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Abstract Background Cancer‐associated fibroblasts (CAFs) play an important role in the induction of chemo‐resistance. This study aimed to clarify the mechanism underlying CAF‐mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC). Methods We performed a systematic integrative analysis of publicly available gene expression datasets and whole‐transcriptome sequencing data from 9 pairs of CAFs and para‐cancer fibroblasts isolated from human HCC and para‐tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression‐free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan‐Meier and Cox regression analysis. Results Bioinformatic analysis identified CAF‐derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF‐induced TKI resistance in vitro and in vivo. CAF‐derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin‐protein kinase C‐alpha (PKCα) signaling pathway and promoted epithelial‐to‐mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment. Conclusions CAF‐derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.

Background Angiotensin II induces glomerular and podocyte injury via systemic and local vasoconstrictive or non-hemodynamic effects including oxidative stress. The release of reactive oxygen species (ROS) from podocytes may participate in the development of glomerular injury and proteinuria. We studied the role of oxidative stress in angiotensin II-induced podocyte apoptosis. Methods Mouse podocytes were incubated in media containing various concentrations of angiotensin II at different incubation times and were transfected with NADH/NADPH oxidase 4 (Nox4) or angiotensin II type 1 receptor for 24 hours. The changes in intracellular and mitochondrial ROS production and podocyte apoptosis were measured according to the presence of angiotensin II. Results Angiotensin II increased the generation of mitochondrial superoxide anions and ROS levels but suppressed superoxide dismutase activity in a dose- and time-dependent manner that was reversed by probucol, an antioxidant. Angiotensin II increased Nox4 protein and expression by a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of Nox4 by small interfering RNA (siRNA) reduced the oxidative stress induced by angiotensin II. Angiotensin II treatment also upregulated AT1R protein. Furthermore, angiotensin II promoted podocyte apoptosis, which was reduced significantly by probucol and Nox4 siRNA and also recovered by angiotensin II type 1 receptor siRNA. Conclusion Our findings suggest that angiotensin II increases the generation of mitochondrial superoxide anions and ROS levels via the upregulation of Nox4 and angiotensin II type 1 receptor. This can be prevented by Nox4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as use of antioxidants.

Abstract As single-cell RNA sequencing (scRNA-seq) has emerged as a great tool for studying cellular heterogeneity within the past decade, the number of available scRNA-seq datasets also rapidly increased. However, reuse of such data is often problematic due to a small cohort size, limited cell types, and insufficient information on cell type classification. Here, we present a large integrated scRNA-seq dataset containing 224,611 cells from human primary non-small cell lung cancer (NSCLC) tumors. Using publicly available resources, we pre-processed and integrated seven independent scRNA-seq datasets using an anchor-based approach, with five datasets utilized as reference and the remaining two, as validation. We created two levels of annotation based on cell type-specific markers conserved across the datasets. To demonstrate usability of the integrated dataset, we created annotation predictions for the two validation datasets using our integrated reference. Additionally, we conducted a trajectory analysis on subsets of T cells and lung cancer cells. This integrated data may serve as a resource for studying NSCLC transcriptome at the single cell level.

Intertidal macroinvertebrates, such as crabs and mud shrimps, are invertebrates inhabiting the intertidal zone that are sufficiently large to be identified with the naked eye. Most intertidal macroinvertebrates typically construct burrows of various shapes in sediment to protect themselves from environmental extremes, with surface openings that reflect features of their species and body size. Especially circular burrow openings correlate with an organism’s body size; thus, measuring these openings can provide estimates of the organism’s size, weight, growth rate, and biomass. Traditional studies of these organisms have relied on field surveys, which are constrained by time, cost, and logistical limitations. This study introduces an innovative method for measuring the burrow opening diameters of intertidal macroinvertebrates using high-resolution optical images from a portable drone system. By leveraging the reflectance disparity between the sediment and burrow openings, this method facilitates the extraction and sizing of burrow openings. Our methodology was applied to three crab species known for their circular burrow opening: the red-clawed fiddler, the milky fiddler, and the ghost crab. Validation was confirmed through field data from the Mageumri and Sinduri tidal flats, South Korea. The method achieved a correlation coefficient (R2) of 0.94 and a root mean squared error (RMSE) of 1.68 mm across a diameter range of 6.21–33.59 mm. These findings suggest the potential of drone remote sensing systems as a non-invasive and efficacious approach for quantifying burrow sizes over extensive intertidal areas, thereby facilitating more accurate biomass estimations and surmounting the limitations of conventional field surveys. Future research could extend this method to additional species and further refine its precision.

Epidemic diseases that arise from infectious RNA viruses, particularly influenza viruses, pose a constant threat to the global economy and public health. Viral evolution has undermined the efficacy of acquired immunity from vaccines and the antiviral effects of FDA-approved drugs. As such, there is an urgent need to develop new antiviral lead agents. Natural compounds, owing to their historical validation of application and safety, have become a promising solution. In this light, a novel marine bacterium, Pseudomonas sp. M20A4R8, has been found to exhibit significant antiviral activity [half maximal inhibitory concentration (IC50) = 1.3 µg/mL, selectivity index (SI) = 919.4] against influenza virus A/Puerto Rico/8/34, surpassing the activity of chloroquine. The antiviral response via M20A4R8 extract was induced during post-entry stages of the influenza virus, indicating suitability for post-application after the establishment of viral infection. Furthermore, post-treatment with M20A4R8 extract protected the host from virus-induced apoptosis, suggesting its potential use in acute respiratory disease complexes resulting from immune effectors’ overstimulation and autophagy-mediated self-apoptosis. The extract demonstrated an outstanding therapeutic index against influenza virus A/Wisconsin/15/2009 (IC50 = 8.1 µg/mL, SI = 146.2) and B/Florida/78/2015 Victoria lineage (IC50 = 3.5 µg/mL, SI = 343.8), indicating a broad anti-influenza virus activity with guaranteed safety and effectiveness. This study provides a new perspective on mechanisms for preventing a broad spectrum of viral infections through antiviral agents from novel and natural origins. Future studies on a single or combined compound from the extract hold promise, encouraging its use in preclinical challenge tests with various influenza virus strains.

Abstract Tumor cells often overexpress immune checkpoint proteins, including CD47, for immune evasion. However, whether or how oncogenic activation of receptor tyrosine kinases, which are crucial drivers in tumor development, regulates CD47 expression is unknown. Here, it is demonstrated that epidermal growth factor receptor (EGFR) activation induces CD47 expression by increasing the binding of c‐Src to CD47, leading to c‐Src‐mediated CD47 Y288 phosphorylation. This phosphorylation inhibits the interaction between the ubiquitin E3 ligase TRIM21 and CD47, thereby abrogating TRIM21‐mediated CD47 K99/102 polyubiquitylation and CD47 degradation. Knock‐in expression of CD47 Y288F reduces CD47 expression, increases macrophage phagocytosis of tumor cells, and inhibits brain tumor growth in mice. In contrast, knock‐in expression of CD47 K99/102R elicits the opposite effects compared to CD47 Y288F expression. Importantly, CD47‐SIRPα blockade with an anti‐CD47 antibody treatment significantly enhances EGFR‐targeted cancer therapy. In addition, CD47 expression levels in human glioblastoma (GBM) specimens correlate with EGFR and c‐Src activation and aggravation of human GBM. These findings elucidate a novel mechanism underlying CD47 upregulation in EGFR‐activated tumor cells and underscore the role of the EGFR‐c‐Src‐TRIM21‐CD47 signaling axis in tumor evasion and the potential to improve the current cancer therapy with a combination of CD47 blockade with EGFR‐targeted remedy.

In this study, the degradation characteristics of glass run channel (GRC) with ethylene-propylene diene monomer (EPDM) substrate coated with polyurethane (PU) that is slid against window glass were systematically investigated. The results showed that GRC degradation mainly resulted from plastic deformation of the GRC lips, which is primarily associated with creep, and wear of PU bump formed on the lip surface. Moreover, the adhesive wear was proposed to be the key wear mechanism responsible for further increase in friction with the sliding distance. Depending on the GRC shape, the applied normal force and contact condition with window glass significantly affected the lips plastic deformation and the PU bump wear. Furthermore, the misalignment of GRC progressed degradation and increased friction significantly. The fundamental degradation characteristics of GRC revealed in this study are expected to be useful for the design of GRC with improved performance and durability.

Abstract Cryptococcus neoformans is an opportunistic human fungal pathogen causing lethal meningoencephalitis. It has several cell wall mannoproteins (MPs) identified as immunoreactive antigens. To investigate the structure and function of N-glycans assembled on cryptococcal cell wall MPs in host cell interactions, we purified MP98 (Cda2) and MP84 (Cda3) expressed in wild-type (WT) and N-glycosylation-defective alg3 mutant (alg3Δ) strains. HPLC and MALDI-TOF analysis of the MP proteins from the WT revealed protein-specific glycan structures with different extents of hypermannosylation and xylose/xylose phosphate addition. In alg3Δ, MP98 and MP84 had truncated core N-glycans, containing mostly five and seven mannoses (M5 and M7 forms), respectively. In vitro adhesion and uptake assays indicated that the altered core N-glycans did not affect adhesion affinities to host cells although the capacity to induce the immune response of bone-marrow derived dendritic cells (BMDCs) decreased. Intriguingly, the removal of all N-glycosylation sites on MP84 increased adhesion to host cells and enhanced the induction of cytokine secretion from BMDCs compared with that on MP84 carrying WT N-glycans. Therefore, the structure-dependent effects of N-glycans suggested their complex roles in modulating the interaction of MPs with host cells to avoid nonspecific adherence to host cells and host immune response hyperactivation.

Abstract Background This study validated the Korean version of the Readiness to Return to Work (RRTW) scale, as an assessment measure, following a musculoskeletal, work-related injury and as a measure of following return to work. Methods The participants of this study were workers with experience in rehabilitation programs at the Workers’ Compensation and Welfare Service (KCOMWEL) Hospital in Korea. Factor analyses were employed to ensure the validity and reliability of the RRTW scale in claimants who were in treatment without working (the not-working group) or who had already returned to work (the working group). To test structural validity, we analyzed exploratory factor analysis (EFA) respectively for the not working group (exploratory factor analysis (EFA) (n = 200), confirmatory factor analysis (CFA) (n = 109), and the working group (n = 123). To verify concurrent validity (multidimensional and assignment approach), the variables that were identified as relevant variables in previous studies were analyzed. Results The not working group EFA, as shown in the original scale, had four dimensions, and one item was deleted: (1) Precontemplation (PC), (2) Contemplation (C), (3) Prepared for Action-Self-evaluative (PAS), and (4) Prepared for Action-Behavioral (PAB). The CFA revealed that a good model fit and reliability were suitable. Regarding the working group of EFA, it appeared in two dimensions as in the original scale, one item was modified from the UM scale to the PM scale, and the reliability was appropriate. Concurrent validity was satisfied based on the correlation between the RRTW factor and related variables. Conclusions RRTW in the Korean version of the instrument was similar to those reported for the original scale, indicating that it may be used in research and clinical settings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made significant impacts on global public health, including the development of several skin diseases that have arisen primarily as a result of the pandemic. Owing to the widespread expansion of coronavirus disease 19 (COVID-19), the development of effective treatments for these skin diseases is drawing attention as an important social issue. For many centuries, ginseng and its major active ingredients, ginsenosides and saponins, have been widely regarded as herbal medicines. Further, the anti-viral action of ginseng suggests its potential effectiveness as a therapeutic agent against COVID-19. Thus, the aim of this review was to examine the association of skin lesions with COVID-19 and the effect of ginseng as a therapeutic agent to treat skin diseases induced by COVID-19 infection. We classified COVID-19-related skin disorders into three categories: caused by inflammatory, immune, and complex (both inflammatory and immune) responses and evaluated the evidence for ginseng as a treatment for each category. This review offers comprehensive evidence on the improvement of skin disorders induced by SARS-CoV-2 infection using ginseng and its active constituents.

Fusarium head blight is an important disease of small grains. It is mainly caused by members of the Fusarium graminearum species complex (FGSC). Barley and wheat growers spray fungicides, especially demethylation-inhibitor fungicides, to suppress the disease. The objective of this study was to examine the changes in the sensitivity of the FGSC population to the triazole fungicide, propiconazole. A total of 124 and 350 isolates of FGSC were obtained from barley and wheat in Jeolla Province during 2010-2016 and 2020-2021, respectively. The species identity and trichothecene chemotypes of the FGSC isolates were determined based on polymerase chain reaction assays targeting translation elongation factor 1-alpha and TRI12 genes, respectively. Sensitivity to propiconazole was determined based on the effective concentration that reduced 50% of the mycelial growth (EC50) using the agar dilution method. Of all isolates, F. asiaticum with the nivalenol chemotype was the most common (83.9% in 2010-2016 and 96.0% in 2020-2021), followed by F. asiaticum with the 3-acetyl deoxynivalenol chemotype (12.1% in 2010-2016 and 2.9% in 2020-2021). The EC50 values of the isolates collected in 2010-2016 and 2020-2021 ranged from 0.0180 to 11.0166 μg/mL and 1.3104 to 17.9587 μg/mL, respectively. The mean EC50 value of the isolates increased from 3.8648 μg/mL in 2010-2016 to 5.9635 μg/mL in 2020-2021. The baseline resistance to propiconazole was determined to be 7 μg/mL, based on the EC50 value of isolates collected in 2010-2016, and the ratio of resistant isolates increased from 9.7% in 2010-2016 to 28.6% in 2020-2021.