Calcium-Mediated Cell Adhesion Enhancement-Based Antimetastasis and Synergistic Antitumor Therapy by Conjugated Polymer-Calcium Composite Nanoparticles.

Strengthening tumor cellular adhesion through regulating the concentration of extracellular Ca2+ is highly challenging and promising for antimetastasis. Herein, a pH-responsive conjugated polymer-calcium composite nanoparticle (PFV/CaCO3/PDA@PEG) is developed for calcium-mediated cell adhesion enhancement-based antimetastasis and reactive oxygen species (ROS)-triggered calcium overload and photodynamic therapy (PDT) synergistic tumor treatment. PFV/CaCO3/PDA@PEG is mainly equipped with conjugated poly(fluorene-co-vinylene) (PFV-COOH)-composited CaCO3 nanoparticles, which can be rapidly decomposed under the tumor acidic microenvironment, effectively releasing Ca2+ and the photosensitizer PFV-COOH. The high extracellular Ca2+ concentration facilitates the generation of dimers between two adjacent cadherin ectodomains, which greatly enhances cell-cell adhesion and suppresses tumor metastasis. The inhibition rates are 97 and 87% for highly metastatic tumor cells 4T1 and MCF-7, respectively. Such a well-designed nanoparticle also contributes to realizing PDT, mitochondrial dysfunction, and ROS-triggered Ca2+ overload synergistic therapy. Furthermore, PFV/CaCO3/PDA@PEG displayed superior in vivo inhibition of 4T1 tumor growth and demonstrated a marked antimetastatic effect by both intravenous and intratumoral injection modes. Thus, this study provides a powerful strategy for calcium-mediated metastasis inhibition for tumor therapy.

Perspectives of healthcare providers on withdrawal of life-sustaining treatment and advanced directives for unresponsive wakefulness syndrome in China.

Objectives: We performed the current research to describe healthcare providers' perspectives toward withdrawal of life-sustaining treatment (WLST) and advanced directive (AD) of patients with unresponsive wakefulness syndrome (UWS) and to identify influencing factors of their perspectives. Methods: Healthcare providers were recruited during a professional conference on disorders of consciousness (DoC). Participants completed self-administered questionnaires which included demographics, personal perspectives regarding WLST and the perception of ADs. Results: A total of 230 Chinese healthcare providers (female: 69.7%) were included. Only a small proportion reported positive attitudes toward withdrawing artificial nutrition and hydration (35.2%), antibiotics (30.9%), and do-not-resuscitation orders (23.5%) in UWS patients. As for predictors' identification, religion was significantly associated with the positive attitude toward DNR order (p = 0.004). Moreover, although 47.4% of the participants had never heard of ADs before of conference, almost all of them would consider ADs (95.7%) thereafter, especially for non-neurologists (p = 0.033). Conclusion: The propensity to WLST for UWS in China is low and perspective on WLST is significantly associated with individual characteristics. The attitudes of healthcare providers toward integrating ADs in the decisional process are positive. Future research regarding ADs and their predictors should be carried out to improve the quality of end-of-life care of UWS in China.

Characterization of the molecular role that ST3GAL1 plays in porcine susceptibility to E. coli F18 infection.

Escherichia coli F18 (E. coli F18) is the main cause of bacterial diarrhea in piglets. Previous transcriptome reported that ST3GAL1 was associated to E. coli F18 infection. However, its role in mediating the resistance to E. coli F18 remains elusive. Here, we revealed that the downregulation of ST3GAL1 expression contributed to the enhancement of E. coli F18 resistance in IPEC-J2 cells. Bisulfite sequencing identified 26 methylated CpG sites in the ST3GAL1 core promoter. Among these, the ST3GAL1 mRNA levels significantly correlated with methylation levels of the mC-8 site in the specificity protein 1 (SP1) transcription factor (P < 0.01). Interestingly, ST3GAL1 expression may enhances the immune response by activating TLRs signaling, meanwhile decreases the production of the E. coli F18 receptor by inhibiting glycosphingolipid biosynthesis signaling, thereby leading to enhance the resistance to E. coli F18 infection. Besides, low ST3GAL1 expression may increase E. coli resistance by reducing sialylation. Together, these results support the status of ST3GAL1 as a viable target for efforts to modulate E. coli F18 susceptibility, offering a theoretical foundation for the use of this gene as a key biomarker for molecular breeding to improve porcine disease resistance.

Fluorescence Lifetime Super-Resolution Imaging Unveil the Dynamic Relationship between Mitochondrial Membrane Potential and Cristae Structure Using the Förster Resonance Energy Transfer Strategy.

Mitochondrial cristae, invaginations of the inner mitochondrial membrane (IMM) into the matrix, are the main site for the generation of ATP via oxidative phosphorylation, and mitochondrial membrane potential (MMP). Synchronous study of the dynamic relationship between cristae and MMP is very important for further understanding of mitochondrial function. Due to the lack of suitable IMM probes and imaging techniques, the dynamic relationship between MMP and cristae structure alterations remains poorly understood. We designed a pair of FRET-based molecular probes, with the donor (OR-LA) being rhodamine modified with mitochondrial coenzyme lipoic acid and the acceptor (SiR-BA) being silicon-rhodamine modified with a butyl chain, for simultaneous dynamic monitoring of mitochondrial cristae structure and MMP. The FRET process of the molecular pair in mitochondria is regulated by MMP, enabling more precise visualization of MMP through fluorescence intensity ratio and fluorescence lifetime. By combining FRET with FLIM super-resolution imaging technology, we achieved simultaneous dynamic monitoring of mitochondrial cristae structure and MMP, revealing that during the decline of MMP, there is a progression involving cristae dilation, fragmentation, mitochondrial vacuolization, and eventual rupture. Significantly, we successfully observed that the rapid decrease in MMP at the site of mitochondrial membrane rupture may be a critical factor in mitochondrial fragmentation. These data collectively reveal the dynamic relationship between cristae structural alterations and MMP decline, laying a foundation for further investigation into cellular energy regulation mechanisms and therapeutic strategies for mitochondria-related diseases.

Perception of diagnosis by family caregivers in severe brain injury patients in China.

OBJECTIVES: Surrogate decision-making by family caregivers for patients with severe brain injury is influenced by the availability and understanding of relevant information and expectations for future rehabilitation. We aimed to compare the consistency of family caregivers' perceptions with clinical diagnoses and to inform their expectation of prognosis in the future. METHODS: The Coma Recovery Scale-Revised was used to assess the diagnosis of inpatients with severe brain injury between February 2019 and February 2020. A main family caregiver was included per patient. The family caregiver's perception of the patient's consciousness and expectations of future recovery were collected through questionnaires and compared consistently with the clinical diagnosis. RESULTS: The final sample included 101 main family caregivers of patients (57 UWS, unresponsive wakefulness syndrome, 37 MCS, minimally conscious state, 7 EMCS, emergence from MCS) with severe brain injury. Only 57 family caregivers correctly assessed the level of consciousness as indicated by the CRS-R, showing weak consistency (Kappa = 0.217, P = 0.002). Family caregivers' demographic characteristics and CRS-R diagnosis influenced the consistency between perception and clinical diagnosis. Family caregivers who provided hands-on care to patients showed higher levels of consistent perception (AOR = 12.24, 95% CI = 2.06-73.00, P = 0.006). Compared to UWS, the family caregivers of MCS patients were more likely to have a correct perception (OR = 7.68, 95% CI = 1.34-44.06). Family caregivers had positive expectations for patients' recovery in terms of both communication and returning to normal life. CONCLUSION: Nearly half of family caregivers have inadequate understanding of their relative's level of consciousness, and most of them report overly optimistic expectations that do not align with clinical diagnosis. Providing more medical information to family caregivers to support their surrogate decision-making process is essential.

Visualization of cristae and mtDNA interactions via STED nanoscopy using a low saturation power probe.

Mitochondria are crucial organelles closely associated with cellular metabolism and function. Mitochondrial DNA (mtDNA) encodes a variety of transcripts and proteins essential for cellular function. However, the interaction between the inner membrane (IM) and mtDNA remains elusive due to the limitations in spatiotemporal resolution offered by conventional microscopy and the absence of suitable in vivo probes specifically targeting the IM. Here, we have developed a novel fluorescence probe called HBmito Crimson, characterized by exceptional photostability, fluorogenicity within lipid membranes, and low saturation power. We successfully achieved over 500 frames of low-power stimulated emission depletion microscopy (STED) imaging to visualize the IM dynamics, with a spatial resolution of 40 nm. By utilizing dual-color imaging of the IM and mtDNA, it has been uncovered that mtDNA tends to habitat at mitochondrial tips or branch points, exhibiting an overall spatially uniform distribution. Notably, the dynamics of mitochondria are intricately associated with the positioning of mtDNA, and fusion consistently occurs in close proximity to mtDNA to minimize pressure during cristae remodeling. In healthy cells, >66% of the mitochondria are Class III (i.e., mitochondria >5 µm or with >12 cristae), while it dropped to <18% in ferroptosis. Mitochondrial dynamics, orchestrated by cristae remodeling, foster the even distribution of mtDNA. Conversely, in conditions of apoptosis and ferroptosis where the cristae structure is compromised, mtDNA distribution becomes irregular. These findings, achieved with unprecedented spatiotemporal resolution, reveal the intricate interplay between cristae and mtDNA and provide insights into the driving forces behind mtDNA distribution.

Cu1-Fe Dual Sites for Superior Neutral Ammonia Electrosynthesis from Nitrate.

The electrochemical nitrate reduction reaction (NO3RR) is able to convert nitrate (NO3 -) into reusable ammonia (NH3), offering a green treatment and resource utilization strategy of nitrate wastewater and ammonia synthesis. The conversion of NO3 - to NH3 undergoes water dissociation to generate active hydrogen atoms and nitrogen-containing intermediates hydrogenation tandemly. The two relay processes compete for the same active sites, especially under pH-neutral condition, resulting in the suboptimal efficiency and selectivity in the electrosynthesis of NH3 from NO3 -. Herein, we constructed a Cu1-Fe dual-site catalyst by anchoring Cu single atoms on amorphous iron oxide shell of nanoscale zero-valent iron (nZVI) for the electrochemical NO3RR, achieving an impressive NO3 - removal efficiency of 94.8 % and NH3 selectivity of 99.2 % under neutral pH and nitrate concentration of 50 mg L-1 NO3 --N conditions, greatly surpassing the performance of nZVI counterpart. This superior performance can be attributed to the synergistic effect of enhanced NO3 - adsorption on Fe sites and strengthened water activation on single-atom Cu sites, decreasing the energy barrier for the rate-determining step of *NO-to-*NOH. This work develops a novel strategy of fabricating dual-site catalysts to enhance the electrosynthesis of NH3 from NO3 -, and presents an environmentally sustainable approach for neutral nitrate wastewater treatment.

Accurate prediction of hyaluronic acid concentration under temperature perturbations using near-infrared spectroscopy and deep learning.

Accurate prediction of the concentration of a large number of hyaluronic acid (HA) samples under temperature perturbations can facilitate the rapid determination of HA's appropriate applications. Near-infrared (NIR) spectroscopy analysis combined with deep learning presents an effective solution to this challenge, with current research in this area being scarce. Initially, we introduced a novel feature fusion method based on an intersection strategy and used two-dimensional correlation spectroscopy (2DCOS) and Aquaphotomics to interpret the interaction information in HA solutions reflected by the fused features. Subsequently, we created an innovative, multi-strategy improved Walrus Optimization Algorithm (MIWaOA) for parameter optimization of the deep extreme learning machine (DELM). The final constructed MIWaOA-DELM model demonstrated superior performance compared to partial least squares (PLS), extreme learning machine (ELM), DELM, and WaOA-DELM models. The results of this study can provide a reference for the quantitative analysis of biomacromolecules in complex systems.

Ultra-high spatio-temporal resolution imaging with parallel acquisition-readout structured illumination microscopy (PAR-SIM).

Structured illumination microscopy (SIM) has emerged as a promising super-resolution fluorescence imaging technique, offering diverse configurations and computational strategies to mitigate phototoxicity during real-time imaging of biological specimens. Traditional efforts to enhance system frame rates have concentrated on processing algorithms, like rolling reconstruction or reduced frame reconstruction, or on investments in costly sCMOS cameras with accelerated row readout rates. In this article, we introduce an approach to elevate SIM frame rates and region of interest (ROI) coverage at the hardware level, without necessitating an upsurge in camera expenses or intricate algorithms. Here, parallel acquisition-readout SIM (PAR-SIM) achieves the highest imaging speed for fluorescence imaging at currently available detector sensitivity. By using the full frame-width of the detector through synchronizing the pattern generation and image exposure-readout process, we have achieved a fundamentally stupendous information spatial-temporal flux of 132.9 MPixels · s-1, 9.6-fold that of the latest techniques, with the lowest SNR of -2.11 dB and 100 nm resolution. PAR-SIM demonstrates its proficiency in successfully reconstructing diverse cellular organelles in dual excitations, even under conditions of low signal due to ultra-short exposure times. Notably, mitochondrial dynamic tubulation and ongoing membrane fusion processes have been captured in live COS-7 cell, recorded with PAR-SIM at an impressive 408 Hz. We posit that this novel parallel exposure-readout mode not only augments SIM pattern modulation for superior frame rates but also holds the potential to benefit other complex imaging systems with a strategic controlling approach.

Emigration and fiscal gap in population-exporting region.

This paper analyzes how emigration impacts fiscal gap of population-exporting region in the long term. We construct a general equilibrium model of emigration and fiscal gap and make empirical verification using two-step system GMM model. Among the major lessons from this work, five general and striking results are worth highlighting: (1) the economic losses of emigration are the immediate cause of widening the fiscal gap. (2) in the short and long term, emigration can expand the fiscal revenue gap through the superimposed effect of tax rate and tax base. (3) the gap in fiscal expenditure is widened by the outflow of people in the short term. However, local governments would change the strategy to keep the spending gap from widening in the long run. (4) a positive impact of emigration on the fiscal gap. the more severe population emigration, the larger the fiscal gap. (5) when the trend of emigration becomes irreversible, the subsequent efforts of local governments to expand fiscal expenditure for attraction population would not only fail to revive the regional economy, but aggravate the expansion of fiscal gap. The contribution of research is twofold. On the one hand, it fills the theoretical gap between emigration and fiscal gap because previous studies have paid little attention to the fiscal problems of local government of population outflow. On the other hand, the selection of Northeast China that has been subject to long-term out-of-population migration is good evidence to verify this theory, which is tested very well using the 2S-GMM model. The comprehensive discussion on the relationship between emigration and fiscal gap is helpful to guide those continuous population-exporting regions that are facing a huge fiscal gap how to solve the fiscal gap and unsustainability from the perspective of fiscal revenue and expenditure.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) activates p38 to affect pulmonary fibrosis.

Objective: We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors. Methods: The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA. Results: In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-ß1 (TGF-ß1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1ß (IL-1ß) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells. Conclusion: Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.

E2F transcription factor 5, a new regulator in adipogenesis to mediate the role of Krüppel-like factor 7 in chicken preadipocyte differentiation and proliferation.

E2F transcription factor 5 (E2F5) gene is a transcription factor, plays an important role in the development of a variety of cells. E2F5 is expressed in human and mouse adipocytes, but its specific function in adipogenesis is unclear. Krüppel-like factor 7 (KLF7) facilitates proliferation and inhibits differentiation in chicken preadipocytes. Our previous KLF7 chromatin immunoprecipitation-sequencing analysis revealed a KLF7-binding peak in the 3' flanking region of the E2F5, indicating a regulatory role of KLF7 in this region. In the present study, we investigated E2F5 potential role, the overexpression and knockdown analyses revealed that E2F5 inhibited the differentiation and promoted the proliferation of chicken preadipocytes. Moreover, we identified enhancer activity in the 3' flanking region (nucleotides +22661/+22900) of E2F5 and found that KLF7 overexpression increased E2F5 expression and luciferase activity in this region. Deleting the putative KLF7-binding site eliminated the promoting effect of KLF7 overexpression on E2F5 expression. Further, E2F5 reversed the KLF7-induced decrease in preadipocyte differentiation and increase in preadipocyte proliferation. Taken together, our findings demonstrate that KLF7 inhibits differentiation and promotes proliferation in preadipocytes by enhancing E2F5 transcription.

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen.

High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen's ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

Phonon Pseudoangular Momentum in α-MoO3.

In recent studies, it has been discovered that phonons can carry angular momentum, leading to a series of investigations into systems with three-fold rotation symmetry. However, for systems with two-fold screw rotational symmetry, such as α-MoO3, there has been no relevant discussion. In this paper, we investigated the pseudoangular momentum of phonons in crystals with two-fold screw rotational symmetry. Taking α-MoO3 as an example, we explain the selection rules in circularly polarized Raman experiments resulting from pseudoangular momentum conservation, providing important guidance for experiments. This study of pseudoangular momentum in α-MoO3 opens up a new degree of freedom for its potential applications, expanding into new application domains.

Ginger exosome-like nanoparticle-derived miRNA therapeutics: A strategic inhibitor of intestinal inflammation.

INTRODUCTION: MicroRNAs (miRNAs) involve in destabilising messenger RNA or repressing translation of target molecules. Ginger-derived exosome-like nanoparticles (GELNs) play a crucial role in modulating intestinal inflammation. Moreover, GELNs contain highly heterogeneous miRNA. However, the role of miRNAs derived from GELNs in immunomodulation remains unclear. OBJECTIVES: This study aimed to elucidate the molecular basis of the unique biological effects mediated by miRNA derived from GELNs on macrophages. METHODS: GELNs were isolated using a combination of commercial exosome isolation kits and the differential centrifugation method, and the lipid composition of GELNs was determined using liquid chromatography-mass spectrometry. Subsequently, PKH26 labelled GELNs were taken up by macrophages. Furthermore, the modulation of inflammatory and immune responses by GELNs or osa-miR164d was assessed through the RNA-seq, RT-qPCR, online databases, and dual luciferase reporter assays to explore the underlying mechanisms of osa-miR164d. Biomimetic exosomes loaded with osa-miR164d were prepared using a microfluidic mixing device and systematically characterized. The therapeutic effects of osa-miR164d on relieving colitis were evaluated. RESULTS: We report for the first time that GELNs-derived osa-miR164d is a regulatory factor of reprogramming macrophage polarization, thereby inhibiting the intestinal inflammatory response. Mechanistically, osa-miR164d directly targets the 3'-UTRs of TAB1, which regulates macrophage polarization through the downregulation of NF-κB expression. In addition, We have designed a biomimetic exosome mimicking GELNs to deliver osa-miR164d (osa-miR164d-MGELNs). Notably, the osa-miR164d-MGELNs can efficiently reprogram macrophages to alleviate colitis-related symptoms. CONCLUSION: Our findings enhance the systematic understanding of how GELNs-derived osa-miR164d mediates cross-kingdom communication and provide an original engineering paradigm for mimicking GELNs to transfer miRNA.

Broccoli extracellular vesicles enhance the therapeutic effects and restore the chemosensitivity of 5-fluorouracil on colon cancer.

Broccoli contains an amount of biologically active substances, which bring beneficial effects on human health. Plant extracellular vesicles have been shown to be novel key factors in cancer diagnosis and tumor therapy. To date, the challenge of overcoming chemoresistance to 5-fluorouracil (5-FU) to facilitate the clinical management of colorectal cancer (CRC) has not been successful. Nevertheless, the functions of broccoli extracellular vesicles (BEVs) in the progression of CRC and 5-FU resistance are predominantly unclear. Herein, we showed that BEVs isolated from broccoli juice were effectively taken up by colorectal cancer HT-29 cells. The co-administration of BEVs and 5-FU significantly inhibited the proliferation and migration of colorectal cancer HT-29 cells, effectively blocking cell cycle progression. Furthermore, the co-administration of BEVs and 5-FU induced apoptosis by stimulating ROS production and disrupting mitochondrial function. Importantly, we found that BEVs reversed 5-FU resistance in HT-29 cells by suppressing the abnormal activation of the PI3K/Akt/mTOR signaling pathway. Collectively, our findings represent a novel strategy for utilizing BEVs to improve the efficacy of colorectal cancer treatment and enhance 5-FU chemosensitivity.

Improved therapeutic consistency and efficacy of CD317+ MSCs through stabilizing TSG6 by PTX3.

BACKGROUND: Previously, we have demonstrated that the batch variations of human platelet lysate (conventional MSC expansion medium) induce MSC heterogeneity and therapeutic inconsistency. On the other hand, the MSCs expanded with chemical defined medium have improved therapeutic consistency. METHODS: In the current study, we studied the MSC subpopulation composition and variation in different types and batches of MSC expansion medium with scRNA-seq analysis. RESULTS: MSCs expanded with different batches of media have higher levels of heterogeneity from the perspective of cell subpopulation composition at transcriptome levels and therapeutic inconsistency. The CD317+ subpopulation has enhanced immune suppression activities. And the percentage of CD317+ MSCs within MSCs is tightly correlated with its immune suppression activities, and also contributes to the heterogeneity and therapeutic inconsistency of MSCs. the CD317+ MSCs have increased expression levels of PTX3, which might stabilize the TSG6 protein and improve the therapeutic effects CONCLUSIONS: Thus, purifying CD317+ MSCs is one efficient strategy to reduce MSC heterogeneity and increase the therapeutic consistency of MSCs.

Chemiluminescent Conjugated Polymer Nanoparticles for Deep-Tissue Inflammation Imaging and Photodynamic Therapy of Cancer.

Deep-tissue optical imaging and photodynamic therapy (PDT) remain a big challenge for the diagnosis and treatment of cancer. Chemiluminescence (CL) has emerged as a promising tool for biological imaging and in vivo therapy. The development of covalent-binding chemiluminescence agents with high stability and high chemiluminescence resonance energy transfer (CRET) efficiency is urgent. Herein, we design and synthesize an unprecedented chemiluminescent conjugated polymer PFV-Luminol, which consists of conjugated polyfluorene vinylene (PFV) main chains and isoluminol-modified side chains. Notably, isoluminol groups with chemiluminescent ability are covalently linked to main chains by amide bonds, which dramatically narrow their distance, greatly improving the CRET efficiency. In the presence of pathologically high levels of various reactive oxygen species (ROS), especially singlet oxygen (1O2), PFV-Luminol emits strong fluorescence and produces more ROS. Furthermore, we construct the PFV-L@PEG-NPs and PFV-L@PEG-FA-NPs nanoparticles by self-assembly of PFV-Luminol and amphiphilic copolymer DSPE-PEG/DSPE-PEG-FA. The chemiluminescent PFV-L@PEG-NPs nanoparticles exhibit excellent capabilities for in vivo imaging in different inflammatory animal models with great tissue penetration and resolution. In addition, PFV-L@PEG-FA-NPs nanoparticles show both sensitive in vivo chemiluminescence imaging and efficient chemiluminescence-mediated PDT for antitumors. This study paves the way for the design of chemiluminescent probes and their applications in the diagnosis and therapy of diseases.

Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer-Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression.

Epigenetic alterations at cis-regulatory elements (CRE) fine-tune transcriptional output. Epigenetic readers interact with CREs and can cooperate with other chromatin regulators to drive oncogene transcription. Here, we found that the YEATS domain-containing histone acetylation reader ENL (eleven-nineteen leukemia) acts as a key regulator of super-enhancers (SE), which are highly active distal CREs, across cancer types. ENL occupied the majority of SEs with substantially higher preference over typical enhancers, and the enrichment of ENL at SEs depended on its ability to bind acetylated histones. Rapid depletion of ENL by auxin-inducible degron tagging severely repressed the transcription of SE-controlled oncogenes, such as MYC, by inducing the decommissioning of their SEs, and restoring ENL protein expression largely reversed these effects. Additionally, ENL was indispensable for the rapid activation of SE-regulated immediate early genes in response to growth factor stimulation. Furthermore, ENL interacted with the histone chaperone FACT complex and was required for the deposition of FACT over CREs, which mediates nucleosome reorganization required for transcription initiation and elongation. Proper control of transcription by ENL and ENL-associated FACT was regulated by the histone reader BRD4. ENL was overexpressed in colorectal cancer and functionally contributed to colorectal cancer growth and metastasis. ENL degradation or inhibition synergized with BET inhibitors that target BRD4 in restraining colorectal cancer progression. These findings establish the essential role of epigenetic reader ENL in governing SE-driven oncogenic transcription and uncover the potential of ENL intervention to increase sensitivity to BET inhibition. SIGNIFICANCE: ENL plays a key role in decoding epigenetic marks at highly active oncogenic super-enhancers and can be targeted in combination with BET inhibition as a promising synergistic strategy for optimizing cancer treatment.