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Introduction: Neuroinflammation serves as a critical local defense mechanism against secondary brain injury following intracerebral hemorrhage (ICH), and astrocytes play a prominent role in this process. In this study, we investigated astrocytic changes during the inflammatory state after ICH to identify new targets for improving the inflammatory response., Methods: We stimulated mouse astrocytes with lipopolysaccharide (LPS) in vitro and analyzed their transcriptomes via ribonucleic acid sequencing. We created an ICH model in living organisms by injecting autologous blood., Results: RNA sequencing revealed that 2,717 genes were differentially expressed in the LPS group compared to those in the saline group, with notable enrichment of the autophagic pathway. By intersecting the 2,717 differentially expressed genes (DEGs) with autophagy-related genes, we identified 36 autophagy-related DEGs and seven hub genes. Previous studies and quantitative reverse transcription-polymerase chain reaction results confirmed the increased expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3), AKT serine/threonine kinase 1 (Akt1), and unc-51 like autophagy activating kinase 2 (Ulk2) in astrocytes after ICH. Transcription factors and target miRNAs were identified for the final three DEGs, and 3-methyladenine and leupeptin were identified as potential therapeutic agents for ICH., Conclusion: Our findings suggest that astrocyte autophagy plays a critical role in ICH complexity, and that Pik3c3, Akt1, and Ulk2 may be potential therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Duan, Yu, Jiang, Shen, Li, Wang, Zhou, Li and He.)

G protein-coupled receptors (GPCRs) are a major gateway to cellular signaling, which respond to ligands binding at extracellular sites through allosteric conformational changes that modulate their interactions with G proteins and arrestins at intracellular sites. High-resolution structures in different ligand states, together with spectroscopic studies and molecular dynamics simulations, have revealed a rich conformational landscape of GPCRs. However, their supramolecular structure and spatiotemporal distribution is also thought to play a significant role in receptor activation and signaling bias within the native cell membrane environment. Here, we applied single-molecule fluorescence techniques, including single-particle tracking, single-molecule photobleaching, and fluorescence correlation spectroscopy, to characterize the diffusion and oligomerization behavior of the muscarinic M 1 receptor (M 1 R) in live cells. Control samples included the monomeric protein CD86 and fixed cells, and experiments performed in the presence of different orthosteric M 1 R ligands and of several compounds known to change the fluidity and organization of the lipid bilayer. M 1 receptors exhibit Brownian diffusion characterized by three diffusion constants: confined/immobile (∼0.01 μm 2 /s), slow (∼0.04 μm 2 /s), and fast (∼0.14 μm 2 /s), whose populations were found to be modulated by both orthosteric ligands and membrane disruptors. The lipid raft disruptor C6 ceramide led to significant changes for CD86, while the diffusion of M 1 R remained unchanged, indicating that M 1 receptors do not partition in lipid rafts. The extent of receptor oligomerization was found to be promoted by increasing the level of expression and the binding of orthosteric ligands; in particular, the agonist carbachol elicited a large increase in the fraction of M 1 R oligomers. This study provides new insights into the balance between conformational and environmental factors that define the movement and oligomerization states of GPCRs in live cells under close-to-native conditions.

Environmental pollution and energy crises have garnered global attention. The substantial discharge of organic waste into water bodies has led to profound environmental contamination. Photocatalytic fuel cells (PFCs) enabling the simultaneous removal of refractory contaminants and recovery of the chemical energy contained in organic pollutants provides a potential strategy to solve environmental issues and the energy crisis. This review will discuss the fundamentals, working principle, and configuration development of PFCs and photocatalytic microbial fuel cells (PMFCs). We particularly focus on the strategies for improving the wastewater treatment performance of PFCs/PMFCs in terms of coupled advanced oxidation processes, the rational design of high-efficiency electrodes, and the strengthening of the mass transfer process. The significant potential of PFCs/PMFCs in various fields is further discussed in detail. This review is intended to provide some guidance for the better implementation and widespread adoption of PFC wastewater treatment technologies.

Key Message: A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for tiller-related traits were reported, and the candidate genes underlying qMtn-KJ-5D, a novel major and stable QTL for maximum tiller number, were characterized. Tiller-related traits play an important role in determining the yield potential of wheat. Therefore, it is important to elucidate the genetic basis for tiller number when attempting to use genetic improvement as a tool for enhancing wheat yields. In this study, a quantitative trait locus (QTL) analysis of three tiller-related traits was performed on the recombinant inbred lines (RILs) of a mapping population, referred to as KJ-RILs, that was derived from a cross between the Kenong 9204 (KN9204) and Jing 411 (J411) lines. A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for spike number per plant (SNPP), maximum tiller number (MTN), and ear-bearing tiller rate (EBTR) were detected in eight different environments. Among these QTLs with additive effects, three major and stable QTLs were first documented herein. Almost all but two pairwise epistatic QTLs showed minor interaction effects accounting for no more than 3.0% of the phenotypic variance. The genetic effects of two colocated major and stable QTLs, i.e., qSnpp-KJ-5D.1 and qMtn-KJ-5D, for yield-related traits were characterized. The breeding selection effect of the beneficial allele for the two QTLs was characterized, and its genetic effects on yield-related traits were evaluated. The candidate genes underlying qMtn-KJ-5D were predicted based on multi-omics data, and TraesKN5D01HG00080 was identified as a likely candidate gene. Overall, our results will help elucidate the genetic architecture of tiller-related traits and can be used to develop novel wheat varieties with high yields., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Photosynthetic bacteria (PSB) has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties. Nevertheless, the actualization of their potential is impeded by inherent constraints, including their considerable size, heightened immunogenicity and compromised biosafety. Conquering these obstacles and pursuing more effective solutions remains a top priority. Similar to extracellular vesicles, bacterial outer membrane vesicles (OMVs) have demonstrated a great potential in biomedical applications. OMVs from PSB encapsulate a rich array of bioactive constituents, including proteins, nucleic acids, and lipids inherited from their parent cells. Consequently, they emerge as a promising and practical alternative. Unfortunately, OMVs have suffered from low yield and inconsistent particle sizes. In response, bacteria-derived nanovesicles (BNVs), created through controlled extrusion, adeptly overcome the challenges associated with OMVs. However, the differences, both in composition and subsequent biological effects, between OMVs and BNVs remain enigmatic. In a groundbreaking endeavor, our study meticulously cultivates PSB-derived OMVs and BNVs, dissecting their nuances. Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs, the latter contains a higher concentration of active ingredients and metabolites. Particularly noteworthy is the elevated levels of lysophosphatidylcholine (LPC) found in BNVs, known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization. Importantly, our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells, while also activating the EGFR/AKT/PI3K pathway. In contrast, OMVs have a pronounced aptitude in anti-cancer efforts, driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines. Thus, our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Accumulating evidence supports the significant role of human microbiome in development and therapeutic response of tumors. Circulating microbial DNA is non-invasive and could show a general view of the microbiome of host, making it a promising biomarker for cancers. However, whether circulating microbiome is associated with prognosis of non-small cell lung cancer (NSCLC) and its potential mechanisms on tumor immune microenvironment still remains unknown., Methods: The blood microbiome data and matching tumor RNA-seq data of TCGA NSCLC patients were obtained from Poore's study and UCSC Xena. Univariate and multivariate Cox regression analysis were used to identify circulating microbiome signatures associated with overall survival (OS) and construct the circulating microbial abundance prognostic scoring (MAPS) model. Nomograms integrating clinical characteristics and circulating MAPS scores were established to predict OS rate of NSCLC patients. Joint analysis of blood microbiome data and matching tumor RNA-seq data was used to deciphered the tumor microenvironment landscape of patients in circulating MAPS-high and MAPS-low groups. Finally, the predictive value of circulating MAPS on the efficacy of immunotherapy and chemotherapy were assessed., Results: A circulating MAPS prediction model consisting of 14 circulating microbes was constructed and had an independent prognostic value for NSCLC. The integration of circulating MAPS into nomograms may improve the prognosis predictive power. Joint analysis revealed potential interactions between prognostic circulating microbiome and tumor immune microenvironment. Especially, intratumor plasma cells and humoral immune response were enriched in circulating MAPS-low group, while intratumor CD4 + Th2 cells and proliferative related pathways were enriched in MAPS-high group. Finally, drug sensitivity analysis indicated the potential of circulating MAPS as a predictor of chemotherapy efficacy., Conclusion: A circulating MAPS prediction model was constructed successfully and showed great prognostic value for NSCLC. Our study provides new insights of interactions between microbes, tumors and immunity, and may further contribute to precision medicine for NSCLC., (© 2023. The Author(s).)

Fluorine-19 ( 19 F) MRI ( 19 F-MRI) is a promising method for quantifying biomedical research and clinical applications without background interference. Nevertheless, dependency on high-field MRI systems limits the applicability of 19 F-MRI. Low-field MRI systems are more common than high-field MRI systems. Hence, developing 19 F-MRI at low-field MRI devices can promote the 19 F-MRI translation in medical diagnosis. The detection sensitivity of fluorine agents is critical in 19 F-MRI. Reduction of the 19 F spin-lattice relaxation time ( T 1 ) enables an improved detection sensitivity while requiring ultrashort echo time (UTE) imaging methods to reduce the negative spin-spin relaxation ( T 2 ) decay effect. However, conventional UTE sequences require hardware with high performance. Herein, we introduce the k -space scaling imaging (KSSI) MRI sequence that accomplishes sampling k -space with variable scales to implement hardware-friendly UTE 19 F-MRI compatible with low-field MRI systems. We implemented experiments with swine bone, a perfluorooctyl bromide (PFOB) phantom, and one tumor-bearing mouse on two self-customized low-field MRI systems. The swine bone imaging validated the ultrashort TE of KSSI. Under high concentrations of manganese ferrite, a high signal-to-noise ratio was shown in the imaging of a fluorine atom concentration of 658 mM, which indicated high-sensitivity detection of KSSI. Moreover, the KSSI sequence exhibited a 7.1 times signal-to-noise ratio of spin echo sequence on the PFOB phantom imaging with a fluorine atom concentration of 3.29 M. Additionally, the various concentrations of the PFOB phantom imaging revealed quantifiable capacity. Finally, the 1 H/ 19 F imaging was implemented with KSSI on one tumor-bearing mouse. This method provides the potential for clinical translation of fluorine probes at low-field MRI systems.

Cancer vaccines represent the most promising strategies in the battle against cancers. Eliciting a robust therapeutic effect with vaccines, however, remains a challenge owing to the weak immunogenicity of autologous tumor antigens and highly immunosuppressive microenvironment. In the present study, we constructed CpG oligodeoxyribonucleotide (CpG ODN)-loaded cancer cell apoptotic bodies (Abs) as cancer vaccines for enhanced immunotherapy through cascade amplification-mediated immunosuppression relief. Abs that contain an abundant source of tumor-specific neoantigens and other tumor-associated antigens (TAAs) can be regarded as vaccines with higher immunogenicity. The de novo synthesized Abs-CpG could target and polarize macrophages to improve the immunosuppressive microenvironment. More importantly, we found that the effect of immunosuppression relief was cascade amplified, which was mediated by M1 macrophage-derived exosome transportation. Our results showed that CpG ODN polarized macrophages to M1 type and produced a large amount of TNF-α, which then activated cell division control protein 42 (Cdc42). Interestingly, we found that exosomes from M1 macrophages delivered Cdc42 and CpG to adjacent macrophages and further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by Abs-CpG with macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved, which then enhanced the performance of cancer vaccine therapy. Thus, we propose that a strategy of combining the Abs-based vaccine platform with the immunomodulatory approach represents the next generation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: 1. We discovered a relieving strategy for tumor immunosuppressive microenvironment: Abs-CpG polarized macrophages to M1 type, and M1 macrophage-derived exosomes delivered Cdc42 and CpG to adjacent macrophages, which then further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by the transfer of macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved. 2. As a vaccine, Abs contained both tumor-specific neoantigens and other tumor-associated antigens with higher immunogenicity and high clinical transformability., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Enhanced angiography based on magnetic resonance imaging (MRI) has emerged as a noninvasive, robust, and high-resolution imaging technique for the clinical evaluation of vascular diseases. However, the effects of clinical Gd-chelating contrast agents are unsatisfactory for MRI contrast enhancement owing to their short blood half-life caused by rapid vascular extravasation, especially in microvessels. To address these issues, nanoprobes based on red blood cell membrane-coated ultrasmall NaGdF 4 nanoparticles that exhibit much higher longitudinal molar relaxivity ( r 1 ) than the clinically used contrast agent gadolinium diethylenetriaminepentaacetic acid have been developed. Furthermore, the appropriate hydrodynamic diameter and stealth nature aid the nanoprobes to reside longer within the blood vessels without extravasation, thereby increasing the contrast between the blood vessels and surrounding tissues. Through probe-enhanced three-dimensional (3D) dynamic contrast-enhanced MR angiography, the main arteries and veins of the mouse were readily discernible, and even tiny vessels with sub-millimeter diameters could be clearly depicted. With this level of outstanding MR angiography performance, the embolization and recanalization processes of the carotid artery can be serially monitored with high imaging resolution using only a single injection. Additionally, the results of clearance studies and the toxicity tests further highlight the safety features of the nanoprobe. To summarize, the nanoprobes used in this study exhibit less extravascular leakage and a longer blood half-life, thus successfully overcoming the defects of the conventional low-molecular-weight Gd-based contrast agents and demonstrating their potential usefulness in enhanced MR angiography.

Background: Hepatocellular carcinoma (HCC) is a malignant tumour with a poor prognosis. The effect of DNA repair on prognosis cannot be ignored, and long non-coding RNA (lncRNA) can regulate the DNA repair process., Objective: To obtain DNA repair-associated lncRNA (DR-lncRNA) prognostic signature for improving the ability to predict HCC prognosis., Methods: Our study used the Cancer Genome Atlas database. Gene set variation analysis was performed to differentiate high and low levels of DNA repair to identify DR-lncRNAs. By performing univariate Cox regression, LASSO regression, and multivariate Cox regression analyses, we finally obtained a DR-lncRNA prognostic signature and constructed a nomogram prognostic model. Time-dependent receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA), and clinical impact curves were used to assess predictive ability and clinical utility. Differentially expressed genes (DEGs) functional enrichment analysis was performed to further explore the underlying mechanisms that influence HCC prognosis., Results: We obtained the following DR-lncRNA prognostic signature:AP002478.1, AC116351.1, LINC02580, and LINC00861. The ROC curves and calibration plots showed good discrimination and calibration properties. Combining the DR-lncRNA prognostic signature and tumour stages, we established a nomogram prognostic model. DCA and clinical impact curves showed the clinical utility of this model. DEGs of high-risk and low-risk groups predicted by the prognostic DRlncRNA were significantly associated with cell cycle, various metabolic pathways and biological processes, such as the oxidation-reduction process and cell division., Conclusion: We identified a DR-lncRNA prognostic signature and constructed a nomogram prognostic model, which could be a beneficial prognostic strategy for HCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tumor immunotherapy has been convincingly demonstrated as a feasible approach for treating cancers. Although promising, the immunosuppressive tumor microenvironment (TME) has been recognized as a major obstacle in tumor immunotherapy. It is highly desirable to release an immunosuppressive "brake" for improving cancer immunotherapy. Among tumor-infiltrated immune cells, tumor-associated macrophages (TAMs) play an important role in the growth, invasion, and metastasis of tumors. The polarization of TAMs (M2) into the M1 type can alleviate the immunosuppression of the TME and enhance the effect of immunotherapy. Inspired by this, we constructed a therapeutic exosomal vaccine from antigen-stimulated M1-type macrophages (M1 OVA -Exos). M1 OVA -Exos are capable of polarizing TAMs into M1 type through downregulation of the Wnt signaling pathway. Mediating the TME further activates the immune response and inhibits tumor growth and metastasis via the exosomal vaccine. Our study provides a new strategy for the polarization of TAMs, which augments cancer vaccine therapy efficacy., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Circulating RNAs (circRNAs) are involved in tumor development and progression by participating in immune regulation. Nevertheless, the circRNAs expression profiles and their roles on the immunomodulatory effects in cutaneous squamous cell carcinoma (cSCC) have rarely been studied. In our study, we identified the differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), mRNAs (DEmRNAs) in cSCC and established the circRNA competing endogenous RNAs (ceRNAs) network. Subsequently, the hub differentially expressed immune-related genes were identified and validated by immunochemistry as well as the GO and KEGG pathway analysis were performed. 54 differentially expressed circRNAs were identified and hub differentially expressed immune-related genes were identified and they were mostly associated with immune response in the progression of cSCC. Our results indicated that the potential immune-related circRNA-miRNA-mRNA network may assist in understanding the molecular mechanisms underlying the carcinogenesis and progression in cSCC. Moreover, the immune-related genes may provide an insight into the pathogenesis, molecular biomarkers, and potential therapeutic targets for cSCC patients., Competing Interests: None., (AJCR Copyright © 2021.)

Objective: To assess the reporting quality of randomized controlled trials (RCTs) with multicenter design, particularly whether necessary information related to multicenter characteristics was adequately reported., Study Design and Setting: Through a search of 4 international electronic databases, we identified multicenter RCTs published in English from 1975 to 2019. Reporting quality was assessed by the CONSORT (Consolidated Standards of Reporting Trials) checklist (37 items) and by a self-designed multicenter-specific checklist (27 items covering multicenter design, implement and analysis). The scores of trials published in three time periods (1975-1995; 1996-2009; and 2010-2019) were also compared., Results: A total of 2,844 multicenter RCTs were included. For the CONSORT checklist, the mean (standard deviation) reporting score was 24.1 (5.5), 12 items were assessed as excellent (>90%), 12 items as good (50%-90%), and 13 items as poor (<50%). For the multicenter checklist, the reporting score was 3.9 (2.2), only 3 items were excellent or good, and the remaining 24 items were poor. Time period comparison showed that reporting quality improved over time, especially after the CONSORT 2010 issued., Conclusion: Although CONSORT appears to have enhanced the reporting quality of multicenter RCTs, further improvement is needed. A "CONSORT extension for multicenter trials" should be developed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of efficient strategies for the magnetic hyperthermia ablation of tumors remains challenging. To overcome the significant safety limitations, we developed a thermally contractible, injectable and biodegradable material for the minimally invasive and highly efficient magnetic hyperthermia ablation of tumors. This material was composed of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA) and Fe 3 O 4 . The thermal contractibility of HPMC/Fe 3 O 4 was designed to avoid damaging the surrounding normal tissue upon heating, which was confirmed by visual inspection, ultrasound imaging and computed tomography (CT). The efficient injectability of HPMC/Fe 3 O 4 was proven using a very small needle. The biosafety of HPMC/Fe 3 O 4 was evaluated by MTT and biochemical assays as well as flow cytometry (FCM). All the aforementioned data demonstrated the safety of HPMC/Fe 3 O 4 . The results of in vitro and ex vivo experiments showed that the temperature and necrotic volume of excised bovine liver were positively correlated with the HPMC/Fe 3 O 4 weight, iron content and heating duration. The in vivo experimental results showed that the tumors could be completely ablated using 0.06 ml of HPMC/60%Fe 3 O 4 after 180 s of induction heating. We believe that this novel, safe and biodegradable material will promote the rapid bench-to-bed translation of magnetic hyperthermia technology, and it is also expected to bring a new concept for the biomaterial research field., (Copyright © 2017 Elsevier Ltd. All rights reserved.)