by coimmunoprecipitation. In this study, we used an in silico analysis to predict the structural conformation of the two binding proteins. However, the function of the protein complex remained unclear. To investigate further, we treated cells with si-PDHA1 and si-PKM2, which led to a reduction in PKM2 and p-Ser293 PDHA1 levels, respectively. Additionally, we found that the PDHA S293A dephospho-mimic reduced PKM2 levels and its associated enzyme activity. Treatment with MG132 and leupeptin impeded the PDHA1 S293A-mediated PKM2 reduction. These results suggest that the association between p-PDHA1 and PKM2 promotes their stability and protects them from protein degradation. Of interest, we observed that p-PDHA1 and PKM2 were localized in the nucleus in liver cancer patients. Under insulin stimulation, the knockdown of both PDHA1 and PKM2 led to a reduction in the expression of common genes, including KDMB1. These findings suggest that p-PDHA1 and PKM2 play a regulatory role in these proteins’ expression and induce tumorigenesis in response to insulin.

The one of critical factor in gas turbine engine performance is high turbine inlet gas temperature. Therefore, the turbine rotor has so many problems which must be considered such as the turbine blade cooling, thermal stress of turbine disk due to severe temperature gradient, turbine rotor tip clearance, under the high operating temperature. The purpose of this study is to provider the temperature distribution and heat flux in turbine disk which is required to considered premensioned problem by the Finite Difference Method and the Finite Element Methods on the steady state condition. In this study, the optimum aspect ratio of turbine disk was analysed for various heat conductivity of turbine disk material by Finite Difference Method, and the effect of laminating method with high conductivity materials to disk thickness direction by Finite Element Methods in order to cool the disk. The laminating method with high conductivity material on the side of the disk is effective.

Infantile spasms (IS) are a clinically and genetically heterogeneous group of epilepsy disorders in early infancy. The genetic backgrounds of IS have been gradually unraveled along with the increased application of next-generation sequencing (NGS). However, to date, only selected genomic regions have been sequenced using a targeted approach in most cases of IS, and the genetic etiologies of the majority of patients remain unknown. We conducted a proof-of-concept study using whole-genome sequencing (WGS) for the genetic diagnosis of IS. We included 16 patients with IS for this study, and WGS was applied as a first-tier test for genetic diagnosis. In total, we sequenced the whole genomes of 28 participants, including the genomes of six patients, which were sequenced with those of their parents. Among variants identified, we focused on those located in epilepsy or seizure-associated genes. We used two different methods to call relevant large deletions from WGS results. We found pathogenic or likely pathogenic variants in four patients (25.0%); a de novo variant in HDAC4, compound heterozygous variants in GRM7, and heterozygous variants in CACNA1E and KMT2E. We also selected two more candidate variants in SOX5 and SHROOM4 intronic regions. Although there are currently several difficulties in applying WGS for genetic diagnosis, especially in clinical interpretation of non-coding variants, we believe that developing sequencing technologies would overcome these hurdles in the near future. Considering the vast genetic heterogeneity and the substantial portion of patients with unknown etiologies, further studies using whole genomic approaches are necessary for patients with IS.

Src, a non-receptor tyrosine kinase, was first discovered as a prototype oncogene and has been shown to critical for cancer progression for a variety of tissues. Src activity is regulated by a number of post-translational modifications in response to various stimuli. Phosphorylations of Src Tyr419 (human; 416 in chicken) and Src Tyr530 (human; 527 in chicken) have been known to be critical for activation and inactivation of Src, respectively. Wnt signaling regulates a variety of cellular functions including for development and cell proliferation, and has a role in certain diseases such as cancer. Wnt signaling is carried out through two pathways: β-catenin-dependent canonical and β-catenin-independent non-canonical pathways as Wnt ligands bind to their receptors, Frizzled, LRP5/6, and ROR1/2. In addition, many signaling components including Axin, APC, Damm, Dishevelled, JNK kinase and Rho GTPases contribute to these canonical and non-canonical Wnt pathways. However, the communication between Wnt signaling and Src tyrosine kinase has not been well reviewed as Src regulates Wnt signaling through LRP6 tyrosine phosphorylation. GSK-3β phosphorylated by Wnt also regulates Src activity. As Wnt signaling and Src mutually regulate each other, it is noted that aberrant regulation of these components give rise to various diseases including typically cancer, and as such, merit a closer look.