Inhibitory role of bone marrow mesenchymal stem cells-derived exosome in non-small-cell lung cancer: microRNA-30b-5p, EZH2 and PI3K/AKT pathway.

Exosomal microRNA (miRNA) exerts potential roles in non-small-cell lung cancer (NSCLC). The current study elucidated the role of miR-30b-5p shuttled by bone marrow mesenchymal stem cells (BMSCs)-derived exosomes in treating NSCLC. Bioinformatics analysis was performed with NSCLC-related miRNA microarray GSE169587 and mRNA data GSE74706 obtained for collection of the differentially expressed miRNAs and mRNAs. The relationship between miR-30b-5p and EZH2 was predicted and confirmed. Exosomes were isolated from BMSCs and identified. BMSCs-derived exosomes overexpressing miR-30b-5p were used to establish subcutaneous tumorigenesis models to study the effects of miR-30b-5p, EZH2 and PI3K/AKT signalling pathway on tumour growth. A total of 86 BMSC-exo-miRNAs were differentially expressed in NSCLC. Bioinfomatics analysis found that BMSC-exo-miR-30b-5p could regulate NSCLC progression by targeting EZH2, which was verified by in vitro cell experiments. Besides, the target genes of miR-30b-5p were enriched in PI3K/AKT signalling pathway. Animal experiments validated that BMSC-exo-miR-30b-5p promoted NSCLC cell apoptosis and prevented tumorigenesis in nude mice via EZH2/PI3K/AKT axis. Collectively, the inhibitory role of BMSC-derived exosomes-loaded miR-30b-5p in NSCLC was achieved through blocking the EZH2/PI3K/AKT axis.

A review of natural plant extracts in beverages: Extraction process, nutritional function, and safety evaluation.

The demand for foods and beverages with therapeutic and functional features has increased as a result of rising consumer awareness of health and wellness. In natural, plants are abundant, widespread, and inexpensive, in addition to being rich in bioactive components that are beneficial to health. The bioactive substances contained in plants include polyphenols, polysaccharides, flavonoids, aromatics, aliphatics, terpenoids, etc., which have rich active functions and application potential for plant-based beverages. In this review, various existing extraction processes and their advantages and disadvantages are introduced. The antioxidant, anti-inflammatory, intestinal flora regulation, metabolism regulation, and nerve protection effects of plant beverages are described. The biotoxicity and sensory properties of plant-based beverages are also summarized. With the diversification of the food industry and commerce, plant-based beverages may become a promising new category of health functional foods in our daily lives.

PTPN2 copper-sensing rapidly relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression.

Fluxes in human intra- and extracellular copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate (cAMP). We herein applied an unbiased temporal evaluation of the whole-genome transcriptional activities modulated by fluctuations in copper levels to identify the copper sensor proteins responsible for driving these activities. We found that fluctuations in physiologically-relevant copper levels rapidly modulate EGFR/MAPK/ERK signal transduction and activation of the transcription factor cAMP response element-binding protein (CREB). Both intracellular and extracellular assays support Cu 1+ inhibition of the EGFR-phosphatase PTPN2 (and potentially the homologous PTPN1)-via direct ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism of copper-stimulated EGFR signal transduction activation. Depletion of copper represses this signaling pathway. We additionally show i ) copper supplementation drives transcriptional repression of the copper importer CTR1 and ii ) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper-stimulated MAPK/ERK/CREB-signaling and CTR1 expression, thereby uncovering a previously unrecognized link between copper levels and cellular signal transduction.

Physical activity, screen time and body composition in 13-year-old adolescents: The Generation R Study.

BACKGROUND: Body composition between prepubertal children and adolescents varies, and it is unclear how physical activity and sedentary behaviour affect adolescent body composition. OBJECTIVES: This study aimed to examine the associations of physical activity and screen time with overall and specific fat depots in the general adolescent population. METHODS: In a population-based prospective cohort study, among 3258 adolescents aged 13 years, physical activity and screen time were assessed via self-report questionnaires. Body mass index, dual-energy X-ray absorptiometry-based measures (i.e. fat mass and lean body mass) and magnetic resonance imaging-based measures (i.e. abdominal subcutaneous and visceral fat mass) were obtained. RESULTS: After adjusting for social-demographic and growth-related factors, each additional hour of daily physical activity was associated with lower fat mass, abdominal visceral fat mass and higher lean body mass (all p < 0.05). However, these associations were not observed in the longitudinal analyses. Each additional hour of daily screen time was associated with higher body mass index, fat mass, abdominal subcutaneous and visceral fat mass (all p < 0.05), which were consistent with the longitudinal analyses. CONCLUSION: Adolescents with higher physical activity and lower screen time had lower levels of adiposity both at the general and visceral levels.

Protective effect of carbon dots derived from scrambled Coptidis Rhizoma against ulcerative colitis in mice.

Introduction: Ulcerative colitis (UC) is a chronic and progressive inflammatory disease of the intestines. The primary symptoms, such as bloody diarrhea, can result in weight loss and significantly diminish the patient's quality of life. Despite considerable research endeavors, this disease remains incurable. The scrambled Coptidis Rhizoma (SCR) has a rich historical background in traditional Chinese medicine as a remedy for UC. Drawing from a wealth of substantial clinical practices, this study is focused on investigating the protective effects and underlying mechanisms of the active component of SCR, namely SCR-based carbon dots (SCR-CDs), in the treatment of UC. Methods: SCR-CDs were extracted and isolated from the decoction of SCR, followed by a comprehensive characterization of their morphological structure and functional groups. Subsequently, we investigated the effects of SCR-CDs on parameters such as colonic length, disease activity index, and histopathological architecture using the dextran sulfate sodium (DSS)-induced colitis mice model. Furthermore, we delved into the assessment of key aspects, including the expression of intestinal tight junction (TJ) proteins, inflammatory cytokines, oxidative stress markers, and gut microbial composition, to unravel the intricate mechanisms underpinning their therapeutic effects. Results: SCR-CDs displayed a consistent spherical morphology, featuring uniform dispersion and diameters ranging from 1.2 to 2.8 nm. These SCR-CDs also exhibited a diverse array of surface chemical functional groups. Importantly, the administration of SCR-CDs, particularly at higher dosage levels, exerted a noteworthy preventive influence on colonic shortening, elevation of the disease activity index and colonic tissue impairment caused by DSS. These observed effects may be closely associated with the hygroscopic capability and hemostatic bioactivity inherent to SCR-CDs. Concurrently, the application of SCR-CDs manifested an augmenting impact on the expression of intestinal TJ proteins, concomitantly leading to a significant reduction in inflammatory cell infiltration and amelioration of oxidative stress. Additionally, SCR-CDs treatment facilitated the restoration of perturbed gut microbial composition, potentially serving as a fundamental mechanism underlying their observed protective effects. Conclusion: This study demonstrates the significant therapeutic potential of SCR-CDs in UC and provides elucidation on some of their mechanisms. Furthermore, these findings hold paramount importance in guiding innovative drug discovery for anti-UC agents.

EXOSC10 is a novel hepatocellular carcinoma prognostic biomarker: a comprehensive bioinformatics analysis and experiment verification.

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor. There are few studies on EXOSC10 (exosome component 10) in HCC; however, the importance of EXOSC10 for HCC remains unclear. Methods: In the study, the prognosis value of EXOSC10 and the immune correlation were explored by bioinformatics. The expression of EXOSC10 was verified by tissue samples from clinical patients and in vitro experiment (liver cancer cell lines HepG2, MHCC97H and Huh-7; normal human liver cell line LO2). Immunohistochemistry (IHC) was used to detect EXOSC10 protein expression in clinical tissue from HCC. Huh-7 cells with siEXOSC10 were constructed using lipofectamine 3000. Cell counting kit 8 (CCK-8) and colony formation were used to test cell proliferation. The wound healing and transwell were used to analyze the cell migration capacity. Mitochondrial membrane potential, Hoechst 33342 dye, and flow cytometer were used to detect the change in cell apoptosis, respectively. Differential expression genes (DEGs) analysis and gene set enrichment analysis (GSEA) were used to investigate the potential mechanism of EXOSC10 and were verified by western blotting. Results: EXOSC10 was highly expressed in tissues from patients with HCC and was an independent prognostic factor for overall survival (OS) in HCC. Increased expression of EXOSC10 was significantly related to histological grade, T stage, and pathological stage. Multivariate analysis indicated that the high expression level of EXOSC10 was correlated with poor overall survival (OS) in HCC. GO and GSEA analysis showed enrichment of the cell cycle and p53-related signaling pathway. Immune analysis showed that EXOSC10 expression was a significant positive correlation with immune infiltration in HCC. In vitro experiments, cell proliferation and migration were inhibited by the elimination of EXOSC10. Furthermore, the elimination of EXOSC10 induced cell apoptosis, suppressed PARP, N-cadherin and Bcl-2 protein expression levels, while increasing Bax, p21, p53, p-p53, and E-cadherin protein expression levels. Conclusions: EXOSC10 had a predictive value for the prognosis of HCC and may regulate the progression of HCC through the p53-related signaling pathway.

Gut microbiota dysbiosis characterized by abnormal elevation of Lactobacillus in patients with immune-mediated necrotizing myopathy.

Aim: The gut microbiota plays an important role in human health. In this study, we aimed to investigate whether and how gut microbiota communities are altered in patients with immune-mediated necrotizing myopathy (IMNM) and provide new ideas to further explore the pathogenesis of IMNM or screen for its clinical therapeutic targets in the future. Methods: The gut microbiota collected from 19 IMNM patients and 23 healthy controls (HCs) were examined by using 16S rRNA gene sequencing. Alpha and beta-diversity analyses were applied to examine the bacterial diversity and community structure. Welch's t test was performed to identify the significantly abundant taxa of bacteria between the two groups. Spearman correlation analysis was performed to analyze the correlation between gut microbiota and clinical indicators. A receiver operator characteristic (ROC) curve was used to reflect the sensitivity and specificity of microbial biomarker prediction of IMNM disease. P < 0.05 was considered statistically significant. Results: Nineteen IMNM patients and 23 HCs were included in the analysis. Among IMNM patients, 94.74% (18/19) of them used glucocorticoids, while 57.89% (11/19) of them used disease-modifying antirheumatic drugs (DMARDs), and the disease was accessed by MITAX (18.26 ± 8.62) and MYOACT (20.68 ± 8.65) scores. Participants in the groups were matched for gender and age. The diversity of the gut microbiota of IMNM patients differed and decreased compared to that of HCs (Chao1, Shannon, and Simpson indexes: p < 0.05). In IMNM patients, the relative abundances of Bacteroides, Roseburia, and Coprococcus were decreased, while that of Lactobacillus and Streptococcus were relatively increased. Furthermore, in IMNM patients, Lactobacillus was positively correlated with the levels of anti-signal recognition particle (SRP) antibodies, anti-Ro52 antibodies, and erythrocyte sedimentation rate (ESR), while Streptococcus was positively correlated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies and C-reactive protein (CRP). Roseburia was negatively correlated with myoglobin (MYO), cardiac troponin T (cTnT), ESR, CRP, and the occurrence of interstitial lung disease (ILD). Bacteroides was negatively correlated with ESR and CRP, and Coprococcus was negatively correlated with ESR. Finally, the prediction model was built using the top five differential genera, which was verified using a ROC curve (area under the curve (AUC): 87%, 95% confidence interval: 73%-100%). Conclusion: We observed a characteristic compositional change in the gut microbiota with an abnormal elevation of Lactobacillus in IMNM patients, which was accompanied by changes in clinical indicators. This suggests that gut microbiota dysbiosis occurs in IMNM patients and is correlated with systemic autoimmune features.

Tuning 3D refractive indices via constrained uniaxial stretch in cellulose triacetate films plasticized with triethyl citrate.

Tuning 3D refractive indices of polymers is urgently needed for optical films, but it is quite challenging. Here, we proposed a simple constrained uniaxial stretch method that successfully tuned the 3D refractive indices in cellulose triacetate (TAC) films plasticized with triethyl citrate (TEC). Our results suggest that, under constrained uniaxial stretch, the main chains and side groups prefer to orientate in the stretch direction and the constrained direction, respectively. Such a unique chain arrangement differentiates the refractive indices in three directions of the film. The branched small molecule TEC is also crucial for tuning refractive indices, which promotes chain activity and enhances the chain orientation under stretching, leading to a considerable change in refractive indices before samples fracture. The polymer film we fabricated possesses a direction-dependent optical performance, where the refractive index in the film thickness direction is between that of the stretch direction and constrained direction. This work provides a fundamental understanding on the chain structure and optical performance of polymer films. The constrained uniaxial stretch method, in general, should also be applicable to tuning other 3D physical properties through tuning the direction-dependent orientation of polymers.

Progress on Single-Atom Photocatalysts for H2 Generation: Material Design, Catalytic Mechanism, and Perspectives.

Solar energy utilization is of great significance to current challenges of the energy crisis and environmental pollution, which benefit the development of the global community to achieve carbon neutrality goals. Hydrogen energy is also treated as a good candidate for future energy supply since its combustion not only supplies high-density energy but also shows no pollution gas. In particular, photocatalytic water splitting has attracted increasing research as a promising method for H2 production. Recently, single-atom (SA) photocatalysts have been proposed as a potential solution to improve catalytic efficiency and lower the costs of photocatalytic water splitting for H2 generation. Owing to the maximized atom utilization rate, abundant surface active sites, and tunable coordination environment, SA photocatalysts have achieved significant progress. This review reviews developments of advanced SA photocatalysts for H2 generation regarding the different support materials. The recent progress of titanium dioxide, metal-organic frameworks, two-dimensional carbon materials, and red phosphorus supported SA photocatalysts are carefully discussed. In particular, the material designs, reaction mechanisms, modulation strategies, and perspectives are highlighted for realizing improved solar-to-energy efficiency and H2 generation rate. This work will supply significant references for future design and synthesis of advanced SA photocatalysts.

Differences between migrasome, a 'new organelle', and exosome.

The migrasome is a new organelle discovered by Professor Yu Li in 2015. When cells migrate, the membranous organelles that appear at the end of the retraction fibres are migrasomes. With the migration of cells, the retraction fibres which connect migrasomes and cells finally break. The migrasomes detach from the cell and are released into the extracellular space or directly absorbed by the recipient cell. The cytoplasmic contents are first transported to the migrasome and then released from the cell through the migrasome. This release mechanism, which depends on cell migration, is named 'migracytosis'. The main components of the migrasome are extracellular vesicles after they leave the cell, which are easy to remind people of the current hot topic of exosomes. Exosomes are extracellular vesicles wrapped by the lipid bimolecular layer. With extensive research, exosomes have solved many disease problems. This review summarizes the differences between migrasomes and exosomes in size, composition, property and function, extraction method and regulation mechanism for generation and release. At the same time, it also prospects for the current hotspot of migrasomes, hoping to provide literature support for further research on the generation and release mechanism of migrasomes and their clinical application in the future.

Single-cell transcriptome analysis and protein profiling reveal broad immune system activation in IgG4-related disease.

IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with unclear pathogenesis. We performed single-cell RNA-seq and surface proteome analyses on 61,379 PBMCs from 9 treatment-naive IgG4-RD patients and 7 age- and sex-matched healthy controls. Integrative analyses were performed for altered gene expression in IgG4-RD, and flow cytometry and immunofluorescence were used for validation. We observed expansion of plasmablasts with enhanced protein processing and activation, which correlated with the number of involved organs in IgG4-RD. Increased proportions of CD4+ cytotoxic T lymphocytes (CTLs), CD8+ CTLs-GNLY (granulysin), and γδT cells with enhanced chemotaxis and cytotoxicity but with suppressed inhibitory receptors characterize IgG4-RD. Prominent infiltration of lymphocytes with distinct compositions were found in different organs of IgG4-RD patients. Transcription factors (TFs), including PRDM1/XBP1 and RUNX3, were upregulated in IgG4-RD, promoting the differentiation of plasmablasts and CTLs, respectively. Monocytes in IgG4-RD have stronger expression of genes related to cell adhesion and chemotaxis, which may give rise to profibrotic macrophages in lesions. The gene activation pattern in peripheral immune cells indicated activation of multiple interaction pathways between cell types, in part through chemokines or growth factors and their receptors. Specific upregulation of TFs and expansion of plasmablasts and CTLs may be involved in the pathogenesis of IgG4-RD, and each of these populations are candidate targets for therapeutic interventions in this disease.

Anomaly prediction of CT equipment based on IoMT data.

BACKGROUND: Large-scale medical equipment, which is extensively implemented in medical services, is of vital importance for diagnosis but vulnerable to various anomalies and failures. Most hospitals that conduct regular maintenance have been suffering from medical equipment-related incidents for years. Currently, the Internet of Medical Things (IoMT) has emerged as a crucial tool in monitoring the real-time status of the medical equipment. In this paper, we develop an IoMT system of Computed Tomography (CT) equipment in the West China Hospital, Sichuan University and collected the system status time-series data. Novel multivariate time-series classification models and frameworks are proposed to predict the anomalies of CT equipment. The important features that are closely related to the equipment anomalies are identified with the model. METHODS: We extracted the real-time CT equipment status time-series data of 11 equipment between May 19, 2020 and May 19, 2021 from the IoMT, which includes the equipment oil temperature, anode voltage, etc. The arcs are identified as labels of anomalies due to their relationship with decreased imaging quality and CT equipment failures. To improve prediction accuracy, the statistics and transformations of the raw historical time-series data segment in the sliding time window are used to construct new features. Due to the particularity of time-series data, two frameworks are proposed for splitting the training and test sets. Then the Decision Tree, Support Vector Machine, Logistic Regression, Naive Bayesian, and K-Nearest Neighbor classification models are used to classify the system status. We also compare our model to state-of-the-art models. RESULTS: The results show that the anomaly prediction accuracy and recall of our method are 79% and 77%, respectively. The oil temperature and anode voltage are identified as the decisive features that may lead to anomalies. The proposed model outperforms the others when predicting the anomalies of the CT equipment based on our dataset. CONCLUSIONS: The proposed method could predict the state of CT equipment and be used as a reference for practical maintenance, where unexpected anomalies of medical equipment could be reduced. It also brings new insights into how to handle non-uniform and imbalanced time series data in practical cases.

A weighted cranial diffusion-weighted imaging scale for Wilson's disease.

Objectives: Cranial magnetic resonance imaging (MRI) could be a crucial tool for the assessment for neurological symptoms in patients with Wilson's disease (WD). Diffusion-weighted imaging (DWI) hyperintensity reflects the acute brain injuries, which mainly occur in specific brain regions. Therefore, this study aimed to develop a weighted cranial DWI scale for patients with WD, with special focus on specific brain regions. Materials and methods: In total, 123 patients with WD were enrolled, 118 of whom underwent 1.5 T-MRI on admission. The imaging score was calculated as described previously and depended on the following sequences: one point was acquired when abnormal intensity occurred in the T1, T2, and fluid-attenuation inversion recovery sequences, and two points were acquired when DWI hyperintensity were found. Consensus weighting was conducted based on the symptoms and response to treatment. Results: Intra-rater agreement were good (r = 0.855 [0.798-0.897], p < 0.0001). DWI hyperintensity in the putamen was a high-risk factor for deterioration during de-copper therapy (OR = 8.656, p < 0.05). The high-risk factors for readmission for intravenous de-copper therapies were DWI hyperintensity in the midbrain (OR = 3.818, p < 0.05) and the corpus callosum (OR = 2.654, p < 0.05). Both scoring systems had positive correlation with UWDRS scale (original semi-quantitative scoring system, r = 0.35, p < 0.001; consensus semi-quantitative scoring system, r = 0.351, p < 0.001.). Compared to the original scoring system, the consensus scoring system had higher correlations with the occurrence of deterioration (OR = 1.052, 95%CI [1.003, 1.0103], p < 0.05) and readmission for intravenous de-copper therapy (OR = 1.043, 95%CI [1.001, 1.086], p < 0.05). Conclusion: The predictive performance of the consensus semi-quantitative scoring system for cranial MRI was improved to guide medication, healthcare management, and prognosis prediction in patients with WD. For every point increase in the neuroimaging score, the risk of exacerbations during treatment increased by 5.2%, and the risk of readmission to the hospital within 6 months increased by 4.3%.

Case Report: Replacement of PD-1 inhibitors with PD-L1 inhibitors in the treatment of squamous non-small-cell lung carcinoma.

Background: Immune checkpoint inhibitor (ICI)-associated cardiotoxicity is a relatively uncommon immune-related adverse effects (irAEs) with a high mortality rate. There are few recommendations for the replacement of different immune checkpoint inhibitors in domestic and international reports. Case presentation: We report a case of a patient with squamous non-small cell lung carcinoma (squamous NSCLC) who developed cardiotoxicity after being treated with a programmed death-1 (PD-1) inhibitor and then changed to a PD-L1 inhibitor to continue the treatment. A significant benefit was observed after four cycles of immunotherapy, and no further cardiotoxicity occurred after the treatment was started. Conclusion: This case demonstrates that myocardial damage induced by tislelizumab (PD-1 inhibitor) can be improved after switching to sugemalimab (PD-L1 inhibitor) and that antitumor immunotherapy is effective. This result may have important implications for optimizing immunotherapy management regimens in cancer patients.

Efficacy and safety of atropine at different concentrations in prevention of myopia progression in Asian children: a systematic review and Meta-analysis of randomized clinical trials.

AIM: To assess the efficacy versus the adverse effects of various concentrations of atropine in the prevention of myopia in Asian children. METHODS: Databases (PubMed, EMBASE, the Cochrane Library and Web of science) were comprehensively searched from inception to April 2022. Types of studies included were randomized clinical trials (RCTs). The published languages were limited to English. Two researchers assessed the quality of included studies independently using Cochrane risk of bias tool based on the Cochrane Handbook for Systematic Reviews of Interventions. Funnel plots and Egger's test were used for detection of publication bias. Meta-analyses were conducted using STATA (version 15.0; StataCorp). RESULTS: A total of 15 RCTs involving 2268 patients were included in the study. In the atropine group, spherical equivalent progressed at a significantly lower rate [weighted mean difference (WMD)=0.39, 95% confidence interval (CI): 0.23, 0.54] than in the control group. A WMD of 0.15 mm was associated with less axial elongation (95%CI -0.19, -0.10). Different doses showed statistically significant differences (P<0.05) and an improved effect could result from a higher concentration. Changes in photopic pupil size and mesopic pupil size in atropine group is 0.70 mm (95%CI: 0.33, 1.06) and 0.38 mm (95%CI: 0.22, 0.54) more than the control group. In the present Meta-analysis, no changes in accommodative amplitude (AA) were associated with atropine administration. Atropine administration increased the risk of adverse effects by 1.37 times. CONCLUSION: Concentrations of less than 1% atropine are able to effectively retard diopter and axis growth of myopia in Asian children in a dose-dependent manner. Meanwhile, it caused pupil enlargement, but induced no change in the AA within this range. Further study is required to determine the dosage needed to achieve maximum efficacy and minimal side effects.

Promoting neurite outgrowth and neural stem cell migration using aligned nanofibers decorated with protrusions and galectin-1 coating.

Biomaterials integrated with both topological cues and biological modifications are urgently needed in regenerative medicine. Here, aligned nanofibrous scaffolds decorated with nanoscale SiO2 protrusions and galectin-1 coating are reported. Prospects in neurite outgrowth and neural stem cell migration are discussed for suitable use in neural tissue engineering.

Bioimaging of a chromenoquinoline-based ratiometric fluorescent probe for detecting ClO.

Hypochlorous acid (HClO) is a reactive oxygen species and a relatively strong antibacterial substance in the immune defense system. The normal concentration of HClO in the human body is approximately 200 µM, and its high concentration can cause tissue damage and some diseases. Herein, a chromenoquinoline-based ratiometric fluorescent probe was developed to detect and quantify HClO. The developed Probe 1 exhibited the advantages of large Stokes shift (137 nm), high synthetic yield (84.7 %), simple synthesis method, short response time (<4 min), low detection limit (5.1 nM), and low toxicity. The probe was successfully validated in live cells and zebrafish.

RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

On four epibiotic peritrichous ciliates (Protozoa, Ciliophora) found in Lake Weishan Wetland: morphological and molecular data support the establishment of a new genus, Parapiosoma gen. nov., and two new species.

During a study on the diversity of ciliated protists in Lake Weishan Wetland, the largest wetland in northern China, four epibiotic sessilid peritrichs were isolated from aquatic host animals. Two of them, i.e., Epistylis cambari Kellicott, 1885 and Epistylis lwoffi Fauré-Fremiet, 1943, were known species whereas the other two, i.e., Parapiosoma typicum gen. nov., sp. nov. and Orborhabdostyla gracilis sp. nov., are new to science. The new genus Parapiosoma gen. nov. is characterized by its branched non-contractile stalk, everted peristomial lip, obconical macronucleus and transverse silverlines. Two species are assigned to the new genus, namely Parapiosoma typicum sp. nov. and Parapiosoma gasterostei (Fauré-Fremiet, 1905) comb. nov. Morphologically, P. typicum sp. nov. is recognized by its goblet-shaped zooids, single-layered peristomial lip, dichotomously branched stalk, and infundibular polykinety 3 (P3) containing three equal-length rows. Orborhabdostyla gracilis sp. nov. is characterized by its slender zooid, curved macronucleus, and three equal-length rows in infundibular P3. Improved diagnoses and redescriptions of E. cambari and E. lwoffi are provided including, for the first time, data on the ciliature of E. cambari. Phylogenetic analyses based on SSU rDNA, ITS1-5.8S rDNA -ITS2, and LSU rDNA sequence data strongly support the assertion that the family Epistylididae comprises morphospecies with different evolutionary lineages and indicate that Parapiosoma gen. nov. may represent a new taxon at family level.

Design, Synthesis and Biological Evaluation of Novel PEG-Rakicidin B1 Hybrid as Clostridium difficile (CD) Targeted Anti-Bacterial Agent.

Rakicidin B1 was isolated and purified from the culture broth of a marine Streptomyces sp. as a potent anti-cancer agent, and lately the compound and its derivatives have firstly been found to possess anti-Clostridium difficile (CD) activity but with high cytotoxicity. Herein, following our previous discovery on anti-CD activity of Rakicidin B1, structure modification was performed at the OH position of Rakicidin B1 and a new Rakicidin B1-PEG hybrids FIMP2 was facilely designed and synthesized by conjugating the PEG2000 with the scaffolds of Rakicidin B1 via the linkage of carbamate. The cytotoxicity of the FIMP2 was first evaluated against three different cancer cell lines, including HCT-8 cells, PANC-1, and Caco-2, with IC50 values at 0.519 µM, 0.815 µM, and 0.586 µM, respectively. Obviously, as compared with a positive control group treated with Rakicidin B1, the IC50 value of FIMP2 increased by nearly 91-fold, 50-fold, and 67-fold, suggesting that the PEGylation strategy significantly reduced the cytotoxicity of FIMP2. Thus, this preliminary result may be beneficial to increase its safety index (SI) value due to the decreased cytotoxicity of FIMP2. In addition, this decreased cytotoxicity of FIMP2 was further confirmed based on a zebrafish screening model in vivo. Thereafter, the anti-CD activity of FIMP2 was evaluated in vivo, and its efficacy to treat CDI was found to be better than that of vancomycin. The mortality and recurrence rate of FIMP2 is not as low compared with that of vancomycin; these results demonstrated that compound FIMP2 is a new, promising anti-CD agent with significant efficacy against CD recurrence with low cytotoxicity towards bodies.