miR-133a and miR-135a Regulate All-Trans Retinoic Acid-Mediated Differentiation in Pediatric Acute Myeloid Leukemia by Inhibiting CDX2 Translation and Serve as Prognostic Biomarkers.

Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.

Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level.

Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.

Establishment and Verification of an Artificial Intelligence Prediction Model for Children With Sepsis.

BACKGROUND: Early identification of high-risk groups of children with sepsis is beneficial to reduce sepsis mortality. This article used artificial intelligence (AI) technology to predict the risk of death effectively and quickly in children with sepsis in the pediatric intensive care unit (PICU). STUDY DESIGN: This retrospective observational study was conducted in the PICUs of the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2019 and Shenzhen Children's Hospital from January 2019 to July 2020. The children were divided into a death group and a survival group. Different machine language (ML) models were used to predict the risk of death in children with sepsis. RESULTS: A total of 671 children with sepsis were enrolled. The accuracy (ACC) of the artificial neural network model was better than that of support vector machine, logical regression analysis, Bayesian, K nearest neighbor method and decision tree models, with a training set ACC of 0.99 and a test set ACC of 0.96. CONCLUSIONS: The AI model can be used to predict the risk of death due to sepsis in children in the PICU, and the artificial neural network model is better than other AI models in predicting mortality risk.

Innexin hemichannel activation by Microplitis bicoloratus ecSOD monopolymer reduces ROS.

The extracellular superoxide dismutases (ecSODs) secreted by Microplitis bicoloratus reduce the reactive oxygen species (ROS) stimulated by the Microplitis bicoloratus bracovirus. Here, we demonstrate that the bacterial transferase hexapeptide (hexapep) motif and bacterial-immunoglobulin-like (BIg-like) domain of ecSODs bind to the cell membrane and transiently open hemichannels, facilitating ROS reductions. RNAi-mediated ecSOD silencing in vivo elevated ROS in host hemocytes, impairing parasitoid larva development. In vitro, the ecSOD-monopolymer needed to be membrane bound to open hemichannels. Furthermore, the hexapep motif in the beta-sandwich of ecSOD49 and ecSOD58, and BIg-like domain in the signal peptides of ecSOD67 were required for cell membrane binding. Hexapep motif and BIg-like domain deletions induced ecSODs loss of adhesion and ROS reduction failure. The hexapep motif and BIg-like domain mediated ecSOD binding via upregulating innexins and stabilizing the opened hemichannels. Our findings reveal a mechanism through which ecSOD reduces ROS, which may aid in developing anti-redox therapy.

Regulation of muscle hypertrophy through granulin: Relayed communication among mesenchymal progenitors, macrophages, and satellite cells.

Skeletal muscles exert remarkable regenerative or adaptive capacities in response to injuries or mechanical loads. However, the cellular networks underlying muscle adaptation are poorly understood compared to those underlying muscle regeneration. We employed single-cell RNA sequencing to investigate the gene expression patterns and cellular networks activated in overloaded muscles and compared these results with those observed in regenerating muscles. The cellular composition of the 4-day overloaded muscle, when macrophage infiltration peaked, closely resembled that of the 10-day regenerating muscle. In addition to the mesenchymal progenitor-muscle satellite cell (MuSC) axis, interactome analyses or targeted depletion experiments revealed communications between mesenchymal progenitors-macrophages and macrophages-MuSCs. Furthermore, granulin, a macrophage-derived factor, inhibited MuSC differentiation, and Granulin-knockout mice exhibited blunted muscle hypertrophy due to the premature differentiation of overloaded MuSCs. These findings reveal the critical role of granulin through the relayed communications of mesenchymal progenitors, macrophages, and MuSCs in facilitating efficient muscle hypertrophy.

LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways.

Excessive inflammatory response and increased oxidative stress play an essential role in the pathophysiology of ischemia/reperfusion (I/R)-induced acute kidney injury (IRI-AKI). Emerging evidence suggests that lipoxin A4 (LXA4), as an endogenous negative regulator in inflammation, can ameliorate several I/R injuries. However, the mechanisms and effects of LXA4 on IRI-AKI remain unknown. In this study, A bilateral renal I/R mouse model was used to evaluate the role of LXA4 in wild-type, IRG1 knockout, and IRAK-M knockout mice. Our results showed that LXA4, as well as 5-LOX and ALXR, were quickly induced, and subsequently decreased by renal I/R. LXA4 pretreatment improved renal I/R-induced renal function impairment and renal damage and inhibited inflammatory responses and oxidative stresses in mice kidneys. Notably, LXA4 inhibited I/R-induced the activation of TLR4 signal pathway including decreased phosphorylation of TAK1, p36, and p65, but did not affect TLR4 and p-IRAK-1. The analysis of transcriptomic sequencing data and immunoblotting suggested that innate immune signal molecules interleukin-1 receptor-associated kinase-M (IRAK-M) and immunoresponsive gene 1 (IRG1) might be the key targets of LXA4. Further, the knockout of IRG1 or IRAK-M abolished the beneficial effects of LXA4 on IRI-AKI. In addition, IRG1 deficiency reversed the up-regulation of IRAK-M by LXA4, while IRAK-M knockout had no impact on the IRG1 expression, indicating that IRAK-M is a downstream molecule of IRG1. Mechanistically, we found that LXA4-promoted IRG1-itaconate not only enhanced Nrf2 activation and increased HO-1 and NQO1, but also upregulated IRAK-M, which interacted with TRAF6 by competing with IRAK-1, resulting in deactivation of TLR4 downstream signal in IRI-AKI. These data suggested that LXA4 protected against IRI-AKI via promoting IRG1/Itaconate-Nrf2 and IRAK-M-TRAF6 signaling pathways, providing the rationale for a novel strategy for preventing and treating IRI-AKI.

Biodegradation of phenolic pollutants and bioaugmentation strategies: A review of current knowledge and future perspectives.

The widespread use of phenolic compounds renders their occurrence in various environmental matrices, posing ecological risks especially the endocrine disruption effects. Biodegradation-based techniques are efficient and cost-effective in degrading phenolic pollutants with less production of secondary pollution. This review focuses on phenol, 4-nonylphenol, 4-nitrophenol, bisphenol A and tetrabromobisphenol A as the representatives, and summarizes the current knowledge and future perspectives of their biodegradation and the enhancement strategy of bioaugmentation. Biodegradation and isolation of degrading microorganisms were mainly investigated under oxic conditions, where phenolic pollutants are typically hydroxylated to 4-hydroxybenzoate or hydroquinone prior to ring opening. Bioaugmentation efficiencies of phenolic pollutants significantly vary under different application conditions (e.g., increased degradation by 10-95% in soil and sediment). To optimize degradation of phenolic pollutants in different matrices, the factors that influence biodegradation capacity of microorganisms and performance of bioaugmentation are discussed. The use of immobilization strategy, indigenous degrading bacteria, and highly competent exogenous bacteria are proposed to facilitate the bioaugmentation process. Further studies are suggested to illustrate 1) biodegradation of phenolic pollutants under anoxic conditions, 2) application of microbial consortia with synergistic effects for phenolic pollutant degradation, and 3) assessment on the uncertain ecological risks associated with bioaugmentation, resulting from changes in degradation pathway of phenolic pollutants and alterations in structure and function of indigenous microbial community.

Treatment of erythematous acne scars using 595-nm pulsed dye laser combined with 1565-nm ResurFX nonablative fractional laser.

BACKGROUND: Acne vulgaris is a common inflammatory disease associated with various sequelae after skin lesion remission. Acne erythema has been considered simple erythema or a vascular lesion; however, because the understanding of this disease has improved, acne erythema is currently considered an early scar with erythematous components. AIMS: This study evaluated the efficacy of using both a 595-nm pulsed dye laser (PDL) and 1565-nm nonablative fractional laser (NAFL) for the treatment of erythematous scars caused by acne. METHODS: Ninety patients with acne scars were equally randomized to two groups. Group A (n = 45) received treatment with the NAFL. Group B (n = 45) received treatment with the PDL and NAFL. Each patient underwent one treatment session and 4 weeks of follow-up. RESULTS: Qualitative (χ2 = 12.415; p < 0.05) and quantitative (t = 2.675; p < 0.05) scores of Groups A and B were determined using a global scarring grading system and exhibited statistically significant differences. The quantitative score of Group A was higher than that of Group B (6.67 ± 3.46 vs. 4.98 ± 2.44). The erythema areas of the groups differed significantly after treatment, with Group B exhibiting more notable score improvements (5.00 [3.10, 7.10] vs. 2.80 [1.65, 4.60]; Z = 3.072; p < 0.05). The erythema regression rate of Group B (88.9%) was significantly higher than that of Group A (66.7%) (χ2 = 20.295; p < 0.001). Adverse events, including redness and swelling (86.6%), scabbing (78.8%), and purpura (36.6%), occurred within 7 days for 86.6% of patients. CONCLUSIONS: The combined use of the PDL and NAFL is safe and effective for erythematous acne scars.

Piperine attenuates hepatic ischemia/reperfusion injury via suppressing the TLR4 signaling cascade in mice.

Piperine, the major active substance in black pepper, has been shown to have anti-inflammatory and antioxidant effects in several ischemic diseases. However, the role of piperine in hepatic ischemia/reperfusion injury (HIRI) and its underlying mechanisms remain unclear. In this study, the mice were administered piperine (30 mg/kg) intragastric administration before surgery. After 24 h of hepatic ischemia-reperfusion, liver histopathological evaluation, serum transaminase measurements, and TUNEL analysis were performed. The infiltration of inflammatory cells and production of inflammatory mediators in the liver tissue were determined by immunofluorescence and immunohistochemical staining. The protein levels of toll-like receptor 4 (TLR4) and related proteins such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin-1 receptor-associated kinase 1 (IRAK1), p65, and p38 were detected by western blotting. The results showed that plasma aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte apoptosis, oxidative stress, and inflammatory cell infiltration significantly increased in HIRI mice. Piperine pretreatment notably repaired liver function, improved the histopathology and apoptosis of liver cells, alleviated oxidative stress injury, and reduced inflammatory cell infiltration. Further analysis showed that piperine attenuated tumor necrosis factor-a (TNF-α) and interleukin 6 (IL-6) production and reduced TLR4 activation and phosphorylation of IRAK1, p38, and NF-κB in HIRI. Piperine has a protective effect against HIRI through the TLR4/IRAK1/NF-κB signaling pathway and may be a safer option for future clinical treatment and prevention of ischemia-related diseases.

Strong, tough and anisotropic bioinspired hydrogels.

Soft materials are widely used in tissue engineering, soft robots, wearable electronics, etc. However, it remains a challenge to fabricate soft materials, such as hydrogels, with both high strength and toughness that are comparable to biological tissues. Inspired by the anisotropic structure of biological tissues, a novel solvent-exchange-assisted wet-stretching strategy is proposed to prepare anisotropic polyvinyl alcohol (PVA) hydrogels by tuning the macromolecular chain movement and optimizing the polymer network. The reinforcing and toughening mechanisms are found to be "macromolecule crystallization and nanofibril formation". These hydrogels exhibit excellent mechanical properties, such as extremely high fracture stress (12.8 ± 0.7 MPa) and fracture strain (1719 ± 77%), excellent modulus (4.51 ± 0.76 MPa), high work of fracture (134.47 ± 9.29 MJ m-3), and fracture toughness (305.04 kJ m-2) compared with other strong hydrogels and even natural tendons. In addition, excellent conductivity, strain sensing capability, water retention, freezing resistance, swelling resistance, and biocompatibility can also be achieved. This work provides a new and effective method to fabricate multifunctional anisotropic hydrogels with high tunable strength and toughness with potential applications in the fields of regenerative medicine, flexible sensors, and soft robotics.

Propyl gallate exposure affects the mouse 2-cell stage embryonic development through inducing oxidative stress and autophagy.

Propyl gallate (PG), owing to its exceptional antioxidant properties, is extensively used in industries such as food processing. The potential harmful impacts of PG have sparked concern among people. It has been reported that exposure of PG has certain reproductive toxicity, which can affect the maturation of mouse oocytes and induce testicular dysfunction. However, its impact on early embryonic development is still unclear. In this study, we explored the toxic effects and potential mechanisms of PG on mouse 2-cell stage embryonic development. The results showed that exposure of PG can decrease the development of 2-cell stage embryos and repress the development of 4-cell stage embryos. Further study found that PG could induce intracellular oxidative stress and the accumulation of DNA damage in 2-cell stage embryos. Moreover, exposure of PG impaired the function of mitochondria and lysosomes in 2-cell stage embryos, thereby triggering the occurrence of autophagy. In addition, exposure of PG altered the epigenetic modification of 2-cell stage embryos, displaying a decreased level of DNA methylation and an increased level of H3K4me3. In summary, our results indicated that exposure of PG can damage the development of mouse 2-cell stage embryos by inducing oxidative stress, DNA damage, and autophagy, and altering epigenetic modification.

Imprinted covalent organic frameworks solid-phase microextraction fiber for in vivo monitoring of acidic per- and polyfluoroalkyl substances in live aloe.

Per- and polyfluoroalkyl substances (PFASs) can lead to risks associated with animal and human health through the transfer along food chains. It is confirmed that PFASs can be transported to each part of plants after taken up by the roots. To better elucidate the underlying mechanisms for such exposure, it is highly valuable to develop analytical capabilities for in vivo monitoring of PFASs in live plants. In this work, a novel imprinted covalent organic frameworks (CMIP) solid-phase microextraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry was developed with low limits of detection for six acidic PFASs (0.1-0.3 ng g-1) and used for in vivo monitoring in live aloe. The CMIP coating shows good precision (RSD of intra and inter ≤9.6 % and 10.2 %, respectively) and possesses much higher extraction efficiency than the commercial coatings. After cultivating aloe in soil spiked PFASs, the in vivo assays gave a wealth of information, including steady-state concentrations, translocation factors, elimination rate constants, and half-life of PFASs. The in vivo tracing method for live plants can provide much needed and unique information to evaluate the risk of PFASs, which are very important for the safety of agriculture production.

Composition, Release, and Transformation of Earthworm Tissue-Bound Residues of Tetrabromobisphenol A in Soil.

Earthworms accumulate organic pollutants to form earthworm tissue-bound residues (EBRs); however, the composition and fate of EBRs in soil remain largely unknown. Here, we investigated the fate of tetrabromobisphenol A (TBBPA)-derived EBRs in soil for 250 days using a 14C-radioactive isotope tracer and the geophagous earthworm Metaphire guillelmi. The EBRs of TBBPA in soil were rapidly transformed into nonextractable residues (NERs), mainly in the form of sequestered and ester-linked residues. After 250 days of incubation, 4.9% of the initially applied EBRs were mineralized and 69.3% were released to extractable residues containing TBBPA and its transformation products (TPs, generated mainly via debromination, O-methylation, and skeletal cleavage). Soil microbial activity and autolytic enzymes of earthworms jointly contributed to the release process. In their full-life period, the earthworms overall retained 24.1% TBBPA and its TPs in soil and thus prolonged the persistence of these pollutants. Our study explored, for the first time, the composition and fate of organic pollutant-derived EBRs in soil and indicated that the decomposition of earthworms may release pollutants and cause potential environmental risks of concern, which should be included in both environmental risk assessment and soil remediation using earthworms.

Exercise-induced Musclin determines the fate of fibro-adipogenic progenitors to control muscle homeostasis.

The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47. Genetic ablation of FILIP1L in FAPs abolishes the effects of exercise or Musclin on FAPs and the benefits on the reduction of fibrosis and fatty infiltration. Overall, exercise forms a microenvironment of myokines in muscle and prevents the abnormal accumulation of FAPs in a Musclin/FILIP1L-dependent manner. The administration of exogenous Musclin exerts a therapeutic effect, demonstrating a potential therapeutic approach for muscle atrophy or acute muscle injury.

The appearance of cytoplasmic cytochrome C precedes apoptosis during Drosophila salivary gland degradation.

Apoptosis is an important process for organism development that functions to eliminate cell damage, maintain homeostasis, and remove obsolete tissues during morphogenesis. In mammals, apoptosis is accompanied by the release of cytochrome C (Cyt-c) from mitochondria to the cytoplasm. However, whether this process is conserved in the fruit fly, Drosophila melanogaster, remains controversial. In this study, we discovered that during the degradation of Drosophila salivary gland, the transcription of mitochondria apoptosis factors (MAPFs), Cyt-c, and death-associated APAF1-related killer (Dark) encoding genes are all upregulated antecedent to initiator and effector caspases encoding genes. The proteins Cyt-c and the active caspase 3 appear gradually in the cytoplasm during salivary gland degradation. Meanwhile, the Cyt-c protein colocates with mito-GFP, the marker indicating cytoplasmic mitochondria, and the change in mitochondrial membrane potential coincides with the appearance of Cyt-c in the cytoplasm. Moreover, impeding or promoting 20E-induced transcription factor E93 suppresses or enhances the staining of Cyt-c and the active caspase 3 in the cytoplasm of salivary gland, and accordingly decreases or increases the mitochondrial membrane potential, respectively. Our research provides evidence that cytoplasmic Cyt-c appears before apoptosis during Drosophila salivary gland degradation, shedding light on partial conserved mechanism in apoptosis between insects and mammals.

Synthesis of an ordered macroporous metal-organic framework for efficient solid-phase extraction of aflatoxins from milk products.

Aflatoxins (AFs) exhibit hepatotoxicity, immunotoxicity, and carcinogenicity, and their detection in food has attracted widespread concern. An ordered macroporous metal-organic framework (OM-ZIF-8) based on solid-phase extraction (SPE) was used to extract six AFs from milk products. The SPE conditions, including eluting solvent, eluting volume, amounts of OM-ZIF-8, pH of loading solution, loading solvent, ionic strength, loading flow rate, and elution flow rate, were exhaustively optimized. Under optimal parameters, the six AFs were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The OM-ZIF-8 exhibited satisfactory AFs extraction performance through ordered macropore structure, π-π interaction, coordination interaction, and electrostatic interaction. Furthermore, linearity in the range of 0.01-100 ng mL-1 with low detection limits of 0.002-0.0150 ng mL-1 was obtained, and the relative recoveries of AFs were 80.3-110 % with relative standard deviation ≤8.7 %. Thus, this research provides a promising platform for the analysis of trace AFs in complex foods.

All-optical geometric image transformations enabled by ultrathin metasurfaces.

Image processing plays a vital role in artificial visual systems, which have diverse applications in areas such as biomedical imaging and machine vision. In particular, optical analog image processing is of great interest because of its parallel processing capability and low power consumption. Here, we present ultra-compact metasurfaces performing all-optical geometric image transformations, which are essential for image processing to correct image distortions, create special image effects, and morph one image into another. We show that our metasurfaces can realize binary image transformations by modifying the spatial relationship between pixels and converting binary images from Cartesian to log-polar coordinates with unparalleled advantages for scale- and rotation-invariant image preprocessing. Furthermore, we extend our approach to grayscale image transformations and convert an image with Gaussian intensity profile into another image with flat-top intensity profile. Our technique will potentially unlock new opportunities for various applications such as target tracking and laser manufacturing.

The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) represents the predominant subtype of lung cancer. MELTF, an oncogene, exhibits high expression in various cancer tissues. Nevertheless, the precise role of MELTF in the progression of LUAD remains enigmatic. This work was devised to investigate the effect of MELTF on LUAD progression and its underlying mechanism. METHODS: mRNA expression data of LUAD were from The Cancer Genome Atlas database, and the enrichment pathway of MELTF was analyzed. The upstream transcription factors of MELTF were predicted, and the correlation between MELTF and E2F1 as well as the expression of the two in LUAD tissues were dissected by bioinformatics. The expression of MELTF and E2F1 in LUAD tissues and cells was assayed by qRT-PCR. Effects of MELTF/E2F1 on proliferation, migration, and invasion of LUAD cells were tested by CCK-8, colony formation, and Transwell assays. The binding relationship between E2F1 and MELTF was estimated by dual-luciferase reporter gene assay and ChIP assay. Western blot was utilized to assay the expression of Notch signaling pathway-related proteins in different treatment groups. RESULTS: Bioinformatics analysis and qRT-PCR results exhibited high expression of E2F1 and MELTF in LUAD tissues and cells, respectively. Dual-luciferase reporter gene assay and ChIP assay ascertained the binding of E2F1 to MELTF. MELTF was ascertained to enrich the Notch signaling pathway by bioinformatics means. In cell experiments, MELTF was shown to foster the malignant progression of LUAD cells and promoted the expression of NOTCH1 and HES1 proteins, but RO4929097 offset the effect of MELTF on cells. Rescue assay confirmed that E2F1 activated MELTF to promote LUAD progression via the Notch signaling pathway. CONCLUSION: Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.

Ecological mechanisms of biofilm development in the hybrid sludge-biofilm process: Implications for process start-up and optimization.

The hybrid sludge-biofilm processes have been widely applied for the construction or upgradation of biological wastewater treatment process. Ecological mechanisms of biofilm development remain unclear in the hybrid ecosystem, because of the intricate interactive effects between sludge and biofilms. Herein, the establishment principles of biofilms with distinct coexisting sludge amounts were uncovered by varying sludge retention times (SRTs) from 5 to 40 days in the hybrid process. With the increasing of SRTs, biofilm biomass decreased with the increase of suspended sludge, resulting in lower biofilm proportion. As estimated by the Gompertz growth model, the increased sludge amounts (i.e., higher SRTs of 20 and 40 days) prolonged the initial colonization stage and decreased the specific development rate of biofilms when compared to lower sludge amounts with the shorter SRTs (i.e., 5 and 10 days). Null model analysis demonstrated that deterministic homogenous selection could facilitate the colonization and accumulation of biofilms with less coexisting sludge (SRT of 10 days). However, stochastic ecological drift and homogenizing dispersal dominated the colonization and accumulation stages of biofilms with more coexisting sludge (SRT of 20 days), respectively. The ecological networks reflected that positively-related taxa presented taxonomic relatedness, whereas high inconsistency of taxonomic relatedness was observed among aggregate forms or development stages as affected by varied SRTs. The high incidence of intra-taxa co-occurrence patterns suggested that taxa with similar ecological niches could be specifically selected in biofilms when being exposed with less coexisting sludge. This study uncovered ecological mechanisms of biofilm development driven by varying the SRTs of suspended sludge, which would help to propose appropriate strategies for the efficient start-up and optimization of the hybrid sludge-biofilm system.