The fate of carbon in a mature forest under carbon dioxide enrichment.

Atmospheric carbon dioxide enrichment (eCO2) can enhance plant carbon uptake and growth1-5, thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration6. Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth3-5, it is unclear whether mature forests respond to eCO2 in a similar way. In mature trees and forest stands7-10, photosynthetic uptake has been found to increase under eCO2 without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO2 unclear4,5,7-11. Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO2 exposure. We show that, although the eCO2 treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO2, and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.

Molecular traces of Drosophila hemocytes reveal transcriptomic conservation with vertebrate myeloid cells.

Drosophila hemocytes serve as the primary defense system against harmful threats, allowing the animals to thrive. Hemocytes are often compared to vertebrate innate immune system cells due to the observed functional similarities between the two. However, the similarities have primarily been established based on a limited number of genes and their functional homologies. Thus, a systematic analysis using transcriptomic data could offer novel insights into Drosophila hemocyte function and provide new perspectives on the evolution of the immune system. Here, we performed cross-species comparative analyses using single-cell RNA sequencing data from Drosophila and vertebrate immune cells. We found several conserved markers for the cluster of differentiation (CD) genes in Drosophila hemocytes and validated the role of CG8501 (CD59) in phagocytosis by plasmatocytes, which function much like macrophages in vertebrates. By comparing whole transcriptome profiles in both supervised and unsupervised analyses, we showed that Drosophila hemocytes are largely homologous to vertebrate myeloid cells, especially plasmatocytes to monocytes/macrophages and prohemocyte 1 (PH1) to hematopoietic stem cells. Furthermore, a small subset of prohemocytes with hematopoietic potential displayed homology with hematopoietic progenitor populations in vertebrates. Overall, our results provide a deeper understanding of molecular conservation in the Drosophila immune system.

Clustering malignant cell states using universally variable genes.

Single-cell RNA sequencing (scRNA-seq) has revealed important insights into the heterogeneity of malignant cells. However, sample-specific genomic alterations often confound such analysis, resulting in patient-specific clusters that are difficult to interpret. Here, we present a novel approach to address the issue. By normalizing gene expression variances to identify universally variable genes (UVGs), we were able to reduce the formation of sample-specific clusters and identify underlying molecular hallmarks in malignant cells. In contrast to highly variable genes vulnerable to a specific sample bias, UVGs led to better detection of clusters corresponding to distinct malignant cell states. Our results demonstrate the utility of this approach for analyzing scRNA-seq data and suggest avenues for further exploration of malignant cell heterogeneity.

Toward the functional interpretation of somatic structural variations: bulk- and single-cell approaches.

Structural variants (SVs) are genomic rearrangements that can take many different forms such as copy number alterations, inversions and translocations. During cell development and aging, somatic SVs accumulate in the genome with potentially neutral, deleterious or pathological effects. Generation of somatic SVs is a key mutational process in cancer development and progression. Despite their importance, the detection of somatic SVs is challenging, making them less studied than somatic single-nucleotide variants. In this review, we summarize recent advances in whole-genome sequencing (WGS)-based approaches for detecting somatic SVs at the tissue and single-cell levels and discuss their advantages and limitations. First, we describe the state-of-the-art computational algorithms for somatic SV calling using bulk WGS data and compare the performance of somatic SV detectors in the presence or absence of a matched-normal control. We then discuss the unique features of cutting-edge single-cell-based techniques for analyzing somatic SVs. The advantages and disadvantages of bulk and single-cell approaches are highlighted, along with a discussion of their sensitivity to copy-neutral SVs, usefulness for functional inferences and experimental and computational costs. Finally, computational approaches for linking somatic SVs to their functional readouts, such as those obtained from single-cell transcriptome and epigenome analyses, are illustrated, with a discussion of the promise of these approaches in health and diseases.

Engineering Magnetic Nanoclusters for Highly Efficient Heating in Radio-Frequency Nanowarming.

Effective thawing of cryopreserved samples requires rapid and uniform heating. This is achievable through nanowarming, an approach that heats magnetic nanoparticles by using alternating magnetic fields. Here we demonstrate the synthesis and surface modification of magnetic nanoclusters for efficient nanowarming. Magnetite (Fe3O4) nanoclusters with an optimal diameter of 58 nm exhibit a high specific absorption rate of 1499 W/g Fe under an alternating magnetic field at 43 kA/m and 413 kHz, more than twice that of commercial iron oxide cores used in prior nanowarming studies. Surface modification with a permeable resorcinol-formaldehyde resin (RFR) polymer layer significantly enhances their colloidal stability in complex cryoprotective solutions, while maintaining their excellent heating capacity. The Fe3O4@RFR nanoparticles achieved a high average heating rate of 175 °C/min in cryopreserved samples at a concentration of 10 mg Fe/mL and were successfully applied in nanowarming porcine iliac arteries, highlighting their potential for enhancing the efficacy of cryopreservation.

The actin cytoskeleton-MRTF/SRF cascade transduces cellular physical niche cues to entrain the circadian clock.

The circadian clock is entrained to daily environmental cues. Integrin-linked signaling via actin cytoskeleton dynamics transduces physical niche cues from the extracellular matrix to myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated transcription. The actin cytoskeleton organization and SRF-MRTF activity display diurnal oscillations. By interrogating disparate upstream events in the actin cytoskeleton-MRTF-A/SRF signaling cascade, we show that this pathway transduces extracellular niche cues to modulate circadian clock function. Pharmacological inhibition of MRTF-A/SRF by disrupting actin polymerization or blocking the ROCK kinase induced period lengthening with augmented clock amplitude, and genetic loss of function of Srf or Mrtfa mimicked the effects of treatment with actin-depolymerizing agents. In contrast, actin polymerization shortened circadian clock period and attenuated clock amplitude. Moreover, interfering with the cell-matrix interaction through blockade of integrin, inhibition of focal adhesion kinase (FAK, encoded by Ptk2) or attenuating matrix rigidity reduced the period length while enhancing amplitude. Mechanistically, we identified that the core clock repressors Per2, Nr1d1 and Nfil3 are direct transcriptional targets of MRTF-A/SRF in mediating actin dynamics-induced clock response. Collectively, our findings defined an integrin-actin cytoskeleton-MRTF/SRF pathway in linking clock entrainment with extracellular cues that might facilitate cellular adaptation to the physical niche environment.

Tumor immune microenvironment lncRNAs.

Long non-coding ribonucleic acids (RNAs) (lncRNAs) are key players in tumorigenesis and immune responses. The nature of their cell type-specific gene expression and other functional evidence support the idea that lncRNAs have distinct cellular functions in the tumor immune microenvironment (TIME). To date, the majority of lncRNA studies have heavily relied on bulk RNA-sequencing data in which various cell types contribute to an averaged signal, limiting the discovery of cell type-specific lncRNA functions. Single-cell RNA-sequencing (scRNA-seq) is a potential solution for tackling this limitation despite the lack of annotations for low abundance yet cell type-specific lncRNAs. Hence, updated annotations and further understanding of the cellular expression of lncRNAs will be necessary for characterizing cell type-specific functions of lncRNA genes in the TIME. In this review, we discuss lncRNAs that are specifically expressed in tumor and immune cells, summarize the regulatory functions of the lncRNAs at the cell type level and highlight how a scRNA-seq approach can help to study the cell type-specific functions of TIME lncRNAs.

Unraveling the ecological threads: How invasive alien plants influence soil carbon dynamics.

Invasive alien plants (IAPs) pose significant threats to native ecosystems and biodiversity worldwide. However, the understanding of their precise impact on soil carbon (C) dynamics in invaded ecosystems remains a crucial area of research. This review comprehensively explores the mechanisms through which IAPs influence soil C pools, fluxes, and C budgets, shedding light on their effects and broader consequences. Key mechanisms identified include changes in litter inputs, rates of organic matter decomposition, alterations in soil microbial communities, and shifts in nutrient cycling, all driving the impact of IAPs on soil C dynamics. These mechanisms affect soil C storage, turnover rates, and ecosystem functioning. Moreover, IAPs tend to increase gross primary productivity and net primary productivity leading to the alterations in fluxes and C budgets. The implications of IAP-induced alterations in soil C dynamics are significant and extend to plant-soil interactions, ecosystem structure, and biodiversity. Additionally, they have profound consequences for C sequestration, potentially impacting climate change mitigation. Restoring native plant communities, promoting soil health, and implementing species-specific management are essential measures to significantly mitigate the impacts of IAPs on soil C dynamics. Overall, understanding and mitigating the effects of IAPs on soil C storage, nutrient cycling, and related processes will contribute to the conservation of native biodiversity and complement global C neutrality efforts.

Survival differences between patients with de novo and relapsed/progressed advanced non-small cell lung cancer without epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements.

BACKGROUND: We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB-IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses. METHODS: This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB-IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups. RESULTS: Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01-1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar. CONCLUSIONS: De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor.

Is a change in economic status associated with anxiety, depression and suicide ideation during the COVID-19 pandemic in South Korean adults?

BACKGROUND: Coronavirus disease 2019 (COVID-19) affected global economic changes and mental health outcomes. However, sex differences are unclear regarding the relationship between economic status change and mental health outcomes during the pandemic. Therefore, we investigated whether change in economic status is associated with depression, anxiety and suicidal ideation, based on sex. METHODS: We used data from the COVID-19 National Mental Health Survey 2021 in South Korea. We used the Generalized Anxiety Disorder (GAD) 7-item scale for measuring anxiety, the Patient Health Questionnaire-9 scale for measuring depression and self-reported questionnaires for investigating suicidal ideation and COVID-19-related suicidal ideation. RESULTS: Among 2000 participants, those with a worse economic status change had a 2.7-fold higher risk of GAD (prevalence ratio [PR], 2.70; 95% confidence interval [CI], 2.07-3.51); 2.5-fold higher depression risk (PR, 2.55; 95%CI, 2.05-3.18); 2.1-fold higher risk of suicidal ideation (PR, 2.09; 95%CI, 1.72-2.53); and 4.0-fold higher risk of COVID-19-related suicidal ideation (PR, 4.03; 95%CI, 2.78-5.83). Women whose economic status worsened had a 3.5-fold higher risk of COVID-19-related suicidal ideation (PR, 3.49; 95%CI, 2.01-6.06). CONCLUSION: Worse economic change is associated with negative mental health outcomes during the COVID-19 pandemic; particularly, women experiencing financial hardships during the pandemic had a higher risk of COVID-19-related suicidal ideation.

The impact of assisted reproductive technology treatment coverage on marriage, pregnancy, and childbirth in women of childbearing age: an interrupted time-series analysis.

BACKGROUND: Korea is encountering major challenges related to its declining birth rate and aging population. Various policies have been introduced to prevent further population decrease and boost the birth rate, but their effectiveness has not been verified. Therefore, this study examined the effects of assisted reproductive technology (ART) insurance coverage on marriage, pregnancy, and childbirth in women of childbearing age. METHODS: All information on marriage, pregnancy, childbirth of women of childbearing age was obtained from Statistics Korea and Korean National Health Insurance Service database. During a total follow-up period of 54 months (July 2015 to December 2019), an average of 12,524,214 women of childbearing age per month, and 29,701 live births per month were included in the analysis. An interrupted time series with segmented regression was performed to analyze the time trend and changes in outcomes. RESULTS: The implementation of ART coverage policies had no significant impact on marriage or pregnancy rates. However, it did affect multiple pregnancy and multiple birth rates, which increased by 1.0% (Exp(ß3) = 1.010, P-value = 0.0001) and 1.4% (Exp(ß3) = 1.014, P-value = < 0.0001), respectively, compared to the pre-intervention period. Although the effect of covering ART treatment on total birth rates were not confirmed, a slightly slower decline was observed after the intervention (Exp(ß1) = 0.993, P-value = < 0.0001, Exp(ß1 + ß3) = 0.996 P-value = 0.012). CONCLUSION: This study identified the effects of ART health insurance coverage policy on the rates of multiple pregnancies and births. After the policy implementation, the downward trend in the total birth rate reduced slightly. Our findings suggest that interventions to support infertile couples should be expanded to solve the problem of low fertility rates. To address the intricate problems related to low birth rates, the Korean government introduced a policy that provides financial support and health insurance coverage for assisted reproductive technology (ART) treatment for infertile couples. As a result of evaluating the effectiveness of the ART coverage policy, it led to higher rates of pregnancies and births. In addition, although the total birth rate has been continuously decreasing over time, the decline may have been slowed down slightly by this policy.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

Comparison of Proportional Mortality Between Korean Atomic Bomb Survivors and the General Population During 1992-2019.

BACKGROUND: Atomic bombs dropped on Hiroshima and Nagasaki in Japan in August 1945 were estimated to have killed approximately 70,000 Koreans. In Japan, studies on the health status and mortality of atomic bomb survivors compared with the non-exposed population have been conducted. However, there have been no studies related to the mortality of Korean atomic bomb survivors. Therefore, we aimed to study the cause of death of atomic bomb survivors compared to that of the general population. METHODS: Of 2,299 atomic bomb survivors registered with the Korean Red Cross, 2,176 were included in the study. In the general population, the number of deaths by age group was calculated from 1992 to 2019, and 6,377,781 individuals were assessed. Causes of death were categorized according to the Korean Standard Classification of Diseases. To compare the proportional mortality between the two groups, the P value for the ratio test was confirmed, and the Cochran-Armitage trend test and χ² test were performed to determine the cause of death according to the distance from the hypocenter. RESULTS: Diseases of the circulatory system were the most common cause of death (25.4%), followed by neoplasms (25.1%) and diseases of the respiratory system (10.6%) in atomic bomb survivors who died between 1992 and 2019. The proportional mortality associated with respiratory diseases, nervous system diseases, and other diseases among atomic bomb survivors was higher than that of the general population. Of the dead people between 1992 and 2019, the age at death of survivors who were exposed at a close distance was younger than those who were exposed at a greater distance. CONCLUSION: Overall, proportional mortality of respiratory diseases and nervous system diseases was high in atomic bomb survivors, compared with the general population. Further studies on the health status of Korean atomic bomb survivors are needed.

Cost-Effectiveness of All-Oral Regimens for the Treatment of Multidrug-Resistant Tuberculosis in Korea: Comparison With Conventional Injectable-Containing Regimens.

BACKGROUND: Regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) have been changed from injectable-containing regimens to all-oral regimens. The economic effectiveness of new all-oral regimens compared with conventional injectable-containing regimens was scarcely evaluated. This study was conducted to compare the cost-effectiveness between all-oral longer-course regimens (the oral regimen group) and conventional injectable-containing regimens (the control group) to treat newly diagnosed MDR-TB patients. METHODS: A health economic analysis over lifetime horizon (20 years) from the perspective of the healthcare system in Korea was conducted. We developed a combined simulation model of a decision tree model (initial two years) and two Markov models (remaining 18 years, six-month cycle length) to calculate the incremental cost-effectiveness ratio (ICER) between the two groups. The transition probabilities and cost in each cycle were assumed based on the published data and the analysis of health big data that combined country-level claims data and TB registry in 2013-2018. RESULTS: The oral regimen group was assumed to spend 20,778 USD more and lived 1.093 years or 1.056 quality-adjusted life year (QALY) longer than the control group. The ICER of the base case was calculated to be 19,007 USD/life year gained and 19,674 USD/QALY. The results of sensitivity analyses showed that base case results were very robust and stable, and the oral regimen was cost-effective with a 100% probability for a willingness to pay more than 21,250 USD/QALY. CONCLUSION: This study confirmed that the new all-oral longer regimens for the treatment of MDR-TB were cost-effective in replacing conventional injectable-containing regimens.

Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis.

Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT-TFF2 axis in the process of fibrogenesis.

The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells.

Epidemiological relationships between cancer and cardiovascular diseases have been reported, but a molecular basis remains unclear. Some proteoglycans that strongly bind low-density-lipoprotein (LDL) are abundant both in atherosclerotic regions and in high metastatic-tumor tissue. LDL retention is crucial for the initiation of atherosclerosis, although its contribution to malignancy of cancer is not known. In our study, we show the importance of the accumulation of LDL in tumor metastasis. We demonstrated that high metastatic-tumor tissue contains high amounts of LDL and forms more oxidized LDL (ox-LDL). Interestingly, lectin-like ox-LDL receptor 1 (LOX-1), a receptor for ox-LDL and a recognized key molecule for cardiovascular diseases, was highly expressed in tumor endothelial cells (TECs). Neutrophils are important for ox-LDL formation. Since we observed the accumulation and activation of neutrophils in HM-tumors, we evaluated the involvement of LOX-1 in neutrophil migration and activation. LOX-1 induced neutrophil migration via CCL2 secretion from TECs, which was enhanced by ox-LDL. Finally, we show genetic manipulation of LOX-1 expression in TECs or tumor stroma tended to reduce lung metastasis. Thus, the LOX-1/ox-LDL axis in TECs may lead to the formation of a high metastatic-tumor microenvironment via attracting neutrophils.

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular barrier and contribute to hematogenous metastasis; however, the role of oral bacteria-induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier-associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF-κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)-cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans-stimulated ECs. Furthermore, S. mutans-induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.

Global analyses of the effect of different cellular contexts on microRNA targeting.

MicroRNA (miRNA) regulation clearly impacts animal development, but the extent to which development-with its resulting diversity of cellular contexts-impacts miRNA regulation is unclear. Here, we compared cohorts of genes repressed by the same miRNAs in different cell lines and tissues and found that target repertoires were largely unaffected, with secondary effects explaining most of the differential responses detected. Outliers resulting from differential direct targeting were often attributable to alternative 3' UTR isoform usage that modulated the presence of miRNA sites. More inclusive examination of alternative 3' UTR isoforms revealed that they influence ∼10% of predicted targets when comparing any two cell types. Indeed, considering alternative 3' UTR isoform usage improved prediction of targeting efficacy significantly beyond the improvements observed when considering constitutive isoform usage. Thus, although miRNA targeting is remarkably consistent in different cell types, considering the 3' UTR landscape helps predict targeting efficacy and explain differential regulation that is observed.

HERES, a lncRNA that regulates canonical and noncanonical Wnt signaling pathways via interaction with EZH2.

Wnt signaling through both canonical and noncanonical pathways plays a core role in development. Dysregulation of these pathways often causes cancer development and progression. Although the pathways independently contribute to the core processes, a regulatory molecule that commonly activates both of them has not yet been reported. Here, we describe a long noncoding RNA (lncRNA), HERES, that epigenetically regulates both canonical and noncanonical Wnt signaling pathways in esophageal squamous cell carcinoma (ESCC). For this study, we performed RNA-seq analysis on Korean ESCC patients and validated these results on a larger ESCC cohort to identify lncRNAs commonly dysregulated in ESCCs. Six of the dysregulated lncRNAs were significantly associated with the clinical outcomes of ESCC patients and defined 4 ESCC subclasses with different prognoses. HERES reduction repressed cell proliferation, migration, invasion, and colony formation in ESCC cell lines and tumor growth in xenograft models. HERES appears to be a transacting factor that regulates CACNA2D3, SFRP2, and CXXC4 simultaneously to activate Wnt signaling pathways through an interaction with EZH2 via its G-quadruple structure-like motif. Our results suggest that HERES holds substantial potential as a therapeutic target for ESCC and probably other cancers caused by defects in Wnt signaling pathways.

Comparison of global indicators for severe maternal morbidity among South Korean women who delivered from 2003 to 2018: a population-based retrospective cohort study.

BACKGROUND: Even though several severe maternal morbidity (SMM) indicators exist globally, indicators that can serve as international standards are needed. Therefore, this study aimed to compare the SMM risk assessment using four international indicators and identify the factors underlying the differences among the risk assessments obtained by the various indicators. METHODS: This study used the National Health Insurance delivery cohort in South Korea from 2003 to 2018. SMM was estimated using four indicators: the United States Centers for Disease Control and Prevention (US-CDC) SMM algorithm, the American College of Obstetricians and Gynecologists (ACOG) gold standard guidelines, Zwart et al.'s indicators for the Netherlands, and the European Network on Severe Acute Maternal Morbidity (EURONET-SAMM) index. Generalized estimating equations models were used to identify the relationships between SMM indicators and risk factors. RESULTS: The SMM incidence rates in 6,421,091 deliveries, were 2.36%, 3.12%, 0.31%, and 1.36% using the US-CDC, ACOG, Zwart et al.'s, and EURONET SAMM indicators, respectively. In sub indicators, hemorrhage-related codes constituted the highest proportion of all SMM indicators. Advanced maternal age was related to high risk in all four SMM indicators (US-CDC: 40-44 years, RR 1.67, 95% CI 1.63-1.71; ACOG's guidelines: 40-44 years, RR 1.52, 95% CI 1.49-1.56; Zwart's indicators: RR 2.72, 95% CI 2.55-2.90; EURONET-SAMM: RR 2.04, 95% CI 1.97-2.11) compared to those aged 25-29 years. In residential area, women who lived in rural area had approximately 1.2- to 1.5-fold higher risk of SMM compared to those who lived in Seoul. Additionally, inadequate prenatal care was associated with a 1.1- to 1.4-fold higher risk of SMM compared to adequate prenatal care. CONCLUSIONS: SMM was associated with maternal age, socioeconomic status, and adverse obstetric factors using various international SMM indicators. Further studies are needed to further determine risk and preventable factors for SMM and to identify more specific causes associated with the frequent sub-indicators of SMM.

There are several indicators of severe maternal morbidity (SMM) globally, but indicators that can serve as international standards are not exist yet. This study compared the SMM risk assessment using four international indicators such as US-CDC's SMM, ACOG's gold standard guidelines, Zwart et al.'s SMM, and EURONET-SAMM, and identify the factors underlying the differences among the risk assessments obtained by the various indicators.This study extracted women who were aged 15­49 years, those who had childbirth in the healthcare institute during 2003 to 2018 in South Korea using the National Health Insurance database.Of the 6,421,091 childbirth cases, the incidence of each SMM indicators were as follow: the US-CDC's SMM: 2.4%; the ACOG's gold standard guidelines: 3.1%; Zwart et al.'s SMM: 0.3%; the EURONET-SAMM: 1.4% indicators. In addition, the highest incidence of each sub-indicators was blood transfusion or obstetric hemorrhage which recorded more than 70% of total SMM cases. In particular, the risk factor on SMM were: advanced maternal age; living rural area; inadequate prenatal care.In conclusion, SMM was associated with maternal age, socioeconomic status, and adverse obstetric factors using various global SMM indicators. Therefore, further studies are needed to identify more specific causes associated with the frequent sub-indicators of SMM and to determine risk and preventable factors for SMM.