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Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed β-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of β-catenin and downregulating β-catenin/LEF and c-jun/AP-1 downstream target genes such as CD44, cyclin-D1 and c-myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN)-mediated AP-1 activity and the activity of the KITENIN 3′-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT² Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo . Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity.

Republic of Korea’s suicide rate is the highest among Organization for Economic Co-operation and Development countries. In Republic of Korea, suicide is the leading cause of death among young people aged 10–19 years. This study aimed to identify changes in patients aged 10–19 years who visited the emergency department in Republic of Korea after inflicting self-harm over the past five years and to compare the situations before and after the outbreak of the COVID-19 pandemic. Analysis of government data revealed that the average daily visits per 100,000 were 6.25, 8.18, 13.26, 15.31, and 15.71 from 2016 to 2020, respectively. The study formed four groups for further analysis, with the population divided by sex and age (10–14 and 15–19 years old). The late-teenage female group showed the sharpest increase and was the only group that continued to increase. A comparison of the figures 10 months before and after the outbreak of the pandemic revealed a statistically significant increase in self-harm attempts by only the late-teenage female group. Meanwhile, visits (per day) in the male group did not increase, but the rates of death and ICU admission increased. Additional studies and preparations that account for age and sex are warranted.

Background: We aimed to create a novel model using a deep learning method to estimate stroke volume variation (SVV), a widely used predictor of fluid responsiveness, from arterial blood pressure waveform (ABPW). Methods: In total, 557 patients and 8,512,564 SVV datasets were collected and were divided into three groups: training, validation, and test. Data was composed of 10 s of ABPW and corresponding SVV data recorded every 2 s. We built a convolutional neural network (CNN) model to estimate SVV from the ABPW with pre-existing commercialized model (EV1000) as a reference. We applied pre-processing, multichannel, and dimension reduction to improve the CNN model with diversified inputs. Results: Our CNN model showed an acceptable performance with sample data (r = 0.91, MSE = 6.92). Diversification of inputs, such as normalization, frequency, and slope of ABPW significantly improved the model correlation (r = 0.95), lowered mean squared error (MSE = 2.13), and resulted in a high concordance rate (96.26%) with the SVV from the commercialized model. Conclusions: We developed a new CNN deep-learning model to estimate SVV. Our CNN model seems to be a viable alternative when the necessary medical device is not available, thereby allowing a wider range of application and resulting in optimal patient management.

δ-Catenin shares common binding partners with β-catenin. As acetylation and deacetylation regulate β-catenin stability, we searched for histone acetyltransferases (HATs) or histone deacetylases (HDACs) affecting δ-catenin acetylation status and protein levels. We showed that p300/CBP-associated factor (PCAF) directly bound to and acetylated δ-catenin, whereas several class I and class II HDACs reversed this effect. Unlike β-catenin, δ-catenin was downregulated by PCAF-mediated acetylation and upregulated by HDAC-mediated deacetylation. The HDAC inhibitor trichostatin A attenuated HDAC1-mediated δ-catenin upregulation, whereas HAT or autophagy inhibitors, but not proteasome inhibitors, abolished PCAF-mediated δ-catenin downregulation. The results suggested that PCAF-mediated δ-catenin acetylation promotes its autophagic degradation in an Atg5/LC3-dependent manner. Deletions or point mutations identified several lysine residues in different δ-catenin domains involved in PCAF-mediated δ-catenin downregulation. PCAF overexpression in prostate cancer cells markedly reduced δ-catenin levels and suppressed cell growth and motility. PCAF-mediated δ-catenin downregulation inhibited E-cadherin processing and decreased the nuclear distribution of β-catenin, resulting in the suppression of β-catenin/LEF-1-mediated downstream effectors. These data demonstrate that PCAF downregulates δ-catenin by promoting its autophagic degradation and suppresses δ-catenin-mediated oncogenic signals.

Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous hemodynamic index. In this study, we aimed to induce hemodynamic variations and clarify the relationship between the heart sounds and hemodynamic variables through an experimental animal study. Changes in the cardiac contractility and vascular resistance were induced in anesthetized pigs by administering dobutamine, esmolol, phenylephrine, and nicardipine. In addition, a decrease in cardiac output was induced by restricting the venous return by clamping the inferior vena cava (IVC). The relationship between the hemodynamic changes and changes in the heart sound indices was analyzed. Experimental data from eight pigs were analyzed. The mean values of the correlation coefficients of changes in S1 amplitude (ΔS1amp) with systolic blood pressure (ΔSBP), pulse pressure (ΔPP), and ΔdP/dt during dobutamine administration were 0.94, 0.96, and 0.96, respectively. The mean values of the correlation coefficients of ΔS1amp with ΔSBP, ΔPP, and ΔdP/dt during esmolol administration were 0.80, 0.82, and 0.86, respectively. The hemodynamic changes caused by the administration of phenylephrine and nicardipine did not correlate significantly with changes in the heart rate. The S1 amplitude of the heart sound was significantly correlated with the hemodynamic changes caused by the changes in cardiac contractility but not with the variations in the vascular resistance. Heart sounds can potentially provide a non-invasive monitoring method to differentiate the cause of hemodynamic variations.

Premature ventricular contraction (PVC) is a common and harmless cardiac arrhythmia that can be asymptomatic or cause palpitations and chest pain in rare instances. However, frequent PVCs can lead to more serious arrhythmias, such as atrial fibrillation. Several PVC detection models have been proposed to enable early diagnosis of arrhythmias; however, they lack reliability and generalizability due to the variability of electrocardiograms across different settings and noise levels. Such weaknesses are known to aggravate with new data. Therefore, we present a deep learning model with a novel attention mechanism that can detect PVC accurately, even on unseen electrocardiograms with various noise levels. Our method, called the Denoise and Contrast Attention Module (DCAM), is a two-step process that denoises signals with a convolutional neural network (CNN) in the frequency domain and attends to differences. It focuses on differences in the morphologies and intervals of the remaining beats, mimicking how trained clinicians identify PVCs. Using three different encoder types, we evaluated 1D U-Net with DCAM on six external test datasets. The results showed that DCAM significantly improved the F1-score of PVC detection performance on all six external datasets and enhanced the performance of balancing both the sensitivity and precision of the models, demonstrating its robustness and generalization ability regardless of the encoder type. This demonstrates the need for a trainable denoising process before applying the attention mechanism. Our DCAM could contribute to the development of a reliable algorithm for cardiac arrhythmia detection under real clinical electrocardiograms. •DCAM mimics human expert PVC reading strategy and its performance was validated using 6 external datasets and attention maps.

The cell surface receptor tyrosine kinase (RTK) exists in a dynamic state, however, it remains unknown how single membrane-spanning RTK proteins are retained in the plasma membrane before their activation. This study was undertaken to investigate how RTK proteins are anchored in the plasma membrane before they bind with their respective extracellular ligands for activation through protein–protein interaction, co-localization, and functional phenotype studies. Here we show that unconventional myosin-I MYO1D functions to hold members of the EGFR family (except ErbB3) at the plasma membrane. MYO1D binds only with unphosphorylated EGFRs and anchors them to underlying actin cytoskeleton at the plasma membrane. The C-terminal end region of the MYO1D tail domain containing a β-meander motif is critical for direct binding with kinase domain of the EGFR family, and expression of the tail domain alone suppresses the oncogenic action of full-length MYO1D. Overexpressed MYO1D increases colorectal and breast cancer cell motility and viability through upregulating EGFR level, and thereby promotes colorectal tumor progression in a syngeneic mouse model. MYO1D is upregulated in human colorectal cancer tissues from advanced stages. Collectively, molecular motor MYO1D plays a distinct role in the dynamic regulation of EGFR family levels by holding them at the plasma membrane before their activation. Overexpressed MYO1D contributes to colorectal carcinogenesis possibly as a novel oncogene and thus may serve as an additional target for suppression of RTK signaling in cancer treatment.

Aging is marked by a decline in tissue integrity, particularly in skin and muscle, driven by oxidative stress and extracellular matrix (ECM) degradation. Superoxide dismutase 1 (SOD1) deficiency exacerbates these processes, accelerating atrophy. Matrix metalloproteinase‐2 (MMP‐2), a key enzyme in ECM breakdown, targets collagen type XVII (COLXVII), which is critical for tissue structure and stability. In this study, we investigated the role of MMP‐2 in SOD1‐deficient models and assessed the therapeutic potential of its inhibition. To assess the impact of MMP inhibition on wound healing and skin atrophy, we applied batimastat, a broad‐spectrum MMP inhibitor, to Sod1‐deficient mice. While batimastat inhibits multiple MMPs, including MMP‐2, MMP‐9, and MMP‐14, its application allows us to evaluate the general role of MMP activity in SOD1‐related ECM degradation and repair processes. Using Sod1/Mmp2 double‐knockout mice and the MMP inhibitor batimastat, we observed that MMP‐2 deletion restored skin thickness, increased COLXVII expression, and improved wound healing. Batimastat application yielded similar benefits, reversing skin atrophy and enhancing repair. In muscle tissue, MMP‐2 inhibition restored muscle mass and function, with parallel improvements in SOD1 mutant Caenorhabditis elegans. Preservation of COLXVII emerged as a critical mechanism, significantly mitigating SOD1‐related tissue degeneration. These findings highlight MMP‐2's pivotal role in senescence‐associated tissue atrophy and underscore the therapeutic potential of targeting the SOD1‒MMP‐2‒COLXVII axis to combat age‐related tissue degeneration. Our work identifies a novel role for MMP‐2 in driving senescence‐associated skin and muscle degeneration through ECM degradation. We demonstrate that inhibiting MMP‐2 activity restores tissue integrity by preserving COLXVII, revealing a new therapeutic pathway for combating oxidative stress‐induced tissue aging. Using both mammalian and nematode models, we provide robust evidence that targeting the SOD1‒MMP‐2‒COLXVII axis can reverse aging‐related structural and functional declines, offering translational potential for clinical intervention in age‐related disorders.

Procollagen type I carboxy-terminal propeptide (PICP), derived from type I procollagen, has been identified as an indicator of type I collagen synthesis in bone matrix formation and skin recovery. PICP is a heterotrimeric glycoprotein consisting of two α1 chains (PICPα1) and one α2 chain (PICPα2). Here, we report the recombinant expression of human PICP using a mammalian expression system. Co-expression of PICPα1 and PICPα2 in HEK293F cells resulted in the production of functional PICP in the correctly assembled heterotrimeric form. Using the recombinant PICP as an antigen, we isolated PICP-specific human monoclonal antibodies from phage-displayed antibody libraries and raised rabbit polyclonal antibodies. Using those antibodies, we then developed a sandwich ELISA for PICP with a limit of detection of 1 ng/mL and a measurable range of 1–640 ng/mL. Both intra- and inter-assay imprecision values were <10%. For measuring PICP levels in human fibroblast cellular extracts and culture supernatants and a human serum, the developed ELISA kit displayed comparable performance to that of a commercialized kit. Our results provide an efficient production strategy for recombinant PICP, facilitating the generation of PICP-specific antibodies and development of PICP sandwich ELISA, with potential use in clinical diagnosis of serum samples and testing of cosmeceutical ingredients in fibroblast cell cultures.

Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.