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Abstract Lung cancer is the second most common cancer worldwide and a leading cause of cancer-related deaths. Despite advances in targeted therapy and immunotherapy, the prognosis remains unfavorable, especially in metastatic cases. This study aims to identify molecular changes in non-small cell lung cancer (NSCLC) patients based on their response to treatment. Using tumor and matched immune cell rich peritumoral tissues, we perform a retrospective, comprehensive spatial transcriptomic analysis of a proven malignant NSCLC sample treated with immune checkpoint inhibitor (ICI). In addition to T cells, other immune cell types, such as B cells and macrophages, were also activated in responders to ICI treatment. In particular, B cells and B cell-mediated immunity pathways are consistently found to be activated. Analysis of the histologic subgroup (lung squamous cell carcinoma, LUSC; lung adenocarcinoma, LUAD) of NSCLC also confirms activation of B cell mediated immunity. Analysis of B cell subtypes shows that B cell subtypes were more activated in immune cell-rich tissues near tumor tissue. Furthermore, increased expression of B cell immunity-related genes is associated with better prognosis. These findings provide insight into predicting ICI treatment responses and identifying appropriate candidates for immunotherapy in NSCLC patients.

Abstract Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo–YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

This study investigated a method for directly estimating methane emissions from rice paddy fields at the field level using drone-based time-series vegetation indices at a town scale. Drone optical and spectral images were captured approximately 15 times from April to November to acquire time-series vegetation indices and optical orthoimages. An empirical regression model validated in previous international studies was applied to calculate cumulative methane emissions throughout the rice cultivation process. Methane emissions were estimated using the vegetation index and yield data were used as input variables for each growth phase. Methane emissions from rice paddies showed maximum values of 309 kg CH4 ha−1, within a 7% range compared to similar studies, and minimum values of 138 kg CH4 ha−1, with differences ranging from 29% to 58%. The average emissions were calculated at 247 kg CH4/ha, revealing slightly lower average values but individual field values within a similar range. The results suggest that drone-based remote sensing technology is an efficient and cost-effective alternative to traditional field measurements for greenhouse gas emission assessments. However, adjustments and validations according to rice varieties and local cultivation environments are necessary. Overcoming these limitations can help establish sustainable agricultural management practices and achieve local greenhouse gas reduction targets.

Abstract Background Under conditions of hypoxia, cancer cells with hypoxia inducible factor-1α (HIF-1α) from heterogeneous tumor cells show greater aggression and progression in an effort to compensate for harsh environmental conditions. Extensive study on the stability of HIF-1α under conditions of acute hypoxia in cancer progression has been conducted, however, understanding of its involvement during the chronic phase is limited. Methods In this study, we investigated the effect of SIRT1 on HIF1 stability in a typical chronic hypoxic conditon that maintains cells for 24 h under hypoxia using Western blotting, co-IP, measurement of intracellular NAD + and NADH levels, semi-quantitative RT-PCR analysis, invasion assay, gene knockdown. Results Here we demonstrated that the high concentration of pyruvate in the medium, which can be easily overlooked, has an effect on the stability of HIF-1α. We also demonstrated that NADH functions as a signal for conveyance of HIF-1α degradation via the SIRT1 and VHL signaling pathway under conditions of chronic hypoxia, which in turn leads to attenuation of hypoxically strengthened invasion and angiogenic activities. A steep increase in the level of NADH occurs during chronic hypoxia, leading to upregulation of acetylation and degradation of HIF-1α via inactivation of SIRT1. Of particular interest, p300-mediated acetylation at lysine 709 of HIF-1α is recogonized by VHL, which leads to degradation of HIF-1α via ubiquitin/proteasome machinary under conditions of chronic hypoxia. In addition, we demonstrated that NADH-elevation-induced acetylation and subsequent degradation of HIF-1α was independent of proline hydroxylation. Conclusions Our findings suggest a critical role of SIRT1 as a metabolic sensor in coordination of hypoxic status via regulation of HIF-1α stability. These results also demonstrate the involvement of VHL in degradation of HIF-1α through recognition of PHD-mediated hydroxylation in normoxia and p300-mediated HIF-1α acetylation in hypoxia.

The integration of remote sensing and state-of-the-art deep learning models has enabled the generation of highly accurate semantic segmentation maps to serve the agricultural sector, for which continuous land monitoring is required. However, despite their wide presence in the research field, only a few such products are used in on-site decision-making processes. This is due to their incompatibility with existing datasets that are at the core of current operating processes. In this study, paddy rice mapping in South Korea was examined to determine whether it produces qualified products that can complement on-site surveys and simultaneously be compatible with existing domestic datasets. Cases of early predictions for timely rice supply control were examined using a recurrent U-Net architecture with diverse applications: chronological batch training (CBT), time-inversed padding (TIP), and super-resolution (SR). In addition, the paddy area was confirmed using diverse datasets by standardizing its spatial extent in the definition of each data manual and calibrating the levee error, which was considered a major source of incompatibility. The robustness of the recurrent U-Net in early predictions dramatically increased upon CBT and TIP, recording an F1 score of over 0.75 on July 10, when the on-site survey was performed; meanwhile, the best performance score was 0.81 at the end of the growing period. SR enhanced the spatial details of rice mapping near the levee area, which had an estimated width of 60 cm; however, the area was more similar to that in existing datasets when it was calibrated with the predicted probability of the levee ratio rather than SR. The calibration was scalable from the patch to city level, with the paddy area at both levels recording high R2 for the farm map and statistics (0.99 for both the farm map and statistics at the city level, and 0.93 and 0.95, respectively, at the patch level). This study shows that remote-sensing-based paddy rice mapping can produce not only accurate but also timely and compatible predictions by integrating deep learning applications. The results show that the predictions are compatible with domestic datasets as much as they are with each other; therefore, remote-sensing approaches are expected to be more actively and practically integrated into agricultural decision-making processes.

BackgroundRecent studies have presented the concept of the obesity paradox, suggesting that individuals with obesity have a lower risk of death than those without obesity. This paradox may arise because body mass index (BMI) alone is insufficient to understand body composition accurately. This study investigated the relationship between fat and muscle mass and the risk of mortality in individuals with overweight/obesity.MethodsWe used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006 and 2011 to 2018, which were linked to mortality information obtained from the National Death Index. Multiple Cox regression analyses were performed to estimate mortality risk. Subgroup analysis was conducted using propensity score-matched (PSM) data for age, sex, and race/ethnicity.ResultsThis study included 16,555 participants who were overweight/obese (BMI≥25 kg/m2). An increase in appendicular skeletal muscle mass index was associated with a lower mortality risk (hazard ratio [HR]: 0.856; 95% confidence interval [CI]: 0.802–0.915). This finding was consistent with the subgroup analysis of the PSM data. Contrastingly, a high fat mass index was associated with an increased risk of mortality. Sarcopenic overweight/obesity was significantly associated with high mortality compared to obesity without sarcopenia (HR: 1.612, 95%CI: 1.328–1.957). This elevated risk was significant in both age- and sex-based subgroups. This finding was consistent with the subgroup analysis using PSM data.ConclusionIn contrast to the obesity paradox, a simple increase in BMI does not protect against mortality. Instead, low body fat and high muscle mass reduce mortality risk.

Abstract Cigarette smoking is one of the leading causes of preventable and premature death worldwide. Even worse, many people are generally exposed to passive smoking, which leads to several respiratory diseases and related mortalities. Considering, more than 7000 compounds are included in cigarettes, their combustion results intoxicants that have deleterious effects on health. However, there is a lack of research analyzing the effects of smoking and passive smoking on all-cause and disease-specific mortality through its chemical compounds including heavy metals. Thus, this study aimed to evaluate the effect of smoking and passive smoking on all-cause and disease-specific mortality mediated by cadmium, one of the representative smoking-related heavy metals using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2018 in the United States. We found that current smoking and passive smoking was related to increased risk of all-cause, CVD-related, and cancer-related mortality. Notably, passive smoking showed a synergistic effect with smoking status on the risk of mortality. In particular, current smokers with passive smoking had the highest risk of all-cause and disease-specific deaths. In addition, the accumulation of cadmium in the blood due to smoking and passive smoking mediates the increased risk of all-cause mortality. Further studies are needed to monitor and treat cadmium toxicity to improve smoking-related mortality rates.

Background: Rapid detection of the causative agents is essential for determining the appropriate treatment for patients with lower respiratory tract infections. We evaluated the performance of the Biofire FilmArray pneumonia panel (FA-PE; BioFire Diagnostics, USA) in the identification of bacterial pathogens and antibiotic resistance genes in endotracheal aspirate specimens. Methods: A total of 43 non-duplicated endotracheal aspirates were included in this study. The performance of the FA-PE was assessed using the routine culture method as the reference standard. Results: The FA-PE demonstrated 92.9% sensitivity and 79.3% specificity for the identification of 15 bacterial targets compared to routine bacterial culture. Four antimicrobial resistance genes in 43 specimens were detected by the FA-PE. The most frequently detected resistance genes were mecA/C and SCCmec in three specimens, followed by CTX-M in one specimen. Conclusion: The FA-PE offers a rapid diagnostic method for lower respiratory tract infections. It may be useful at the early stage of pneumonia, before routine culture and antimicrobial susceptibility results are available.

Acral melanoma affects the soles of the feet but the etiology is unknown. Here, the authors show that melanoma cells implanted into the foot pad of mice and exposed to mechanical stress show features of nuclear rupture, DNA damage, and Yap activation.

The interplay between adipokines and pancreatic beta cells, often referred to as the adipo-insular axis, plays a crucial role in regulating metabolic homeostasis. Adipokines are signaling molecules secreted by adipocytes that have profound effects on several physiological processes. Adipokines such as adiponectin, leptin, resistin, and visfatin influence the function of pancreatic beta cells. The reciprocal communication between adipocytes and beta cells is remarkable. Insulin secreted by beta cells affects adipose tissue metabolism, influencing lipid storage and lipolysis. Conversely, adipokines released from adipocytes can influence beta cell function and survival. Chronic obesity and insulin resistance can lead to the release of excess fatty acids and inflammatory molecules from the adipose tissue, contributing to beta cell dysfunction and apoptosis, which are key factors in developing type 2 diabetes. Understanding the complex interplay of the adipo-insular axis provides insights into the mechanisms underlying metabolic regulation and pathogenesis of metabolic disorders. By elucidating the molecular mediators involved in this interaction, new therapeutic targets and strategies may emerge to reduce the risk and progression of diseases, such as type 2 diabetes and its associated complications. This review summarizes the interactions between adipokines and pancreatic beta cells, and their roles in the pathogenesis of diabetes and metabolic diseases.

One of the primary means through which people protect themselves and their loved ones from COVID-19 is by communicating with others, as they discuss preventive health behaviors and make decisions about safe social interaction. These conversations are sometimes quite challenging. Guided by the conceptual lens of communication work, this study was an investigation of how communication during the pandemic was experienced by people as work. Findings validated and extended the communication work construct. Communication during the pandemic is effortful because it is high stakes, relentless, and takes an emotional toll. Nonetheless, many people feel a sense of responsibility and obligation to have these conversations. Communication about COVID-19 is divisible labor that can be shared. People engage in strategic preparation and message design to accomplish multiple goals before, during, and after discussions about pandemic topics.

Ribosomal protein S3 (rpS3), a member of 40S small ribosomal subunit, is a multifunctional protein with various extra-ribosomal functions including DNA repair endonuclease activity and is secreted from cancer cells. Therefore, antibodies with high specificity against rpS3 protein could be useful cancer biomarkers. In this study, polyclonal antibody (pAb) and monoclonal antibodies (mAbs) were raised against rpS3 protein and epitope mapping was performed for each antibody; the amino acid residues of rpS3 were scanned from amino acid 185 to 243 through peptide scanning to reveal the epitopes of each mAb. Results showed that pAb R2 has an epitope from amino acid 203 to 230, mAb M7 has an epitope from amino acid 213 to 221, and mAb M8 has an epitope from amino acid 197 to 219. Taken together, novel mAbs and pAb against rpS3 were raised and mapped against rpS3 with different specific epitopes.

Abstract Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.

The data presented in this article is related to a rapid communication entitled “β-arrestin 2 suppresses the activation of YAP by promoting LATS kinase activity”. This article describes the correlation of β-arrestin 2 and YAP phosphorylation in patient-derived organoid models. Here, we analyzed 45 colon cancer organoids (CCOs) selected in the related research article to investigate the role of β-arrestin 2 in YAP phosphorylation. Hematoxylin and eosin (H&E) staining and immunohistochemistry data showed that the CCOs maintained tissue architecture and histological features of their original cancer tissues. Moreover, mutation data detected from RNA-seq (RNA-sequencing) analysis showed that these CCOs retained the genetic features of their original colon cancer tissues as well. We also confirmed at the protein level that organoids expressing β-arrestin 2 showed high expression of phosphorylated YAP. These organoid model studies strongly support the related research article that β-arrestin 2 suppresses the activation of YAP in colon cancer.

Background and Objectives: Developing effective treatment outcomes for multidrug-resistant Acinetobacter baumannii (MRAB) infections, with colistin and tigecycline the current frontline therapies, is challenging, because of the risk of renal toxicity and low blood concentrations of active ingredients when administered intravenously. This study aimed to identify the effect of combination therapy using conventional antimicrobial agents that are used for treating drug-resistant bacteria and the additional synergistic effect of four probiotic culture extracts isolated from the human body and Lactobacillus preparations. Materials and Methods: The antimicrobial combination and synergistic effect of adding Lactobacillus extract against 33 strains of A. baumannii isolated from pus, urine, and other specimens submitted to the Department of Laboratory Medicine of a university hospital, located in Gyeonggi-do, Korea, was investigated over a 3-year period between January 2017 and December 2019. Results: Antimicrobial susceptibility tests on bacteria isolated in clinical practice demonstrated that 26 strains (79%) were MRAB, while multi-locus sequence typing indicated that ST191 was the predominant type (45%; n = 15). Checkerboard test results demonstrated that combination therapy using meropenem and colistin had the highest synergistic effect (fractional inhibitory concentration index = 0.5), while the time–kill assay test using Lactobacillus spp. culture extract exhibited an inhibitory effect within 1 h and complete inhibition of MRAB within 3 h. Lactobacillus paracasei exhibited the fastest antimicrobial reactivity and longest sustained antimicrobial activity. Conclusion: These findings provide useful foundational data for an appropriate combination of colistin with other antimicrobial agents for treating MRAB infection in clinical settings, and the use of various probiotic culture extracts to reduce the required dosage, and therefore toxicity of colistin.

Mechanisms underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin treatment during anticancer therapy remain poorly understood. Here the authors show that treatment with an antibody against the L1 cell adhesion molecule inhibits nuclear L1CAM translocation, thereby controlling vascular DNA damage and preventing cardiotoxicity.

Head and neck cancer: Protein dysfunction may give cancer the edge Abnormal activity of a protein involved in cell proliferation may influence the progression of head and neck cancers. Head and neck squamous cell carcinoma (HNSCC) affects the skin, throat, mouth and nose tissues. Disruption to the Hippo-YAP signaling pathway, which plays a key role in cell proliferation and differentiation, is implicated in multiple cancers. Joon Kim and Eunbie Shin at the Korea Advanced Institute of Science and Technology, Daejeon, South Korea, reviewed recent research into the role of YAP in HNSCC. Abnormal YAP protein activity triggers the expression of genes that encourage cancer cell proliferation. Mice with over-expressed YAP showed tissue overgrowth and tumor formation. High YAP levels have been found at the invasive front of HNSCC tumors, suggesting a role in metastasis. Further research is needed to verify whether YAP is a potential therapeutic target.

Modified agarose cell-block (CB) technique can be effectively used to have the CB embedded in the OCT compound for the preparation of frozen CB (F-CB) sections in the same way as in the preparation of frozen sections from cryoembedded fresh tissue samples for the intraoperative consultation. In this report, we demonstrate the amenability of F-CB sections to the diagnostic immunocytochemistry. The pelleted cytologic material was at first compactly embedded in ultralow-gelling temperature agarose gel and then re-embedded in conventional agarose gel. The resulting agarose-embedded cell-pellet was cut in halves so that one half is embedded in OCT compound for cryosectioning on a cryostat, while the other half is reserved for the preparation of paraffin-embedded CB (P-CB). The F-CB sections were comparable to sections cut from the paraffin-embedded CB in terms of the quality of H&E-staining and immunocytochemistry. We suppose this method can also facilitate a rapid quantitative and qualitative assessment of the future P-CB. We have extended this technique to the cryo-embedded cell-block method, in which the compact agarose cell pellet is directly embedded in the OCT compound so that the frozen sections can be cut from the cryo-embedded cell block in the same way as in intraoperative frozen section analysis. In this technical report, we illustrate how the frozen cell blocks (F-CBs) can be effectively prepared not only from liquid-based cytology samples but also from conventional fine-needle aspiration cytology slides.

Abstract Background The development of microalgal strains for enhanced biomass and biofuel production has received increased attention. Moreover, strain development via metabolic engineering for commercial production is being considered as the most efficient strategy. Pyruvate is an essential metabolite in the cells and plays an essential role in amino acid biosynthesis and de novo fatty acid biosynthesis in plastids. Although pyruvate can be a valuable target for metabolic engineering, its transporters have rarely been studied in microalgae. In this study, we aimed to identify the plastidial pyruvate transporter of Phaeodactylum tricornutum and utilize it for strain development. Results We identified putative pyruvate transporter localized in the plastid membrane of Phaeodactylum tricornutum. Transformants overexpressing the pyruvate transporter were generated to increase the influx of pyruvate into plastids. Overexpression of a plastidial pyruvate transporter in P. tricornutum resulted in enhanced biomass (13.6% to 21.9%), lipid contents (11% to 30%), and growth (3.3% to 8.0%) compared to those of wild type during one-stage cultivation. Conclusion To regulate the pyruvate influx and its metabolism in plastids, we generated transformants overexpressing the putative plastidial pyruvate transporter in P. tricornutum. They showed that its overexpression for compartmentalizing pyruvate in plastids could be an attractive strategy for the effective production of biomass and lipids with better growth, via enhanced pyruvate metabolism in plastids.

Silver nitrate is a commonly used substance in the cauterization of the traumatic soft tissue wounds to stop bleeding. As an inorganic compound with high density, silver nitrate is very radiodense. We present a case of topical silver nitrate application on a fingertip laceration of a 32-year-old diabetic woman, which was misinterpreted as heterotopic ossification. The appearance of silver nitrate on radiographic studies is not widely known, which can lead to misdiagnosis, further unnecessary imaging, and inappropriate surgery. Keywords: Silver nitrate cauterization, Radiograph, Heterotopic ossification

The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3’,4’:6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.

The measurement of carbon dioxide (CO2) fluxes using the eddy covariance technique is difficult in forests in complex terrain because of the horizontal advection of CO2 at night. This results the under- or overestimation of net ecosystem exchanges of CO2. We propose a technique for nighttime filtering (and correction) of CO2 fluxes to eliminate (and replace) those significantly affected by horizontal advection: the modified moving point test method. This was developed by merging the friction velocity filtering and van Gorsel methods. It is based on an approach using moving windows for time and friction velocity, allowing a nighttime CO2 flux correction that includes an assessment of CO2 drainage at midnight. We tested the method using datasets from two flux towers in forests in hilly and complex terrains, where the application of generic nighttime filtering methods is difficult because CO2 drainage is generated earlier than the time assumed by the generic methods. The method produced carbon budgets consistent with previous research results, while showing improved applicability. • We propose a nighttime CO2 flux filtering method for hilly and complex terrain that combines the friction velocity filtering and van Gorsel methods. • This method determines the friction velocity threshold and the significance of CO2 drainage at midnight based on an approach using moving windows for time and friction velocity. • The method produced consistent results and shows improved applicability. Method name: Modified moving point test method, Keywords: Eddy covariance, Advection, Nighttime CO2 flux correction, Moving point test, Hilly and complex terrain

Radiation-induced skin injury (RISI) is a main side effect of radiotherapy for cancer patients, with vascular damage being a common pathogenesis of acute and chronic RISI. Despite the severity of RISI, there are few treatments for it that are in clinical use. 2-Methoxyestradiol (2-ME) has been reported to regulate the radiation-induced vascular endothelial-to-mesenchymal transition. Thus, we investigated 2-ME as a potent anti-cancer and hypoxia-inducible factor 1 alpha (HIF-1α) inhibitor drug that prevents RISI by targeting HIF-1α. 2-ME treatment prior to and post irradiation inhibited RISI on the skin of C57/BL6 mice. 2-ME also reduced radiation-induced inflammation, skin thickness, and vascular fibrosis. In particular, post-treatment with 2-ME after irradiation repaired the damaged vessels on the irradiated dermal skin, inhibiting endothelial HIF-1α expression. In addition to the increase in vascular density, post-treatment with 2-ME showed fibrotic changes in residual vessels with SMA+CD31+ on the irradiated skin. Furthermore, 2-ME significantly inhibited fibrotic changes and accumulated DNA damage in irradiated human dermal microvascular endothelial cells. Therefore, we suggest that 2-ME may be a potent therapeutic agent for RISI.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V–propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Morphogenesis contributes to the virulence of the opportunistic human fungal pathogen Candida albicans. Ras1-MAPK pathways play a critical role in the virulence of C. albicans by regulating cell growth, morphogenesis, and biofilm formation. Ume6 acts as a transcription factor, and Nrg1 is a transcriptional repressor for the expression of hyphal-specific genes in morphogenesis. Azoles or echinocandin drugs have been extensively prescribed for C. albicans infections, which has led to the development of drug-resistant strains. Therefore, it is necessary to develop new molecules to effectively treat fungal infections. Here, we showed that Molecule B and Molecule C, which contained a carbazole structure, attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that Molecule B and Molecule C inhibit morphogenesis through repressing protein and RNA levels of Ras/MAPK-related genes, including UME6 and NRG1. Furthermore, we determined the antifungal effects of Molecule B and Molecule C in vivo using a candidiasis murine model. We anticipate our findings are that Molecule B and Molecule C, which inhibits the Ras1/MAPK pathway, are promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.

More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.

The role of forests to sequester carbon is considered an important strategy for mitigating climate change and achieving net zero emissions. However, forests in North Korea have continued to be cleared since the 1990s due to the lack of food and energy resources. Deforestation in this country has not been accurately classified nor consistently reported because of the characteristics of small patches. This study precisely determined the area of deforested land in North Korea through the vegetation phenological classification using high-resolution satellite imagery and deep learning algorithms. Effective afforestation target sites in North Korea were identified with priority grade. The U-Net deep learning algorithm and time-series Sentinel-2 satellite images were applied to phenological classification; the results reflected the small patch-like characteristics of deforestation in North Korea. Based on the phenological classification, the land cover of the country was classified with an accuracy of 84.6%; this included 2.6 million ha of unstocked forest and reclaimed forest. Sites for afforestation were prioritized into five grades based on deforested characteristics, altitude and slope. Forest area is expanded and the forest ecosystem is restored through successful afforestation, this may improve the overall ecosystem services in North Korea. In the long term, it will be possible to contribute to carbon neutrality and greenhouse gas reduction on the Korean Peninsula level through optimal afforestation by using these outcomes.

Abstract Reproductive phenological pattern on tetrasporophytes and carposporophytes of Grateloupia subpectinata thalli were observed at Yangyang, on the middle east coast of Korea from January to December 2013. DNA sequences of cox1 gene from 48 selected samples were compared to assure that sample collection is single species, and they were all identical G. subpectinata. Density, length and width of thalli were significantly changed monthly. The maximum of density, length and fresh weight occurred in September, and continuous growth was observed during the autumn and winter. Tetrasporophytes were grown dominantly in October and November, whereas carposporophytes were dominated in September and March. Upright thalli disappeared in June and July and then juveniles were abundant in August. There was a significant difference in length between tetrasporophytes and carposporophytes. These reproductive pattern and seasonality together with phenological data of G. subpectinata would provide valuable information about successful seedling supply for aquaculture of the species in the future.

Rising atmospheric CO _2 concentration ([CO _2 ]) enhances photosynthesis and reduces transpiration at the leaf, ecosystem, and global scale via the CO _2 fertilization effect. The CO _2 fertilization effect is among the most important processes for predicting the terrestrial carbon budget and future climate, yet it has been elusive to quantify. For evaluating the CO _2 fertilization effect on land photosynthesis and transpiration, we developed a technique that isolated this effect from other confounding effects, such as changes in climate, using a noisy time series of observed land-atmosphere CO _2 and water vapor exchange. Here, we evaluate the magnitude of this effect from 2000 to 2014 globally based on constraint optimization of gross primary productivity (GPP) and evapotranspiration in a canopy photosynthesis model over 104 global eddy-covariance stations. We found a consistent increase of GPP (0.138 ± 0.007% ppm ^−1 ; percentile per rising ppm of [CO _2 ]) and a concomitant decrease in transpiration (−0.073% ± 0.006% ppm ^−1 ) due to rising [CO _2 ]. Enhanced GPP from CO _2 fertilization after the baseline year 2000 is, on average, 1.2% of global GPP, 12.4 g C m ^−2 yr ^−1 or 1.8 Pg C yr ^−1 at the years from 2001 to 2014. Our result demonstrates that the current increase in [CO _2 ] could potentially explain the recent land CO _2 sink at the global scale.

This is a base research to analyze the evolution of fishing gear shapes in response to the types of marine benthic organisms and ‘getbatang-harvesting tidal flat’ in Daebu Island in Gyeonggi Bay. Daebu Island has variety of relatively well preserved natural coast lines and fishing gears. Hand hoes were divided into two categories, one for manila clam collecting and the other for mud octopus collecting. The ones used to catch mud octopuses are much larger and heavier. Clear distinction of shapes and forms were found even among the hand hoes used for collecting the similar types of catch, depending on the getbatang that they were used on. Also, mud octopus hand hoes varied in shapes and forms depending on the region that they were found in and the sex of the user. Fishing gears of other islands in Gyeonggi Bay, Oi Island, Jangbong Island and Ganghwa–Donggum Island, showed differences as getbatang varies, and each region sometimes had different uses of the same tool from each other. It is necessary that we continue the investigation and analysis on the relationship between the shape of fishing gears, organisms, and getbatang sediment conditions before the traditional fishing gears disappear any further.

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

In the Korea Flux Monitoring Network, Haenam Farmland has the longest record of carbon/water/energy flux measurements produced using the eddy covariance (EC) technique. Unfortunately, there are long gaps (i.e., gaps longer than 30 days), particularly in 2007 and 2014, which hinder attempts to analyze these decade-long time-series data. The open source and standardized gap-filling methods are impractical for such long gaps. The data-driven approach using machine learning and remote-sensing or reanalysis data (i.e., interpolating/extrapolating EC measurements via available networks temporally/spatially) for estimating terrestrial CO2/H2O fluxes at the regional/global scale is applicable after appropriate modifications. In this study, we evaluated the applicability of the data-driven approach for filling long gaps in flux data (i.e., gross primary production, ecosystem respiration, net ecosystem exchange, and evapotranspiration). We found that using a longer training dataset in the machine learning generally produced better model performance, although there was a greater possibility of missing interannual variations caused by ecosystem state changes (e.g., changes in crop variety). Based on the results, we proposed gap-filling strategies for long-period flux data gaps and used them to quantify the annual sums with uncertainties in 2007 and 2014. The results from this study have broad implications for long-period gap-filling at other sites, and for the estimation of regional/global CO2/H2O fluxes using a data-driven approach.

BackgroundIt was reported that N,N,N'N'-tetrakis-[2-pyridylmethyl]-ethylenediamine (TPEN), a transition metal chelator, confers cardioprotection against myocardial ischemic injury. In this study, we investigated the effect of TPEN targeting reperfusion period in isolated rat hearts.MethodsLangendorff perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Hearts were randomly assigned to either control (n = 9) or 10 µM of TPEN (n = 8) groups. TPEN was perfused for a period of 5 min before and 30 min after reperfusion.ResultsThe ratio of infarct area/ischemic area (AN/AR) was significantly reduced in TPEN treated hearts (6.9 ± 1.7%, P < 0.001) compared to control hearts (29.5 ± 3.2%). Recovery of left ventricular developed pressure (LVDP), rate-pressure product (RPP), +dP/dtmax, and -dP/dtmin in the control group after reperfusion were 53.8 ± 6.2%, 51.0 ± 6.3%, 51.9 ± 5.7%, and 51.4 ± 5.7%, respectively, of the baseline levels. In the TPEN group, LVDP, RPP, +dP/dtmax, and -dP/dtmin returned to 58.5 ± 4.6%, 54.8 ± 6.4%, 61.7 ± 4.9%, and 53.4 ± 3.9%, respectively, of the baseline levels. There were no significant differences in the cardiodynamic variables between the two groups (P > 0.05).ConclusionsPharmacological postconditioning with TPEN reduces myocardial infarction however, TPEN does not modify post-ischemic systolic dysfunction in isolated rat hearts.

We examined the nonlinear effect of spatial heterogeneity in atmospheric conditions on the simulation of surface fluxes in the mesoscale model, MM5 by testing their scale-invariance from a tower footprint to regional scales. The test domain was a homogeneous shortgrass prairie in the central part of the Tibetan Plateau with an eddy-covariance flux tower at the center. We found that the spatial variability resulting from changing distribution of clouds and precipitation in the model domain affected radiative forcing at the ground surface, thereby altering the partitioning of surface fluxes. Consequently, due to increasing spatial variability in atmospheric conditions, the results of MM5 did not produce convergent estimates of surface fluxes with increasing grid sizes. Our finding demonstrates that an atmospheric model can underestimate surface fluxes in regional scale not necessarily due to intrinsic model inaccuracy (e.g., inaccurate parameterization) but due to scale-dependent nonlinear effect of spatial variability in atmospheric conditions.

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.

Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti-angiogenic fragments, which play a key role in tumorprogression. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C-terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung progression in wild-type mice. Also, intact HSPB1 was more detected on tumor endothelium of MMP9 null mice than wild type mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung and liver tumor progression of B16F10 melanoma cells and lung tumor progression of CT26 colon carcinoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to regulate VEGF-induced ECs activation for tumor progression, releasing anti-angiogenic HSPB1 fragments. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation.