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Rice paddies are a major source of methane emission. To meet the food demand of the growing population and to cope with global warming, reducing greenhouse gases and enhancing yield are critical. Here, we demonstrate for the first time that a novel loss-of-function rice allele, gs3, mitigates methane emission from methanogens by allocating more photosynthates to the grain and less to the root, and increases yield by enlarging grain size and weight.

Acute myocardial infarction (AMI) is highly prevalent and remains the leading cause of mortality. Particularly in women, under-recognition and management of AMI have been raised. The aim of this study was to investigate the long-term trends of prevalence, treatment methodologies, and mortality of AMI by gender. The subjects of this study were patients hospitalized for AMI according to the Korean National Health Insurance Claims Database from 2002 to 2018. Total 633,097 AMI patients were hospitalized, 40% women. The incidence of AMI has been increasing since 2011, with a lower incidence in women. Overall, 53.1% of patients underwent CAG, with a lower tendency in women than in men (39.8% vs. 62.3%). Furthermore, fewer women underwent PCI than men (77.5% vs. 85.8% in 2018, p

Objectives: This study examined the case of a patient with recurrent salivary duct carcinoma and hepatic metastasis.Methods: The patient was treated with Casodex/Nolvadex from January 25th 2021 onward with doses of bicalutamide (150 mg/day) and tamoxifen (10 mg/day) every four weeks. Simultaneously, the patient was treated with Korean medicine. The tumor size was measured using computed tomography (CT). Adverse events were evaluated according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.Results: Following the four-month treatment, the extent of the proximal portion of hepatic metastasis decreased, and discomfort and physical activity gradually improved.Conclusions: The results suggest that combined chemotherapy and Korean medicine may help to reduce tumor size and improve quality of life.

Objectives: This study examined the case of a patient with ROS1-positive recurrent non-small-cell lung cancer treated with crizotinib and traditional Korean medicine.Methods: The patient was treated with crizotinib from January 20 2021 to May 22 2021, together with Haedogyangpye-tang and Haengso-tang. The tumor size was measured using computed tomography (CT), and adverse events were evaluated according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.Results: After four months of combined treatment, the sizes of the lymph nodes in the porta hepatis, hepatoduodenal, retrocrural, aortocaval, and para-aortic areas had decreased, and no lymph nodes larger than 1 cm in diameter were observed. The side effects of chemotherapy also improved.Conclusions: This case study suggests that traditional Korean medicine may alleviate the side effects of chemotherapy, improve quality of life, and complement chemotherapy itself.

Yujin Choi,1 Ae-Ran Kim,2 Ji-Yoon Lee,3 Hae Sook Kim,3 Changsop Yang,1 Jae Kwang Kim,4 Younghoon Go,4 In Chul Jung3 1KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 2R&D Strategy Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 3Department of Neuropsychiatry, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea; 4KM Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of KoreaCorrespondence: In Chul JungDepartment of Neuropsychiatry, College of Korean Medicine, Daejeon University, 75 Daedeok-daero 176beon-gil, Seo-gu, Daejeon, Republic of KoreaTel +82-42-470-9129Fax +82-42-470-9005Email npjeong@dju.krPurpose: The potential effects of herbal medicine for patients with cognitive disorders have been reported in various human and animal studies. This study aimed to explore the effect of herbal medicine treatment according to the Korean Medicine (KM) pattern identification for patients with mild cognitive impairment and early dementia.Patients and Methods: Twenty patients with mild cognitive impairment or mild dementia who planned to receive herbal medicine treatment were enrolled. Herbal formulae were prescribed based on the KM pattern for 12– 24 weeks. Seoul Neuropsychological Screening Battery II (SNSB-II) and Montreal Cognitive Assessment (MoCA) were assessed at the baseline, after 12 weeks, and after 24 weeks (Trial registration: cris.nih.go.kr, KCT0004799).Results: Herbal medicine products, including Yukmijihwang-tang, Samhwangsasim-tang, Palmul-tang, Banhasasim-tang, and Yukgunja-tang, were prescribed to the patients. Among the SNSB-II five cognitive function domains, the T scores for language, visuospatial function, memory, and frontal/executive function increased over time. The MoCA score also improved following the treatment (mean difference 4.23 [95% CI: 2.60, 5.86], p < 0.0001 at 12-week follow-up compared to the baseline). Considering the KM pattern scores, phlegm-dampness and fire-heat scores tended to improve after the treatment. No serious adverse events related to the intervention were reported.Conclusion: The potential effect of herbal medicine formulae products on improving cognitive functions in patients with cognitive impairment was observed. Further research is needed to objectify the KM pattern identification process and evaluate the KM pattern-related signs and symptoms.Keywords: mild cognitive impairment, mild dementia, herbal medicine, Korean medicine, traditional east Asian medicine, observational study

In this study, we fermented ‘Makgeolli’ prepared using brown or white rice from ‘Mirchal’ for seven days to investigate the differences in their quality characteristics. Moreover, the physicochemical characteristics and antioxidant activities of ‘Makgeolli’ were assessed using principal component analysis (PCA). From the second day of fermentation, brown rice ‘Makgeolli’ exhibited a higher alcohol content (7.00%) than that of white rice ‘Makgeolli’ (3.60%). Additionally, the total polyphenol contents and antioxidant activities increased with the duration of fermentation (p

Background Tumor-based classification of human glioma portends patient prognosis, but considerable unexplained survival variability remains. Host factors (eg, age) also strongly influence survival times, partly reflecting a compromised immune system. How blood epigenetic measures of immune characteristics and age augment molecular classifications in glioma survival has not been investigated. We assess the prognostic impact of immune cell fractions and epigenetic age in archived blood across glioma molecular subtypes for the first time. Methods We evaluated immune cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, which included a training set of 197 patients with IDH-wild type, 1p19q intact, TERT wild type (IDH/1p19q/TERT-WT) glioma, an evaluation set of 350 patients with other subtypes of glioma, and 454 patients without glioma. Results IDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+ T, CD8+ T, natural killer, and B cells) and higher neutrophil fractions than people without glioma. Recursive partitioning analysis delineated 4 statistically significantly different survival groups for patients with IDH/1p19q/TERT-WT based on an interaction between chronological age and 2 blood immune factors, CD4+ T cells, and neutrophils. Median overall survival ranged from 0.76 years (95% confidence interval = 0.55-0.99) for the worst survival group (n = 28) to 9.72 years (95% confidence interval = 6.18 to not available) for the best (n = 33). The recursive partitioning analysis also statistically significantly delineated 4 risk groups in patients with other glioma subtypes. Conclusions The delineation of different survival groups in the training and evaluation sets based on an interaction between chronological age and blood immune characteristics suggests that common host immune factors among different glioma types may affect survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate noninvasive, personalized patient evaluation in the neuro-oncology clinic.

ImportanceThe association of tamoxifen use with the risk of uterine diseases, such as endometrial cancer, in premenopausal women with breast cancer remains controversial. However, many studies have reported an increased risk of uterine disease among postmenopausal tamoxifen users.ObjectiveTo investigate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer.Design, Setting, and ParticipantsA nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period was conducted using data obtained from the Korean National Health Insurance Service. Participants included premenopausal women aged 20 to 50 years with breast cancer diagnoses between January 2003 and December 2018. Data were analyzed from April to December 2021.ExposuresTamoxifen treatment.Main Outcomes and MeasuresThe incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and other uterine cancers, was identified in the study cohort using insurance claim codes. The incidence of uterine diseases per 1000 person-years was compared between women receiving tamoxifen and those not treated with adjuvant hormone therapy. Multivariable Cox proportional hazard regression analysis was performed to determine the risk of each uterine disease.ResultsAmong 78 320 female participants with a mean (SD) age of 42.1 (6.1) years, 34 637 (44.2%) were categorized into the tamoxifen group and 43 683 (55.8%) were categorized into the control group. Among tamoxifen users, during the mean (SD) follow-up duration of 6.13 (4.15) years, the incidence of newly diagnosed endometrial polyps was 20.13 cases per 1000 person-years, that of endometrial hyperplasia was 13.49 cases per 1000 person-years, that of endometrial cancer was 2.01 cases per 1000 person-years, and that of other uterine cancers was 0.45 cases per 1000 person-years. The risk of endometrial cancer was higher in the tamoxifen group than in the control group (hazard ratio, 3.77; 95% CI, 3.04-4.66) after adjusting for age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment.Conclusions and RelevanceIn this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. These findings suggest that clinicians should consider the risk of uterine disease among tamoxifen users, including premenopausal women.

Hemogenic endothelium (HE) plays a pivotal and inevitable role in haematopoiesis and can generate all blood and endothelial lineage cells in the aorta-gonad-mesonephros of mouse embryos. Whether definitive HE can prospectively isolate pure HE from human pluripotent stem cells that can spontaneously differentiate into heterogeneous cells remains unknown. Here, we identified and validated a CD34

Background. Although the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR- TKI) therapy has been proven in non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs presents a serious clinical problem. Hence, the identification of new therapeutic strategy is needed to treat EGFR-TKI-resistant NSCLC. Methods. Acquired EGFR-TKI-resistant lung cancer cell lines (HCC827, H1993, and H292 cells with acquired resistance to gefitinib or erlotinib) were used for cell-based studies. IncuCyte live cell analysis system and XFp analyzer were used for the determination of cell proliferation and energy metabolism, respectively. In vivo anticancer effect of phenformin was assessed in xenografts implanting HCC827 and gefitinib-resistant HCC827 (HCC827 GR) cells. Results. HCC827 GR and erlotinib-resistant H1993 (H1993 ER) cells exhibited different metabolic properties compared with their respective parental cells, HCC827, and H1993. In EGFR-TKI-resistant NSCLC cells, glycolysis markers including the glucose consumption rate, intracellular lactate level, and extracellular acidification rate were decreased; however, mitochondrial oxidative phosphorylation (OXPHOS) markers including mitochondria-driven ATP production, mitochondrial membrane potential, and maximal OXPHOS capacity were increased. Cell proliferation and tumor growth were strongly inhibited by biguanide phenformin via targeting of mitochondrial OXPHOS complex 1 in EGFR-TKI-resistant NSCLC cells. Inhibition of OXPHOS resulted in a reduced NAD+/NADH ratio and intracellular aspartate levels. Recovery of glycolysis by hexokinase 2 overexpression in erlotinib-resistant H292 (H292 ER) cells significantly reduced the anticancer effects of phenformin. Conclusion. Long-term treatment with EGFR-TKIs causes reactivation of mitochondrial metabolism, resulting in vulnerability to OXPHOS inhibitor such as phenformin. We propose a new therapeutic option for NSCLC with acquired EGFR-TKI resistance that focuses on cancer metabolism.

The Rh(III)-catalyzed C-H functionalization and subsequent intramolecular cyclization between azobenzenes and vinylene carbonate is described herein. Depending on the electronic property of azobenzenes, this transformation results in the formation of (2H)-indazoles or dihydrocinnolin-4-ones through the generation of ortho-alkylated azo-intermediates followed by decarboxylation. Surprisingly, vinylene carbonate acts as an acetaldehyde or acetyl surrogate to enable the [4 + 1] or [4 + 2] annulation reaction. This transformation is characterized by its mild reaction conditions, simplicity, and excellent functional group compatibility.

Background: Fms-related tyrosine kinase-4 (FLT4) is involved in tumor progression. Previously, we found that dysfunctional natural killer (NK) cells with low interferon-gamma (IFN-γ) were restored in acute myeloid leukemia (AML) by the FLT4 antagonist MAZ51. We developed 12 peptides targeting FLT4 for clinical application and ultimately selected 4 of them to examine whether they restored the frequency of lymphocytes, especially T cells and NK cells, and high IFN-γ expression, as MAZ51 treatment did in our previous study. Although clinical data from using intracellular kinase domain–targeting peptides are currently available, peptides targeting FLT4 to modulate immune cells have not been fully elucidated. Methods: To end this, designed 12 peptides were screened in vitro their potential for IFN-gamma expression by ELISpot assays. And then 4 peptides were finally selected to apply leukemic mice. To assess the changes of immune subset in leukemic mice, FACS analysis was performed using BM, PB, and spleen from leukemic mice. Results: In this study, we focus on novel peptide 4 (P4) from the intracellular domain of FLT4 because it had dominant negative activity. Similar to MAZ51, high IFN-γ levels were expressed in AML-mononuclear cells (MNCs) exposed to P4. In addition, T and NK cell levels were restored, as were high IFN-γ levels, in a leukemic environment when P4 was co-cultured with cytosine β-D-arabinofuranoside. Interestingly, the frequency of regulatory T cells was significantly decreased by P4, implying that the peptide plays a role in modulating the tumor niche. Conclusion: Overall, we demonstrated the therapeutic value of functionally modulating lymphocytes using a peptide targeting FLT4 and propose the development of advanced therapeutic approaches against AML by using immune cells.

γδ T cells are a rare and unique prototype of T cells that share properties with natural killer cells in secondary lymphoid organs. Although many studies have revealed the function and importance of adult-derived γδ T cells in cancer biology and regenerative medicine, the low numbers of these cells hamper their application as therapeutic cell sources in the clinic. To solve this problem, pluripotent stem cell-derived γδ T cells are considered alternative cell sources; however, few studies have reported the generation of human pluripotent stem cell-derived γδ T cells. In the present study, we investigated whether lymphoid lineage γδ T cells were successfully generated from human pluripotent stem cells via hemogenic endothelium under defined culture conditions. Our results revealed that pluripotent stem cells successfully generated γδ T cells with an overall increase in transcriptional activity of lymphoid lineage genes and cytolytic factors, indicating the importance of the optimization of culture conditions in generating lymphoid lineage γδ T cells. We uncovered an initial step in differentiating γδ T cells that could be applied to basic and translational investigations in the field of cancer biology. Based on our result, we will develop an appropriate method to purify γδ T cells with functionality and it helpful for the study of basic mechanism of γδ T cells in pathophysiologic condition as well as clinic application.

Universally acceptable donor cells have been developed to address the unmet need for immunotypically matched materials for regenerative medicine. Since forced expression of hypoimmunogenic genes represses the immune response, we established universal pluripotent stem cells (PSCs) by replacing endogenous β2-microglobulin (β2m) with β2m directly conjugated to human leukocyte antigen (HLA)-G, thereby simultaneously suppressing HLA-I expression and the natural killer (NK) cell-mediated immune response. These modified human PSCs retained their pluripotency and differentiation capacity; however, surface presentation of HLA-G was absent from subsequently differentiated cells, particularly cells of neural lineages, due to the downregulation of antigen processing and presentation machinery (APM) genes. Induction of APM genes by overexpression of NLR-family CARD domain-containing 5 (NLRC5) or activator subunit of nuclear factor kappa B (NF-κB) heterodimer (RelA) recovered the surface expression of HLA-G and the hypoimmunogenicity of neural cells. Our findings enhance the utility of hypoimmunogenic cells as universal donors and will contribute to the development of off-the-shelf stem-cell therapeutics.

Nuclear receptor are major regulators of hepatic drug metabolizing enzymes and antioxidants enzymes. Nuclear receptor humanized mice were used for overcome species differences between experimental animals and human. The present study was performed to investigate the hepatic regulation of antioxidant enzymes in pregnane X receptor (PXR) and constitutive androstane receptor (CAR) double humanized mice treated with the human PXR ligand, rifampicin (RIF; 10 mg/kg for 4 days). RIF decreased the hepatic protein levels of superoxide dismutase-1, thioredoxin-1, and γ-glutamylcysteine ligase catalytic subunit in wild-type (WT) mice, but not in the double humanized mice. Catalase protein levels were decreased by RIF in both WT and double humanized mice. The hepatic protein level and activity of glutathione reductase (GR) were increased in the humanized mice treated with RIF, but decreased in WT mice. Glutathione S-transferase (GST) alpha-class (GSTA) and mu-class (GSTM) but not pi-class were induced by RIF in the humanized mice, but not in WT mice. The activities of total GST, GSTA and GSTM were also increased only in humanized mice treated with RIF. These results suggest that PXR and CAR may play roles in xenobiotic-induced hepatic regulation of GSTA, GSTM, and GR. The PXR/CAR double humanized mouse can be used as a suitable predictive model of the regulation of human antioxidant enzymes by xenobiotics.

Introduction: EGFR mutations holds the major targets for drug in lung adenocarcinoma (LUAD). Despite the tremendous study of EGFR mutant (MT) LUAD, the comprehensive interpretation of the heterogeneous character of LUAD harboring EGFR MT remains a key challenge. Here, we investigated the heterogeneity of EGFR MT LUAD and explored the tumor microenvironment (TME) in EGFR MT LUAD. Method: We performed single-cell RNA sequencing (scRNA-seq) from 135 LUAD patients which consist of normal(n=24), EGFR wild (WT)(n=18), and MT(n=93). Also, we used whole genome sequencing and bulk-RNA sequencing to validate with scRNA-seq results. From 898,648 cells, main cell types were classified. To explore the various characteristics of MT LUAD tumor cells, we used two ways: i) We re-clustered epithelial cells populating the normal, WT, and MT. ii) We re-clustered only MT epithelial cells. In each analysis, we identified the tumor character in the clusters using differential expressed genes analysis, lineage tracing, clinical information, mutation, and trajectory analysis. Also, we extracted each main cell type except epithelial cells, and identified subtypes of main cell types. Finally, we revealed the interaction of cellular components in TME. Results: In the analysis of epithelial cells, we identified characteristics of specific EGFR MT by comparing of EGFR WT and MT tumors in clusters with similar biological features. The cluster represented by alveolar type 2 (AT2) known as initiation of LUAD was populating normal, WT, and MT. In this cluster, MT- and WT-associated pathway shared but differently significant between MT and WT in the pathway analysis. The cluster represented by proliferative is mostly comprised tumor cells and we found significantly increased the expression of MDK, CD24 in the MT of the cluster. In the analysis of only MT epithelial cells, 2 of clusters were stage-specific cluster: i) The cluster annotated as early stage cluster, ii) The cluster annotated as advanced stage cluster. Trajectory showed that there is a pseudotemporal continuum, following the stage from early stage cluster to advanced stage cluster. Also, based on the lineage tracing, 2 of clusters revealed lineage-specific clusters: i) The cluster annotated as AT2 was enriched from early stage cells, ii) The cluster annotated as basal cell known as origin of lung squamous cell carcinoma(LUSC) was enriched from advanced stage cells. Psedotemporal ordering of these cluster revealed AT2 cluster transdifferentiate into basal cell cluster which implied the possibility of LUAD to LUSC transition by drug resistance. In the interaction of MT and WT TME, the number of signaling received epithelial cells from myeloid cells, endothelial cells, and fibroblasts as sender increased compared with the interaction of normal. Conclusion: We shed light on the ecosystem of TME according to clinical and biological feature of tumor in EGFR mutant LUAD. Citation Format: You Won Lee, Eun Ji Lee, Seung Yeon Oh, Kyoung-Ho Pyo, Seong Gu Heo, YoungJoon Park, Su-Jin Choi, Kyumin Lim, Ju-hyeon Lee, Jae Hwan Kim, Jii Bum Lee, Ji Yoon Lee, Sun Min Lim, Chang Gon Kim, Min Hee Hong, Mi Ran Yun, Byoung Chul Cho. Phenotype profiling of tumor microenvironment in EGFR mutant lung adenocarcinoma with multi-omics data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5935.

We investigated differences in quantitative electroencephalogram (EEG) patterns associated with game usage patterns and genre among patients with Internet gaming disorder (IGD). Data from 140 participants (76 IGD patients and 64 healthy controls) were analysed. The IGD group was divided into subgroups based on game usage patterns (single game [SG] or multiple games [MGs]) and genre (multiplayer online battle arena, first-person shooter [FPS], or massively multiplayer online role-playing game [MMORPG; hereafter, MMG]). A resting-state, eye-closed quantitative EEG was recorded, and the absolute power and coherence of brain waves were analysed. IGD patients who played SGs showed increased beta activity compared with those who played MGs and controls. Increased absolute beta power was significantly associated with higher tendencies towards behavioural inhibition compared with controls. FPS gamers showed increased delta power in the frontal region compared with controls, which was related to the severity of IGD. Furthermore, decreased intrahemispheric coherence in the left frontoparietal region was observed in the MMG and FPS groups compared with controls. This decreased coherence was observed in the theta (MMG and FPS), delta (MMG), and beta (FPS) bands. These features were related to impairment in visuospatial working memory. Unique neurophysiological features related to preoccupation with an SG may be associated with the inhibition of behavioural changes. The present study suggests that the underlying neurophysiological networks in IGD differ according to game usage patterns and genre.

In regenerative medicine, humanized mice (hu-mice) are extremely valuable for verifying the cross talk between immune cells and therapeutic cells. Given the highly dynamic nature of the activities of immune cells, the in vitro platform does not allow for screening of their exact interactions with different therapeutic cells. By contrast, hu-mice have been widely applied for in vivo studies, especially those on immune rejection. However, the full reconstitution of lymphoid lineage cells in hu-mice remains to be realized. In this study, we investigated whether lysates from healthy donor-derived pooled mononuclear cells (MNCs) can promote the increase of lymphoid lineage cells in hu-mice. The pooled MNC lysate treatment of hu-mice possessing a low proportion of CD45 cells resulted in significant increases in CD3 cells and CD45 cells with the RO phenotype. The diverse epitopes from the pooled MNC lysates significantly induced the proportion of lymphoid lineage cells in the thymus and spleen after therapeutic cells with mismatched HLAs were co-injected into the hu-mice. These findings demonstrate the technical benefits of using pooled MNC lysates for reconstituting lymphoid lineage cells in hu-mice, providing a valuable in vivo platform for investigating the cross talk between lymphoid immune cells and therapeutic cells.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Glutinous rice is a key grain quality trait occupying an important part during rice processing in most rice growing areas. In this study, a gene pyramiding approach was used to introduce two dull genes, responsible for low amylose content, for glutinous rice breeding using marker assisted selection (MAS). The genotyping results revealed that rice cultivar Milyang319 carries both dull genes on chromosome 6, derived from cv. Milky-queen (Wx-mq) and cv. LGS-soft (du12(t)), respectively. Milyang319 had a significantly low amylose content (9.0%) compared to those observed in donor parents Milky-queen (15.7%) and LGS-soft (14.5%). In addition, the amylogram analysis of Milyang319 showed a similar pattern of glutinous rice. Originally, Milyang319 had a low hardness and more stickiness compared to those recorded in cooked rice of both dull parental lines. Therefore, Milyang319 is proposed as a promising candidate rice cultivar that could be used as a new source of waxy germplasms with same physicochemical features of glutinous rice in further breeding programs.

Significance A major yet perplexing question in the field of necroptosis is the role and involvement of necroptosis in cancer cells. Many cancer cells have protective mechanisms against necroptosis, but the underlying mechanism remains elusive. We report findings of cross-talk and a regulatory pathway that exist between MYC, a potent oncogene, and RIPK3, a pivotal factor in necroptosis. We find that MYC pathway is downregulated upon necroptotic, while MYC inhibits TNF-α–induced necroptosis. The inhibitory effect of MYC on necroptosis is unexpected because no transcriptional activity by MYC is required. Mechanistically, a direct interaction between MYC and RIPK3 takes place in the cytosol, preventing RIPK1–RIPK3 complex formation. Finally, MYC depletion enhances antitumor activity of necroptosis-inducing agents in a xenograft model., The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.

Purpose To compare the protective effects of cyclosporine A emulsion (Restasis: 0.05% cyclosporine A) (CsAE) and cyclosporine A cationic emulsion (Ikervis: 0.1% cyclosporine A) (CsACE) on cellular inflammation, apoptosis, proliferation, and survival in an in vitro dry eye model. Methods The concentration of CsA in CsAE and CsACE was verified using a liquid chromatography tandem mass spectrometry system. Human corneal epithelial cells were subjected to desiccation stress. Human corneal epithelial cells were incubated with or without 3 groups of cyclosporine A medium (CsAE 1:50, CsACE 1:50, and CsACE 1:100). p-NF-κB p65, p-IκBα, Bax, Bcl-xL, p-Erk1/2, and p-Akt levels were determined using Western blots, and TNF-α levels were quantified using an enzyme-linked immunosorbent assay. Results The CsA concentration of CsACE 1:100 was nearly the same as that of CsAE 1:50. Compared with CsAE 1:50 (0.78 ± 0.19 fold), the p-NF-κB p65 level was further reduced in CsACE 1:50 (0.38 ± 1.20 fold) and 1:100 (0.29 ± 0.11 fold) as well as p-IκBα. Levels of TNF-α were also lower in CsACE 1:50 and 1:100 than in CsAE 1:50. Induction of the apoptotic protein Bax was significantly decreased in CsACE 1:50 and 1:100 compared with CsAE 1:50, whereas that of the antiapoptotic protein Bcl-xL was increased in CsACE 1:50 and 1:100. p-ERK1/2 and p-Akt levels were higher in CsACE 1:50 and 1:100 than in CsAE 1:50. Conclusions CsACE had more potent anti-inflammatory and antiapoptotic effects than CsAE in a transwell desiccation stress model. CsACE also enhanced proliferation and survival factors under desiccation stress compared with CsAE in this in vitro dry eye model.

Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse, and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their contributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies for effective therapy.

Ophiorrhiza pumila is a medicinal plant that grows in subtropical forests and produces camptothecin (CPT). To determine an optimal harvest time of O. pumila in a plant factory with artificial light (PFAL), we investigated the CPT distribution in each organ and at the developmental stage and estimated the annual CPT production. For this study, the O. pumila plants were grown in controlled environments (16 h light period, photosynthetic photon flux density of 100 μmol m−2 s−1 under white light-emitting diode lamps, air temperature of 28 °C, relative humidity of 80%, and CO2 concentration of 1000 μmol mol−1). First, the stem, root, and seed pod had higher CPT contents than the leaves, flower, and ovary. The optimal harvest time of O. pumila in a PFAL was 63 days after transplanting (DAT), because the CPT content in the whole organs was the highest at the seed-ripening stage. Second, based on these results, the estimated annual CPT production of O. pumila cultivated in a PFAL was 380 mg m−2 y−1 (63 DAT). This value was 4.3 times greater than the annual CPT production by Camptotheca acuminata in a greenhouse. We concluded that the CPT production by O. pumila in a PFAL throughout the year has many advantages, although the demand for electrical energy was high compared to that of Camptotheca acuminata in a greenhouse.

Stress plays an important role in the pathophysiology of addictive disorders. The kynurenine (KYN) pathway involved in neuroimmune and cognitive functions is activated under stress. However, the neuroimmunological–neurocognitive mechanisms in the role of stress in addictive disorders are unclear still now. Ninety-nine young adults aged 18–35 years [alcohol use disorder (AUD), N = 30; Internet gaming disorder (IGD), N = 34; healthy controls (HCs), N = 35] participated in this study. Stress levels, resilience, addiction severity, and neurocognitive functions were evaluated, and serum levels of tryptophan (TRP), 5-hydroxytryptamine (5-HT), KYN, and kynurenine acid (KYNA) were determined using liquid chromatography coupled with tandem mass spectrometry through blood samples. Both addictive disorder groups showed higher levels of stress, lower resilience, and impaired executive functions compared to the HC group. Importantly, the AUD group revealed significantly increased KYN levels and KYN/TRP ratios, as well as decreased KYNA levels and KYNA/KYN ratios compared to HCs (p < 0.001, p < 0.001, p = 0.033, and p < 0.001, respectively). The IGD group showed KYN levels and KYNA/KYN ratios intermediate between those of the AUD group and HCs. Furthermore, in the AUD group, the mediating effect of AUD on KYN through stress level was moderated by resilience [index of moderated mediation = −0.557, boot S.E = 0.331, BCa CI (−1.349, −0.081)]. Stress may induce an imbalance in downstream of KYN pathway metabolites, and the KYN/TRP ratio may play as a neuromediator between stress and behavioral changes in both addictive disorders. This study suggests that regulation of the KYN pathway is critical in the pathophysiology of addictive disorders and it may serve as an important target for future treatment modalities.

DNA methylation plays key roles in various areas, such as gene expression, regulation, epigenetics, and cancers. Since 5-methylcytosine (5mC) is commonly present in methylated DNA, characterizing the binding kinetics and thermodynamics of the nucleotide to the enzymatic pocket can help to understand the DNA replication process. Furthermore, 5-carboxycytosine (5caC) is a form that appears through the iterative oxidation of 5mC, and its effect on the DNA replication process is still not well known. Here, we immobilized a DNA polymerase (DNAP) with an orientation control on a tip of an atomic force microscope (AFM), and observed the interaction between the immobilized deoxyguanosine triphosphate (dGTP) on the surface and the DNAP in the presence of a DNA duplex. The interaction probability increased as the concentration of the DNA strand, and the affinity constant between the DNAP and DNA was obtained by fitting the change. Increasing the concentration of dGTP in solution diminished the interaction probability, and a fitting allowed us to retrieve the affinity constant between dGTP and the DNAP holding the DNA in the reaction pocket. Because the dissociation constant could be obtained through the loading rate dependence of the unbinding force value, both affinity and kinetic constants for cytosine (C), 5mC, and 5caC in the DNAP were compared in the light of the steric and electronic effect of the substituents at 5-position of cytosine.