Egfl6 promotes ovarian cancer progression by enhancing the immunosuppressive functions of tumor-associated myeloid cells.

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a new regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with ß3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cells migration and promotes their differentiation towards an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intra-tumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10 and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to a-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of a-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression co-localized with myeloid cell infiltration. scRNAseq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the onco-immunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential novel therapeutic target to enhance immunotherapy in OvCa patients.

Experimental research on the horizontally getting together behaviors of acoustically manipulated bi-particle.

This study aims at the controllability of acoustically manipulated non-contact aggregation of bi-particle. Based on the acoustic wave radiation model of the transducer and the acoustic wave interference theory, the mathematical model between the spatial levitation point and the phase of the phased array ultrasonic array unit is established. A double-sided phased array test system was developed and the phase calculation algorithm for independently manipulating bi-particle was optimized. The algorithm is capable of independently distributing the energy applied to each levitation point. Through simulation and experiment, the horizontally aggregation characteristics of two levitated particles are investigated, and a interesting relationship between particles aggregation and standing wave phase difference is revealed, which follows the law of "attraction in the same phase but repulsion in the opposite phase". By adjusting the tilt angle of the standing wave acoustic trap, the critical distance when particles to accelerate and collision is sharply reduced from 1.5λ to 0.5λ, which provides a new perspective and potential application path for acoustic manipulation technology.

STAN, a computational framework for inferring spatially informed transcription factor activity.

Transcription factors (TFs) drive significant cellular changes in response to environmental cues and intercellular signaling. Neighboring cells influence TF activity and, consequently, cellular fate and function. Spatial transcriptomics (ST) captures mRNA expression patterns across tissue samples, enabling characterization of the local microenvironment. However, these datasets have not been fully leveraged to systematically estimate TF activity governing cell identity. Here, we present STAN ( S patially informed T ranscription factor A ctivity N etwork), a linear mixed-effects computational method that predicts spot-specific, spatially informed TF activities by integrating curated TF-target gene priors, mRNA expression, spatial coordinates, and morphological features from corresponding imaging data. We tested STAN using lymph node, breast cancer, and glioblastoma ST datasets to demonstrate its applicability by identifying TFs associated with specific cell types, spatial domains, pathological regions, and ligand‒receptor pairs. STAN augments the utility of STs to reveal the intricate interplay between TFs and spatial organization across a spectrum of cellular contexts.

Leaching characteristics and environmental impact of heavy metals in tailings under rainfall conditions: A case study of an ion-adsorption rare earth mining area.

Following ion-adsorption rare earth mining, the residual tailings experience considerable heavy metal contamination and gradually evolve into a pollution source. Therefore, the leaching characteristics and environmental impact of heavy metals in ion-adsorption rare earth tailings require immediate and thorough investigation. This study adopted batch and column experiments to investigate the leaching behaviour of heavy metals in tailings and assess the impact of tailings on paddy soil, thereby providing a scientific basis for environmental protection in mining areas. The results showed that Mn, Zn, and Pb contents were 431.67, 155.05, and 264.33 mg·kg-1, respectively, which were several times higher than their respective background values, thereby indicating significant heavy metal contamination in the tailings. The batch leaching experiment indicated that Mn and Pb were priority control heavy metals. Heavy metals were divided into fast and slow leaching stages. The Mn and Pb leaching concentrations far exceeded environmental limits. The DoseResp model perfectly fitted the leaching of all heavy metals from the tailings (R2 > 0.99). In conjunction with the findings of the column experiment and correlation analysis, the chemical form, rainfall pH, ammonia nitrogen, and mineral properties were identified as the primary factors controlling heavy metal release from tailings. Rainfall primarily caused heavy metal migration in the acid-extraction form from the tailings. The tailing leachate not only introduced heavy metals into the paddy soil but also caused the transformation of the chemical form of heavy metals in the paddy soil, further exacerbating the environmental risk posed by heavy metals. The study findings are significant for environmental conservation in mining areas and implementing environmentally friendly practices in rare earth mining.

Upconversion-Mediated Optogenetics for the Treatment of Surgery-Induced Postoperative Neurocognitive Dysfunction.

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND. Optogenetics in the DTT brain region was conducted using upconversion nanoparticles (UCNPs) with the ability to convert 808 nm near-infrared light to visible wavelengths, which triggered the activation of excitatory neurons with minimal damage in the DTT brain region, thus improving cognitive impairment symptoms in the PND model. Moreover, this noninvasive intervention to modulate E-I imbalance showed a positive influence on mouse behavior in the Morris water maze test, which demonstrates that UCNP-mediated optogenetics is a promising tool for the treatment of neurological imbalance disorders.

Rice receptor kinase FLR7 regulates rhizosphere oxygen levels and enriches the dominant Anaeromyxobacter that improves submergence tolerance in rice.

Oxygen is one of the determinants of root microbiome formation. However, whether plants regulate rhizosphere oxygen levels to affect microbiota composition and the underlying molecular mechanisms remain elusive. The receptor-like kinase (RLK) family member FERONIA modulates the growth-defense tradeoff in Arabidopsis. Here, we established that rice FERONIA-like RLK 7 (FLR7) controls rhizosphere oxygen levels by methylene blue staining, oxygen flux, and potential measurements. The formation of oxygen-transporting aerenchyma in roots is negatively regulated by FLR7. We further characterized the root microbiota of 11 FLR mutants including flr7 and wild-type Nipponbare (Nip) grown in the field by 16S ribosomal RNA gene profiling and demonstrated that the 11 FLRs are involved in regulating rice root microbiome formation. The most abundant anaerobic-dependent genus Anaeromyxobacter in the Nip root microbiota was less abundant in the root microbiota of all these mutants, and this contributed the most to the community differences between most mutants and Nip. Metagenomic sequencing revealed that flr7 increases aerobic respiration and decreases anaerobic respiration in the root microbiome. Finally, we showed that a representative Anaeromyxobacter strain improved submergence tolerance in rice via FLR7. Collectively, our findings indicate that FLR7 mediates changes in rhizosphere oxygen levels and enriches the beneficial dominant genus Anaeromyxobacter and may provide insights for developing plant flood prevention strategies via the use of environment-specific functional soil microorganisms.

Enhancing Conjugation Effect to Develop Nitrogen-Rich Energetic Materials with Higher Energy and Stability.

This work reports a strategy by enhancing conjugation effect and synthesizes a symmetrical and planar compound, 1,2-bis (4,5-di(1H-tetrazol-5-yl)-2H-1,2,3-triazol-2-yl)diazene (NL24). The incorporation of azo and 1,2,3-triazole moieties manifests a synergistic effect, amplifying the conjugation effect of the azo bridge and thereby elevating the stability of NL24 (Td: 263 °C, IS: 7 J). Notably, NL24, possessing a structural configuration comprising four tetrazoles harboring a total of 24 nitrogen atoms, exhibits excellent detonation performances (ΔHf: 6.06 kJ g-1, VD: 9002 m s-1). This strategy achieves the balance of energy and stability of polycyclic tetrazoles and provides a direction for high-performance energetic materials.

Revealing new insights: Two-center evidence of microplastics in human vitreous humor and their implications for ocular health.

Microplastics (MPs), an emerging environmental contaminant, have raised growing health apprehension due to their detection in various human biospecimens. Despite extensive research into their prevalence in the environment and the human body, the ramifications of their existence within the enclosed confines of the human eye remain largely unexplored. Herein, we assembled a cohort of 49 patients with four ocular diseases (macular hole, macular epiretinal membrane, retinopathy and rhegmatogenous retinal detachment) from two medical centers. After processing the samples with an optimized method, we utilized Laser Direct Infrared (LD-IR) spectroscopy and Pyrolysis Gas Chromatography/Mass Spectrometry (Py-GC/MS) to analyze 49 vitreous samples, evaluating the characteristics of MPs within the internal environment of the human eye. Our results showed that LD-IR scanned a total of 8543 particles in the composite sample from 49 individual vitreous humor samples, identifying 1745 as plastic particles, predominantly below 50 µm. Concurrently, Py-GC/MS analysis of the 49 individual samples corroborated these findings, with nylon 66 exhibiting the highest content, followed by polyvinyl chloride, and detection of polystyrene. Notably, correlations were observed between MP levels and key ocular health parameters, particularly intraocular pressure and the presence of aqueous humor opacities. Intriguingly, individuals afflicted with retinopathy demonstrated heightened ocular health risks associated with MPs. In summary, this research provides significant insights into infiltration of MP pollutants within the human eye, shedding light on their potential implications for ocular health and advocating for further exploration of this emerging health risk.

Multiple Tissues Transcriptome of Zig-Zag Eel (Mastacembelus armatus) with Different Growth Rates.

In order to explore the main regulatory genes and related pathways of growth traits, transcriptome sequencing was first performed on the brain, liver, and muscle tissues of 3-month-old M. armatus with different growth rates. By comparative transcriptome analysis of fast-growing and slow-growing groups of M. armatus, a total of 2887 DEGs were screened, of which 59 up-regulated genes and 105 down-regulated genes were detected in the brain, 146 up-regulated genes and 202 down-regulated genes were detected in the liver, and 529 up-regulated genes and 1846 down-regulated genes were detected in muscle, including insulin-like growth factor binding protein 1a (IGFBP1A), insulin-like growth factor binding protein 1b (IGFBP1B), myosin, light chain 1 (MYL1), and myoglobin (MB). Through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we identified a total of 288 significantly enriched GO entries and 68 significantly enriched KEGG pathways related to growth, such as skeletal muscle tissue development, insulin-like growth factor binding, and the mitotic cell cycle. These key genes and signaling pathways may play a key role in regulating the growth of M. armatus. Digging into the regulatory mechanisms of these key genes will provide a theoretical basis for further exploration of the molecular mechanisms related to the growth and development of M. armatus, and help to breed new varieties of M. armatus with rapid growth.

Near-infrared light-activatable, analgesic nanocomposite delivery system for comprehensive therapy of diabetic wounds in rats.

Impaired angiogenesis, bacterial infection, persistent severe pain, exacerbated inflammation, and oxidative stress injury are intractable problems in the treatment of chronic diabetic ulcer wounds. A strategy that effectively targets all these issues has proven challenging. Herein, an in-situ sprayable nanoparticle-gel composite comprising platinum clusters (Pt) loaded-mesoporous polydopamine (MPDA) nanoparticle and QX-314-loaded fibrin gel (Pt@MPDA/QX314@Fibrin) was developed for diabetic wound analgesia and therapy. The composite shows good local analgesic effect of QX-314 mediated by near-infrared light (NIR) activation of transient receptor potential vanilloid 1 (TRPV1) channel, as well as multifunctional therapeutic effects of rapid hemostasis, anti-inflammation, antioxidation, and antibacterial properties that benefit the fast-healing of diabetic wounds. Furthermore, it demonstrates that the composite, with good biodegradability and biosafety, significantly relieved wound pain by inhibiting the expression of c-Fos in the dorsal root ganglion and the activation of glial cells in the spinal cord dorsal horn. Consequently, our designed sprayable Pt@MPDA/QX314@Fibrin composite with good biocompatibility, NIR activation of TRPV1 channel-mediated QX-314 local wound analgesia and comprehensive treatments, is promising for chronic diabetic wound therapy.

Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.

Thermodynamic Analysis and Pyrolysis Mechanism of 4,4'-Azobis-1,2,4-triazole.

The nonisothermal thermal decomposition kinetics of 4,4'-azobis-1,2,4-triazole (ATRZ) at different heating rates (5, 10, 15, and 20 °C·min-1) were investigated by thermogravimetry (TG) and differential scanning calorimetry (DSC) studies. The thermal decomposition kinetic parameters such as apparent activation energy (E) and pre-exponential factor (A) were calculated by the Kissinger, Ozawa, and Satava-Sestak methods. The E and A values calculated by the above three methods are very close, which are 391.1 kJ·mol-1/1034.92 s-1, 381.1 kJ·mol-1/1034.30 s-1, and 393.4 kJ·mol-1/1035.76 s-1, respectively. Then, the decomposition mechanism function of ATRZ is analyzed by the calculated results. The results show that the decomposition temperature of ATRZ is about 300 °C and the exothermic decomposition speed is fast. The decomposition pathway of ATRZ was analyzed by pyrolysis-gas chromatography-mass spectrometry (PY-GC-MS). The thermal decomposition kinetic equation of the ATRZ was deduced.

Polyvalent Ionic Energetic Salts Based on 4-Amino-3-hydrazino-5-methyl-1,2,4-triazole.

The synthesis of the new energetic material 4-amino-3-hydrazino-5-methyl-1,2,4-triazole, which shows excellent performance and reliable safety, has drawn attention recently. To fully characterize this material, a comprehensive analysis was performed using various techniques, including differential scanning calorimetry (DSC), infrared spectroscopy (IR), elemental analysis, and 1H and 13C NMR spectroscopy. Additionally, three compounds, 3, 5 and 9, were further characterized using single X-ray diffraction. The X-ray data suggested that extensive hydrogen bonds affect molecular structure by means of intermolecular interactions. In order to evaluate the explosive properties of these synthesized compounds, detonation pressures and velocities were calculated using EXPLO5 (V6.01). These calculations were carried out utilizing experimental data, including density and heat of formation. Among the explosives tested, compounds 7 and 8 exhibited zero oxygen balance and demonstrated exceptional detonation properties. Compound 7 achieved the highest recorded detonation pressure, at 34.2 GPa, while compound 8 displayed the highest detonation velocity, at 8887 m s-1.

Genome-Wide Identification and Expression Analysis of Calmodulin (CaM) and Calmodulin-Like (CML) Genes in the Brown Algae Saccharina japonica.

Calmodulins (CaMs) and Calmodulin-like proteins (CMLs) are vital in plant growth, development, and stress responses. However, CaMs and CMLs have not been fully identified and characterized in brown algae, which has been evolving independently of the well-studied green plant lineage. In this study, whole-genome searches revealed one SjCaM and eight SjCMLs in Saccharina japonica, and one EsCaM and eleven EsCMLs in Ectocarpus sp. SjCaM and EsCaM encoded identical protein products and shared 88.59-89.93% amino acid identities with Arabidopsis thaliana AtCaMs, thereby indicating that brown algae CaMs retained a similar Ca2+ sensors function as in plants. The phylogenetic and gene structure analysis results showed that there was significant divergence in the gene sequences among brown algae CMLs. Furthermore, evolutionary analysis indicated that the function of brown alga CMLs was relatively conserved, which may be related to the fact that brown algae do not need to face complex environments like terrestrial plants. Regulatory elements prediction and the expression analysis revealed the probable functioning of SjCaM/CML genes in gametophyte development and the stress response in S. japonica. In addition, the SjCaM/SjCMLs interacting proteins and chemicals were preliminarily predicted, suggesting that SjCaM/SjCMLs might play putative roles in Ca2+/CaM-mediated growth and development processes and stimulus responses. Therefore, these results will facilitate our understanding of the evolution of brown algae CaMs/CMLs and the functional identification of SjCaM/SjCMLs.

2,2'-Azobis(1,5'-bitetrazole) with a N10 Chain and 1,5'-Bitetrazolate-2N-oxides: Construction of Highly Energetic Nitrogen-Rich Materials Based on C-N-Linked Tetrazoles.

A series of high-nitrogen compounds, including a unique molecule 2,2'-azobis(1,5'-bitetrazole) with a branched N10 chain and 1,5'-bitetrazolate-2N-oxides, were synthesized successfully based on C-N-linked 1,5'-bistetrazoles using azo coupling of N-amine bonds and N-oxide introduction strategies. All compounds were characterized by NMR spectroscopy, IR spectroscopy, elemental analysis, and differential scanning calorimetry, in which the structures of five compounds were further determined by single-crystal X-ray diffraction analysis (2, T-N10B, 3a, 3b, and THX). The nitrogen contents of these five compounds range from 63.62 (THX) to 83.43% (T-N10B), which are much higher than that of CL-20 (38.34%). The heat of formation for the prepared compounds was calculated by using the Gaussian 09 program, with T-N10B having the highest value of 5.13 kJ g-1, about 6 times higher than that of CL-20 (0.83 kJ g-1). The calculated detonation performances by EXPLO5 v6.05.04 show that THX has excellent detonation performance (D = 9581 m s-1, P = 35.93 GPa) and a remarkable specific impulse (Isp = 284.9 s).

SerpinB1 is required for Rev-erbα-mediated protection against acute lung injury induced by lipopolysaccharide-in mice.

BACKGROUND AND PURPOSE: Acute lung injury (ALI) is a serious, life-threatening inflammation of the lungs that still lacks effective treatment. We previously showed that serine protease inhibitor B1 (SerpinB1) protects against ALI induced by orthotopic autologous liver transplantation. However, the role of SerpinB1 in lipopolysaccharide (LPS)-induced ALI and its regulatory mechanisms are not known. EXPERIMENTAL APPROACH: Wild-type (WT) and SerpinB1 knockout (KO) mice were treated with intratracheal LPS stimulation to induce ALI. Some of the WT and KO mice were injected i.p. with melatonin, a rhythm-related protein Rev-erbα agonist. The circadian rhythm in WT mice was disrupted by exposing mice to 24 h of continuous dark or light conditions after intratracheal LPS. Neutrophils were isolated from alveolar lavage fluid of WT and KO mice, and from human peripheral blood. Neutrophils were treated with LPS and melatonin. KEY RESULTS: Disruption of circadian rhythm by either 24-h dark or light conditions exacerbated LPS-induced ALI and decreased expression of Rev-erbα and SerpinB1 protein in lung, whereas melatonin treatment increased SerpinB1 expression and attenuated LPS-induced ALI in WT mice, but not in KO mice. In isolated neutrophils, Rev-erbα was co-localized with SerpinB1 and bound to its promoter to trigger SerpinB1 transcription. Furthermore, LPS stimulation increased formation of neutrophil extracellular traps, which was reversed by melatonin treatment in neutrophils from WT mice, but not from KO mice. CONCLUSION AND IMPLICATIONS: In mice, SerpinB1 is rhythmically regulated by Rev-erbα, and its down-regulation exacerbates LPS-induced ALI by inducing formation of neutrophil extracellular traps.

Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a high stromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. Single-cell transcriptomics of the HGSOC TME from public and in-house datasets revealed a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors had a lower fraction of certain T cells, natural killer (NK) cells, and macrophages and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicated that epithelial cancer cells and CA-MSCs secreted CXCL12 that interacted with the CXCR4 receptor, which was overexpressed on NK and CD8 + T cells. CXCL12 and/or CXCR4 antibodies confirmed the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.