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Cellular dynamics and fate decision in early human embryogenesis remain largely unknown owing to the challenges of performing studies in human embryos 1 . Here, we explored whole-genomes of 334 single-cell colonies and targeted deep sequences of 379 bulk tissues obtained from various anatomical locations of seven recently deceased adult human donors. Using somatic mutations as an intrinsic barcode, we reconstructed early cellular phylogenies that demonstrate (1) an endogenous mutational rate that is higher in the first cell division but decreases to approximately one per cell per cell division later in life; (2) universal unequal contribution of early cells to embryo proper, resulting from early cellular bottlenecks that stochastically set aside epiblast cells within the embryo; (3) examples of varying degrees of early clonal imbalances between tissues on the left and right sides of the body, different germ layers and specific anatomical parts and organs; (4) emergence of a few ancestral cells that will substantially contribute to adult cell pools in blood and liver; and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach also provides insights into the age-related mutational processes and loss of sex chromosomes in normal somatic cells. In sum, this study provides a foundation for future studies to complete cellular phylogenies in human embryogenesis. Adult human tissues from diverse sites around the body are used to reconstruct cellular phylogenies from early development, using somatic mutations as an internal barcode.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10 −8 per base pair) and a turnover frequency of 10–20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells. Analysis of 2,096 single-cell clones from three tissues of 31 healthy donors characterizes mitochondrial DNA mosaicism and highlights the following two origins of mtDNA variants: heteroplasmy in the fertilized egg and postzygotic mutations.

Background The C:G > T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G > T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database. Results Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G > T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G > T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change. Conclusions This study provides the first unbiased rate of C:G > T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.

This study examines the financially feasibility of the proper terminal capacity by each berth size of the automatic container terminal (ACT) from the perspective of Terminal Operating Company (TOC). ACT is a highly productive and eco-friendly port facility, but it requires a lot of capital investment. Thus, the investment of ACT should consider the TOC’s operating profit preservation to determine the proper terminal capacity. In this study, we attempt to conduct financial analysis using the net present value method and estimate breakeven handling volume of five berth sizes (nine, five, four, three, and two berths). In particular, as the aim of this study is to propose a capacity model of ACT, the model must be able to adapt to a variety of situations reflecting the number of berths and financial discount rate. The case study focused on the new port of Busan, introducing ACT. As a result, the breakeven terminal capacity changes from 560,421 TEU of the 9-berth model to 633,102 TEU of the 2-berth model, applying a 4.5% standard discount ratio. In a sensitivity test considering the change in discount rate and the size of the berth at the same time, the net present value (NPV) has a positive value at the level of at least 550,000 TEU (nine berths and 3.5% discount rate) and up to 650,000 TEU (two berths and 5.5% discount rate). The method of optimizing financial efficiency by analyzing the appropriate loading capacity will be an important support tool in decision-making by providing the analysis results and reasonable information obtained during the analysis process to the TOC, the main stakeholder in the adoption of ACT.

This study provides a systematic method for determining the proper rent fee of a port railway station with a litigation case study of Busan port container terminal. The Port Rail Station Operating Company (PRSOC) leases and operates the port railway station of the port authority (PA). The PA wants to receive a rent fee with the goal of recovering the investment cost, and the PRSOC wants to pay rent to the extent that it can generate an appropriate profit. In order to reasonably estimate the rent fee, this study attempted using a method of estimating the capacity-based demand of the rail station. A recent discussion of terminal rentals concerns what to rent. That is, will only the infrastructure be leased, or will the substructure and the superstructure be leased? Will the infrastructure, superstructure, and equipment be leased? Rail station capacity encounters a bottleneck when measuring railroad track capacity, i.e. RMGC capacity. In other words, arbitrary demand estimation leads to operating losses for PRSOC and may also cause losses to investors because investment costs cannot be recovered. In this study, data such as investment cost, operating cost, and sales required for the construction of the rail station were collected from the Ministry of Ocean and Fishery, PA, and PRSOC. Based on these data, a proper rent fee is proposed by analyzing the cash flow on the premise of operation for the next 30 years. This study adopts the discounted cashflow (DCF) method because DCF allows an objective and consistent comparison of rent fee levels from the PA and PRSOC perspectives. Using DCF, this study finds that the proper rent fee from the perspective of the PA is USD 397,045, while the PRSOC’s proper rent fee is USD 355,801. Thus, it is reasonable to set the standard for determining the proper rent fee by calculating and comparing the rent fee level from the perspective of PA’s investment cost recovery and PRSOC’s operating balance maintenance perspective. This study suggests that the DCF method should be applied to standardize the rent fee calculation system for the port railway station.

The LNG terminals are characterized by a large number of ships entering the port during the winter season due to the seasonality of rapidly increasing demand for heating. In winter, there is a shortage of dolphin jetty wharf (dolphins), which increases the waiting rate for ships. Therefore, there is a practical argument that dolphins should be additionally built to solve the ship standby problem. This study proposes the proper LNG handling capacity of a terminal with multiple dolphins of different size. Studies on calculating the LNG handling capacity of LNG terminal dolphins have been proposed by UNCTAD and Ministry of Transport of China (MTC). The formula-based calculation of LNG handling capacity has the advantage of being simple, but it has the disadvantage of not reflecting the actual operation. In this study, the proper LNG handling capacity is measured using a simulation method to overcome the limitations of formula-based calculation for Incheon port in South Korea. In order to check whether the method by simulation is justified, it is compared with the unloading capacity by the calculation formula. This study finds that the proper (or optimal) LNG handling capacity of Incheon port is determined by a dolphin occupancy of 49%, where the dolphin’s profits are maximized. As the results of simulation model, the proper (or optimal) loading capacity is 38.5 million m3 when dolphin occupancy is 49%. The capacity of individual dolphin is estimated at 17.0 million m3 for 70,000 DWT dolphin and 21.2 million m3 for 120,000 DWT dolphin, respectively. The main points of this study to use simulation model are as follows: First, the number of non-working days should be considered. Second, the optimal dolphin occupancy should be determined by finding the maximum profit point of using the pier. Third, if the size of the dolphin is different, an appropriate simulation will be implemented. Fourth, the data of the peak season should be analyzed. Finally, it should be checked whether the ship waiting rate is acceptable level or not.

The purpose of this case study is to conduct an economic analysis to calculate the proper terminal capacity of automated container terminal (ACT) investment from the perspective of the public sector. As a key element of smart port, the ACT is an important terminal operating facility for import/export and transshipment cargo between countries and must have facilities with sufficient capacity to load/unload export/import cargo in a timely manner according to the user’s request. Recently, the method of calculating the capacity of seaport infrastructure is changing from the method of applying the maximum capacity to the method of applying the proper capacity. Therefore, it is desirable to expand port facilities by investigating proper capacity rather than expanding port facilities based on the maximum performance. This study is a case study focusing on the new port of Busan introducing the ACT. From the perspective of national fiscal income and national economy from the ACT investment, this study determines the proper terminal capacity for each berth. As a result of economic analysis, the break-even terminal capacity to secure economic feasibility is from 544,272TEU of the nine berths to 600,138TEU of two berths applying a 2.96% discount ratio. In a sensitivity analysis considering the social discount rate and the change in the size of berths, the net present value has a positive value from a minimum of 530,000 TEU (nine berths with 1.96% social discount ratio) to a maximum of 620,000 TEU (three berths with 3.46% social discount ratio).

Patient‐derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole‐exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an ‘organoid score’ based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard‐of‐care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression‐free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA‐approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients. Patient‐derived organoids (PDOs) represent valuable ex vivo models in evaluating personalized therapeutic options. Here, we demonstrated that organoid score, calculated according to organoid response to drugs prescribed to the matched patient, can be predictive of disease progression in patients with colorectal cancer. We also evaluated additional therapeutic options by in vitro drug library screening of FDA‐approved drugs in PDOs. Our data suggest that PDOs could be used for the preclinical evaluation of off‐label therapeutics in patients with cancer.

This study investigates whether corporate social responsibility (CSR) activities and board gender diversity affect bankruptcy. The core issue focuses on the moderating effect between CSR activities and board gender diversity on bankruptcy. Using 4,654 firmyear observations from a sample of 581 non-financial firms listed on the Korean Stock Exchange over the period 2009–2017, we employ the fixed effect estimation and two-way fixed effect estimation of panel analysis to control endogenous. We find firms engaging more in CSR activities reduce the level of bankruptcy, but board gender diversity does not reduce the level of bankruptcy due to tiny portion of female director in the boardroom. The moderating effect on the relationship between CSR activities and board gender diversity reduce the level of bankruptcy. This result indicates that the influence of female directors on the boards of Korean listed firms is not yet strong but board gender diversity with good CSR activities positively operate to reduce the level of bankruptcy.

Purpose: This study investigates whether quality of audit committee affects audit quality of Korean listed firms using panel data during the period 2008 to 2018.   Theoretical framework: Recent studies show that characteristics of audit committees such as size, activity, and expertise have a significant impact on the monitoring of the financial reporting process (He and Yang, 2014; Asiriuwa et al. 2018). Therefore, it is necessary to carry out systematic empirical studies to understand the effectiveness of the audit committee from various perspectives.   Design/methodology/approach: The quality of audit committee is classified into four categories: 1) activity, 2) independence, 3) expertise, and 4) the presence of female audit committee member. Audit quality is measured by auditor size and accruals quality.   Findings: This study finds that activity and expertise of audit committee enhance audit quality whereas independence of audit committee does not affect audit quality. The female audit committee member partially enhances audit quality.   Research, Practical & Social implications: This study suggests that the high quality of the audit committee enhances the audit quality and increases the accounting transparency of the firm.   Originality/value: The empirical results of this study suggest that firm should concentrate the optimal composition of the audit committee, not simply the establishment of the audit committee.