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Pulmonary invasive fungal infection in immunocompromised hosts is difficult to diagnose, and current tools for diagnosis or monitoring of response to antifungal treatments have inherent limitations. Droplet digital PCR (ddPCR) has emerged as a promising tool for pulmonary pathogen detection with high sensitivity. This study presents a novel ddPCR panel for rapid and sensitive identification of pulmonary fungal pathogens. First, a ddPCR method for detecting three fungal genera, including Pneumocystis, Aspergillus, and Cryptococcus, was established and evaluated. Then, the clinical validation performance of ddPCR was compared with that of qPCR using 170 specimens, and the 6 specimens with inconsistent results were further verified by metagenomics next-generation sequencing, which yielded results consistent with the ddPCR findings. Finally, the area under the ROC curve (AUC) was used to evaluate the efficiency of ddPCR. While the qPCR identified 16 (9.41%) cases of Aspergillus and 6 (3.53%) cases of Pneumocystis, ddPCR detected 20 (11.76%) Aspergillus cases and 8 (4.71%) Pneumocystis cases. The AUC for Aspergillus, Cryptococcus, and Pneumocystis was 0.974, 0.998, and 0.975, respectively. These findings demonstrated that the ddPCR assay is a highly sensitive method for identifying pathogens responsible for invasive fungal pulmonary infections, and is a promising tool for early diagnosis. [ABSTRACT FROM AUTHOR]

Tripartite motif‐containing protein 21 (TRIM21), identified as both a cytosolic E3 ubiquitin ligase and FcR (Fragment crystallizable receptor), primarily interacts with proteins via its PRY/SPRY domains and promotes their proteasomal degradation to regulate intracellular immunity. But how TRIM21 involves in intracellular immunity still lacks systematical understanding. Herein, it is probed into the TRIM21‐related literature and raises an interacting model about how TRIM21 orchestrates proteins in cytosol. In this novel model, TRIM21 generally interacts with miscellaneous protein in intracellular immunity in two ways: For one, TRIM21 solely plays as an E3, ubiquitylating a glut of proteins that contain specific interferon‐regulatory factor, nuclear transcription factor kappaB, virus sensors and others, and involving inflammatory responses. For another, TRIM21 serves as both E3 and specific FcR that detects antibody‐complexes and facilitates antibody destroying target proteins. Correspondingly delineated as Fc‐independent signaling and Fc‐dependent signaling in this review, how TRIM21's interactions contribute to intracellular immunity, expecting to provide a systematical understanding of this important protein and invest enlightenment for further research on the pathogenesis of related diseases and its prospective application is elaborated. [ABSTRACT FROM AUTHOR]

Abstract: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a highly promising therapeutic agent for cancer treatment, owing to its ability to selectively target tumor cells for cell death while [...]

The activity of glycogen synthase kinase beta (GSK3β) is mainly regulated by its Ser9 phosphorylation. It has been believed for a long time that Ser9 phosphorylation regulates the functions of GSK3β through inhibition of its kinase activity. In this study, we have confirmed the interaction of Ser9-phosphorylated GSK3β with 14-3-3θ by using GST pull- down assays. We show that 14-3-3θ enhances Ser9 phosphorylation of GSK3β by PKC. Surprisingly, using a NF-κB luciferase reporter system, we find that Ser9-phosphorylation of GSK3β promoted by 14-3-3θ is critical for the activation of NF-κB pathway, which may thwart the pro-apoptotic activity of GSK3β. Inhibition of either NF-κB or GSK3β significantly abolishes the anti-apoptotic effect of 14-3-3θ and Ser9-phosphorylated GSK3β, suggesting that Ser9-phosphorylated GSK3β actively antagonizes cell apoptosis in a NF-κB dependent manner. Keywords: 14-3-3θ, GSK3β, Ser9 phosphorylation, interaction, apoptosis. L'activite de la glycogene synthase kinase beta (GSK3β) est principalement regulee par sa phosphorylation sur la Ser9. On croit depuis longtemps que la phosphorylation sur la Ser9 regule les fonctions de la GSK3β au moyen de l'inhibition de son activite kinase. Dans cette etude, les auteurs ont confirme l'interaction de la GSK3β phosphorylee sur la Ser9 et la proteine 14-3-3θ a l'aide d'un test de precipitation sur GST. Ils montrent que la 14-3-3θ accroit la phosphorylation de la GSK3β sur la Ser9 par la PKC. De maniere inattendue, les auteurs ont trouve a l'aide d'un systeme rapporteur NF-κB luciferase que la phosphorylation de la GSK3β sur la Ser9 favorisee par la 14-3-3θ est critique a l'activation de la voie du NF-κB, ce qui pourrait bloquer l'activite pro-apoptotique de la GSK3β. L'inhibition du NF-κB ou de la GSK3β diminue significativement l'effet anti-apoptotique de la 14-3-3θ et de la GSK3β phosphorylee sur la Ser9, ce qui suggere que la GSK3β phosphorylee sur la Ser9 agit activement comme antagoniste de l'apoptose de maniere dependante du NF-κB. [Traduit par la Redaction] Mots-cles: 14-3-3θ, GSK3β, phosphorylation sur la Ser9, interaction, apoptose., Introduction Glycogen synthase kinase beta (GSK3β), a ubiquitous serine/ threonine kinase and a member of the GSK3 family, was initially identified as an enzyme capable of phosphorylating glycogen synthase (Embi [...]

Ferroptosis is a type of programmed cell death depending on iron and reactive oxygen species. This unique cell death process has attracted a great deal of attention in the field of cancer research over the past decade. Research on the association of ferroptosis signal pathways and cancer development indicated that targeting ferroptosis has great potential for cancer therapy. In the present study, the latest research progress of ferroptosis was reviewed, focusing on the relationship between ferroptosis and the development of cancer, in order to further promote the clinical application of ferroptosis in cancer. [ABSTRACT FROM AUTHOR]

Motivation Transcriptional surges generated by two-component systems (TCSs) have been observed experimentally in various bacteria. Suppression of the transcriptional surge may reduce the activity, virulence and drug resistance of bacteria. In order to investigate the general mechanisms, we use a PhoP/PhoQ TCS as a model system to derive a comprehensive mathematical modeling that governs the surge. PhoP is a response regulator, which serves as a transcription factor under a phosphorylation-dependent modulation by PhoQ, a histidine kinase. Results Our model reveals two major signaling pathways to modulate the phosphorylated PhoP (P-PhoP) level, one of which promotes the generation of P-PhoP, while the other depresses the level of P-PhoP. The competition between the P-PhoP-promoting and the P-PhoP-depressing pathways determines the generation of the P-PhoP surge. Furthermore, besides PhoQ, PhoP is also a bifunctional modulator that contributes to the dynamic control of P-PhoP state, leading to a biphasic regulation of the surge by the gene feedback loop. In summary, the mechanisms derived from the PhoP/PhoQ system for the transcriptional surges provide a better understanding on such a sophisticated signal transduction system and aid to develop new antimicrobial strategies targeting TCSs. Availability and implementation https://github.com/jianweishuai/TCS. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Cryptochromes photoreceptors, CRY1 and CRY2 in Arabidopsis, mediate blue light responses in plants and metazoa. The signalling interactions underlying photomorphogenesis of cryptochromes action have been extensively studied in experiment, expecting a systematical analysis of the dynamic mechanisms of photosensory signalling network from a global view. In this study, we developed a signalling network model to quantitatively investigate the different response modes and cooperation modulations on photomorphogenesis for CRY1 and CRY2 under blue light. The model shows that the different modes of time‐dependent and fluence‐rate‐dependent phosphorylations for CRY1 and CRY2 are originated from their different phosphorylation rates and degradation rates. Our study indicates that, due to the strong association between blue‐light inhibitor of cryptochromes (BIC) and CRY2, BIC negatively modulates CRY2 phosphorylation, which was confirmed by our experiment. The experiment also validated the model prediction that the time‐dependent BIC‐CRY1 and the fluence‐rate‐dependent BIC‐CRY2 are both bell‐shaped under blue light. Importantly, the model proposes that the COP1‐SPA abundance can strongly inhibit the phosphorylation response of CRY2, resulting in the positive regulation of CRY2 phosphorylation by CRY1 through COP1‐SPA. The model also predicts that the CRY1‐HY5 axis, rather than CRY2‐HY5 pathway, plays a dominant role in blue‐light‐dependent photomorphogenesis. We built a theoretical model to provide explanation and prediction about different responses and cooperation mechanisms of CRY1 and CRY2, including fast phosphorylation and degradation of CRY2, domination of BIC in CRY2‐signalling, mediation of CRY1 in CRY2 phosphorylation and domination of CRY1 in photomorphogenesis. [ABSTRACT FROM AUTHOR]

Abstract Low power laser irradiation (LPLI) promotes proliferation of multiple cells, which (especially red and near infrared light) is mainly through the activation of mitochondrial respiratory chain and the initiation of cellular signaling. Recently, the signaling proteins involved in LPLI-induced proliferation merit special attention, some of which are regulated by mitochondrial signaling. Hepatocyte growth factor receptor (c-Met), a member of tyrosine protein kinase receptors (TPKR), is phosphorylated during LPLI-induced proliferation, but tumor necrosis factor alpha (TNF-alpha) receptor has not been affected. Activated TPKR could activate its downstream signaling elements, like Ras/Raf/MEK/ERK, PI3K/Akt/eIF4E, PI3K/Akt/eNOS and PLC-gamma/PKC pathways. Other two pathways, ΔΨm/ATP/cAMP/JNK/AP-1 and ROS/Src, are also involved in LPLI-induced proliferation. LPLI-induced cell cycle progression can be regulated by the activation or elevated expressions of cell cycle-specific proteins. Furthermore, LPLI induces the synthesis or release of many molecules, like growth factors, interleukins, inflammatory cytokines and others, which are related to promotive effects of LPLI.

Purpose: To analyze the distribution of epidermal growth factor receptor (EGFR) mutations; characterize the clinical and imageological features of lung squamous cell carcinoma (LSCC) in a large population of patients; and assess correlations between clinical and imageological characteristics and clinical outcomes of LSCC patients harboring EGFR mutations. Patients and methods: Three pathologists retrospectively evaluated the morphological and immunohistochemical data of 2,322 patients with LSCC resected between February 2013 and December 2017. Data on the distribution of EGFR mutations and the clinical and imageological characteristics of the patients were retrospectively collected. Correlations between the EGFR mutation status and clinical outcomes were evaluated using univariate and multivariate analyses. Results: EGFR mutations were found in 3.4% of patients with LSCC and predominantly in female and non-smoking patients. Tumor lesions in patients with EGFR-positive mutations were more irregularly shaped than those in patients with EGFR-negative mutations (P = 0.045). In non-smoking patients with LSCC, the proportion of marked spiculation was significantly higher in the EGFR-positive group than in the EGFR-negative group (P = 0.043). No significant difference in recurrence-free survival was noted between LSCC patients harboring EGFR-positive and those harboring EGFR-negative mutations. No difference in metastases was observed between the EGFR-positive and EGFR-negative cohorts. Conclusion: Female gender, non-smoking habit, irregularly shaped tumor, and marked spiculation might predict the presence of EGFR mutations in LSCC. The administration of tyrosine kinase inhibitors to patients with LSCC after screening for EGFR mutations based on their clinical and imageological features would likely result in a population with a greater sensitivity to afatinib. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 beta (GSK3β) was initially identified as a key protein in glucose metabolism. GSK3β might be involved in cell growth, motility and apoptosis. Systematic identification of GSK3β-associated proteins is crucial for the exhaustive understanding of its functions. Using GST pull-down experiment and LCMS/MS analysis coupled to bioinformatics tools, we have identified 114 proteins that interacted with GSK3β1 in hepatocellular carcinoma HepG2 cells. Most of the identified proteins are implicated in metabolic process, whereas other proteins are important for cell proliferation or migration, and have been associated with cancer development and metastasis. Several representative proteins, such as hnRNPK, PCNA, Ezrin and STAT1, have been confirmed to interact with GSK-3β1 by co-immunoprecipitation in HepG2 cells. Further studies of these interactions may discover the precise roles and the underlying mechanisms of GSK-3β1 in tumour growth and metastasis. [ABSTRACT FROM AUTHOR]

Metastasis determines the lethality of cancer. In most clinical cases, patients are able to live with tumor proliferation before metastasis. Thus, the transition from tumor proliferation to metastasis/invasion is essential. However, the mechanism is still unclear and especially, the proliferation-to-metastasis/invasion transition point has not been well defined. Therefore, quantitative characterization of this transition is urgently needed. We have successfully developed a home-built living-cell incubation system combined with an inverted optical microscope, and a systematic, quantitative approach to describing the major characteristic morphological parameters for the identification of the critical transition points for tumor-cell spheroids in a collagen fiber scaffold. The system focuses on in vitro tumor modeling, e.g. the development of tumor-cell spheroids in a collagen fiber scaffold and the monitoring of cell transition from proliferation to invasion. By applying this approach to multiple tumor spheroid models, such as U87 (glioma tumor), H1299 (lung cancer), and MDA-MB-231 (breast cancer) cells, we have obtained quantitative morphological references to evaluate the proliferation-to-invasion transition time, as well as differentiating the invasion potential of tumor cells upon environmental changes, i.e. drug application. Our quantitative approach provides a feasible clarification for the proliferation-to-invasion transition of in vitro tumor models (spheroids). Moreover, the transition time is a useful reference for the invasive potential of tumor cells. This quantitative approach is potentially applicable to primary tumor cells, and thus has potential applications in the fields of cancer metastasis investigations and clinical diagnostics. • Proliferation-to-invasion transition model by tumor spheroids in defined conditions • Image-based, automated and quantitative analysis of the morphological transitions • Proposed suitable parameters for well definition of the transition point • Transition point and time provide good assistance for cancer invasion investigation [ABSTRACT FROM AUTHOR]

14-3-3 proteins have been shown to regulate the actin cytoskeleton remodeling, cell adhesion and migration. In this study, we identified ezrin, a cross-linker between plasma membrane and actin cytoskeleton, as a novel 14-3-3ζ interacting partner. The direct interaction between 14-3-3ζ and ezrin was validated in the cells and by in vitro assays. We showed that the 14-3-3ζ binding region in ezrin was located within the N-terminal and central α-helical domains and that the αG-to-αI helices of 14-3-3ζ are responsible for the binding to ezrin. Functional analyses revealed that the regulation of cell migration and membrane ruffling by 14-3-3ζ is ezrin dependent, for which the integrity of ezrin protein was required. Conversely, the knockdown of 14-3-3ζ abrogates also the stimulatory effect of ezrin on cell migration and membrane ruffling. Moreover, we found that the phosphorylation of Thr567 in ezrin facilitates the 14-3-3ζ–ezrin interaction and the formation of membrane ruffles. Taken together, these results suggest strongly that the functions of these two proteins in cell migration are linked and might be mediated by their direct physical interaction, which is important for the formation of membrane ruffles. [ABSTRACT FROM AUTHOR]

Pulmonary invasive fungal infection in immunocompromised hosts is difficult to diagnose, and current tools for diagnosis or monitoring of response to antifungal treatments have inherent limitations. Droplet digital PCR (ddPCR) has emerged as a promising tool for pulmonary pathogen detection with high sensitivity. This study presents a novel ddPCR panel for rapid and sensitive identification of pulmonary fungal pathogens. First, a ddPCR method for detecting three fungal genera, including Pneumocystis , Aspergillus , and Cryptococcus , was established and evaluated. Then, the clinical validation performance of ddPCR was compared with that of qPCR using 170 specimens, and the 6 specimens with inconsistent results were further verified by metagenomics next-generation sequencing, which yielded results consistent with the ddPCR findings. Finally, the area under the ROC curve (AUC) was used to evaluate the efficiency of ddPCR. While the qPCR identified 16 (9.41%) cases of Aspergillus and 6 (3.53%) cases of Pneumocystis , ddPCR detected 20 (11.76%) Aspergillus cases and 8 (4.71%) Pneumocystis cases. The AUC for Aspergillus , Cryptococcus , and Pneumocystis was 0.974, 0.998, and 0.975, respectively. These findings demonstrated that the ddPCR assay is a highly sensitive method for identifying pathogens responsible for invasive fungal pulmonary infections, and is a promising tool for early diagnosis.      ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Aims: Further investigation on the mechanism of action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in NSCLC would shed light on the understanding of TRAIL resistance and provide new clues for the counter-strategy., Background: Cellular FLICE-inhibitory protein (c-FLIP) is a critical inhibitor of TRAIL-induced apoptosis. Our previous study suggested that glycogen synthase kinase 3β (GSK3β) positively regulated c-FLIP expression in human lung adenocarcinoma cells. Meanwhile, other studies reported that c-FLIP was degraded by HECT-type E3 ligase ITCH (Itchy E3 Ubiquitin Protein Ligase) via the proteasome pathway., Objective: We will explore whether ITCH is involved in the expression regulation of c-FLIP positively controlled by GSK3β during the treatment of TRAIL., Methods: Human lung adenocarcinoma cells were used to stably overexpress and knockdown GSK3β. Quantitative real-time PCR (qRT-PCR) assay was used to test the expressional level of mRNA of genes. Western blot analysis was employed to detect the expression of proteins at the protein level. siRNA of ITCH was used to knock down its expression. TRAIL treatment was used to cause apoptosis., Results: In the present study, we have confirmed the degradation of c-FLIP by ITCH protein and the downregulation of ITCH expression by GSK3β in lung adenocarcinoma cells. Moreover, ITCH silencing reversed the downregulation of c-FLIP protein caused by GSK3β-knockdown in the cells. Accordingly, TRAIL-induced apoptosis facilitated by GSK3β knockdown was blocked by the combined interference of ITCH., Conclusion: These results suggested that GSK3β/ITCH axis regulated the stability of c-FLIP and influenced TRAIL-induced apoptosis. Taken together, our study revealed a GSK3β/ITCH/c-FLIP axis, which counteracts TRAIL-induced apoptosis in human lung adenocarcinoma cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: OS is the most frequent malignant bone tumor with a poor prognosis. TRIM21 has been reported to play a critical role in OS by regulating the expression of the TXNIP/p21 axis and inhibiting the senescence of OS cells., Aim: Investigation of the molecular mechanism of tripartite motif 21 (TRIM21) in osteosarcoma (OS) would shed light on the understanding of the pathogenesis of OS., Objective: This study aimed to explore the mechanism regulating the protein stability of TRIM21 in the process of OS senescence., Methods: Human U2 OS cells were used to establish stable cells overexpressing TRIM21 (induced by Dox) or knocking down TRIM21. The co-immunoprecipitation (co-IP) assay was used to examine the interaction between TRIM21 and HSP90. Immunofluorescence (IF) assay was used to observe colocalization in OS cells. Western blot analysis was applied to detect the protein expression, and quantitative real-time PCR (qRT-PCR) assay was used to test the mRNA expression of corresponding genes. SA-β-gal staining was used to evaluate OS senescence., Results: In this study, we verified the interaction between HSP90 and TRIM21 using a co-IP assay. Knockdown or inhibition of HSP90 with its inhibitor 17-AAG accelerated the degradation of TRIM21 by the proteasome in OS cells. CHIP E3 ligase mediated this degradation of TRIM21, with the knockdown of CHIP rescuing the downregulation of TRIM21 induced by 17-AAG. TRIM21 inhibited OS senescence and downregulated the expression of senescence marker p21, while CHIP exhibited an opposite regulatory role on p21 expression., Conclusion: Taken together, our results demonstrated that HSP90 is responsible for the stabilization of TRIM21 in OS and that the CHIP/TRIM21/p21 axis controlled by HSP90 affects the senescence of OS cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: This study aimed to identify biological markers for diabetic nephropathy (DN) and explore their underlying mechanisms., Methods: Four datasets, GSE30528, GSE47183, GSE104948, and GSE96804, were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the "limma" package, and the "RobustRankAggreg" package was used to screen the overlapping DEGs. The hub genes were identified using cytoHubba of Cytoscape. Logistic regression analysis was used to further analyse the hub genes, followed by receiver operating characteristic (ROC) curve analysis to predict the diagnostic effectiveness of the hub genes. Correlation analysis and enrichment analysis of the hub genes were performed to identify the potential functions of the hub genes involved in DN., Results: In total, 55 DEGs, including 38 upregulated and 17 downregulated genes, were identified from the three datasets. Four hub genes ( FN1 , CD44 , C1QB , and C1QA ) were screened out by the "UpSetR" package, and FN1 was identified as a key gene for DN by logistic regression analysis. Correlation analysis and enrichment analysis showed that FN1 was positively correlated with four genes ( COL6A3 , COL1A2 , THBS2 , and CD44 ) and with the development of DN through the extracellular matrix (ECM)-receptor interaction pathway., Conclusions: We identified four candidate genes: FN1 , C1QA , C1QB , and CD44 . On further investigating the biological functions of FN1 , we showed that FN1 was positively correlated with THBS2 , COL1A2 , COL6A3 , and CD44 and involved in the development of DN through the ECM-receptor interaction pathway. THBS2 , COL1A2 , COL6A3 , and CD44 may be novel biomarkers and target therapeutic candidates for DN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Feng, Zhong, Lu, Gao and Zhang.)

RNA-based therapeutics has attracted substantial interest from both academics and pharmaceutical companies. In this study, we investigated the function and the underlying mechanism of Gelsolin (GSN) 3'UTR in NSCLC H1299 and A549 cells. We found that transfected Flag-GSN plasmids significantly increased the proliferation, migration and invasion of NSCLC cells, whereas GSN 3'UTR could suppress the promotional effect of GSN protein on the development of NSCLC in vitro . Interestingly, we observed that these in vitro anticancer effects of GSN 3'UTR was independent of the co-expression with GSN coding sequence. Moreover, transfected GSN 3'UTR affected the actin-cytoskeleton remodeling and epithelial-mesenchymal transition (EMT) processes in H1299 and A549 cells, and targeted the co-expressed proteins to the plasma membrane. Subsequently, RNA pull-down assays have been performed to identify Tra2β protein as a GSN 3'UTR binder. We then showed that Tra2β was important for the localized protein expression mediated by GSN 3'UTR. Taken together, our results suggested that GSN 3'UTR may exert anticancer functions in NSCLC cells through regulating the subcellular localized expression of GSN protein mediated by the interaction between GSN 3'UTR-Tra2β., Competing Interests: None., (AJCR Copyright © 2021.)

Background: Peritonitis is a common complication in which the peritoneum becomes inflamed. Peroxisome proliferator-activated receptor (PPAR)γ agonists and extracellular signal-regulated kinases 1/2 (ERK1/2) inactivation have been found to restore damage caused by lipopolysaccharide-induced (LPS) inflammation. This study aimed to investigate the association between PPARγ and ERK1/2 in LPS-induced inflammation in peritonitis., Methods: Human peritoneal mesothelial cells were maintained in Dulbecco's Modified Eagle Medium and treated with LPS under a series of different concentrations and treatment times. Cellular interleukins-1βeta (IL-1β), cellular interleukins-6 (IL-6), cellular interleukins-12 (IL-12) were measured by enzyme-linked immunosorbent assay (ELISA) assay. Expression or activation of cyclin-dependent kinase (CDK)5, ERK1/2, and PPARγ was detected using quantitative real-time PCR and/or western blot., Results: LPS induced dose- and time-dependent increments in the cellular IL-1β, IL-6, and IL-12 contents, cyclin-dependent kinase 5 (CDK5) expression, and PPARγ Ser273 phosphorylation. Treatment with 1 µg/mL LPS for 12 hours was the optimal experimental design for inflammation stimulation. The concentration of LPS over 1 µg/mL or treatment more than 12 hours reduced the inflammatory status. LPS stimulation also activated ERK1/2 and increased its interaction with CDK5. Further, ERK1/2 inhibition by AZD0364 prevented IL-1β, IL-6, IL-12, and CDK5 expression, as well as activation of ERK1/2 and phosphorylation of PPARγ, induced by LPS. Knockdown of CDK5 using its siRNA caused similar changes as AZD0364, minus ERK1/2 inactivation., Conclusions: Our results suggested that LPS-induced inflammation in human peritoneal mesothelial cells can be partly suppressed by inhibiting the ERK1/2/CDK5/PPARγ axis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-1623). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Few reports have investigated the genetic status of large cell carcinoma (LCC) in Chinese patients under the 2015 World Health Organization (WHO) classification. We aimed to analyze the distribution of druggable driver gene alterations, including mutations in epidermal growth factor receptor ( EGFR) , Kirsten rat sarcoma 2 viral oncogene homolog ( KRAS ), proto-oncogene B-Raf ( BRAF ), and phosphatidylinositol-4,5 biphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) and translocations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase ( EML4-ALK ) and ROS proto-oncogene 1 ( ROS1 ), in a large population of patients with LCC under the 2015 WHO classification, and to assess the clinical outcomes of patients with LCC harboring these genetic alterations., Methods: A cohort of 322 patients with LCC resected between June 2015 and December 2018 was included in this study. The clinical characteristics of the patients and data on the distribution of EGFR , KRAS , BRAF , PIK3CA , EML4-ALK , and ROS1 alterations were retrospectively collected. The disease-free survival (DFS) of patients with LCC was analyzed using the log-rank test., Results: Among the patients with redefined LCC, the proportion of males was much higher than that of females. Detection of LCC was more frequent in patients >60 years of age (71.4%). Mutations of EGFR were found in 3.6% of the LCC participants, predominantly in non-smokers. Mutations in KRAS were observed in 7.8% of the LCC patients, mainly in males and smokers. Mutations in PIK3CA and EML4-ALK translocations comprised 2.1% and 0.52% of the identified alterations, respectively. No alterations were identified in ROS1 and BRAF . After molecular stratification, no significant difference in DFS was identified between wild-type (WT) and mutation groups (29.91±3.83 vs. 25.33±6.04 months, P=0.48)., Conclusions: Under the 2015 WHO criteria, LCC was more frequently detected in elderly male patients with inferior prognoses. The frequency of EGFR and KRAS mutations was found to be the highest. Mutations in EGFR occurred more frequently in non-smokers, whereas KRAS mutations occurred predominantly in males and smokers. The PIK3CA mutations and EML4-ALK translocations were rare in patients with LCC. Our data revealed that the identification of clinically actionable molecular alterations in LCC may help guide personalized cancer treatment decisions in the future., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-1675). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Osteoporosis (OP) is an age-related osteolytic disease and characterized by low bone mass and more prone to fracture due to active osteoclasts. Proliferating cell nuclear antigen (PCNA) has been long identified as a nuclear protein playing critical roles in the regulation of DNA replication and repair. Recently, a few studies have demonstrated the cytoplasmic localization of PCNA and its function associated with apoptosis in neutrophil and neuroblastoma cells. However, the involvement of PCNA, including the cytoplasmic PCNA, in the osteoclast differentiation remains unclear. In the present study, we show that PCNA is translocated from nucleus to cytoplasm during the RANKL-induced osteoclast differentiation, and localized in the actin belt of mature osteoclast. Knockdown of PCNA significantly affected the integrity of actin belt, the formation of multinucleated osteoclasts, the expression of osteoclast-specific genes, and the in vitro bone resorption. Interactomic study has revealed β-actin as the major interacting partner of the cytoplasmic PCNA, suggesting that cytoplasmic PCNA might play a critical role in the differentiation of osteoclast through regulation of actin-cytoskeleton remodeling. Taken together, our results demonstrate the critical role of cytoplasmic PCNA during the process of osteoclast differentiation, and provided a potential therapeutic target for treatment of osteoclast-related bone diseases.

We show that a non-Markovian behavior can appear in a type of Markovian multimeric channel. Such a channel consists of N independent subunits, and each subunit has at least one open state and more than one closed state. Suppose the open state of the channel is defined as M out of N subunits in the open state with N>M>0. We show that, although the gating dynamics for each subunit between open and closed states is Markovian, the channel can show a memory behavior of weak anti-cross-correlation between the adjacent open and closed durations. Our study indicates that a non-Markovian binary time series can be obtained from a linear superposition of some independent channel subunits with Markovian gating dynamics.

As an important intracellular signal, Ca^{2+} ions control diverse cellular functions. In this paper, we discuss the Ca^{2+} signaling with a two-dimensional model in which the inositol 1,4,5-trisphosphate (IP_{3}) receptor channels are distributed in clusters on the endoplasmic reticulum membrane. The wave failure at large Ca^{2+} diffusion coupling is discussed in detail in the model. We show that with varying model parameters the wave failure is a robust behavior with either deterministic or stochastic channel dynamics. We suggest that the wave failure should be a general behavior in inhomogeneous diffusing systems with clustered excitable regions and may occur in biological Ca^{2+} signaling systems.