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Abstract Background Streptococcus mutans (S. mutans) is an important pathogenic bacterium that causes dental caries, while Streptococcus gordonii (S. gordonii) is a non-cariogenic bacterium that inhibits the growth of S. mutans. The SepM protein can promote the inhibitory ability of S. mutans against S. gordonii by cleaving CSP-21 and activating the ComDE two-component system. This study was designed to explore sepM mutation in S. mutans clinical isolates and related function in the regulation of interactions with S. gordonii. Methods The S. mutans clinical strains that can inhibit the growth of S. gordonii constitute the inhibitory group. 286 C-serotype S. mutans strains were categorized into S. gordonii inhibitory (n = 114) and non-inhibitory bacteria (n = 172). We detected sanger sequencing of sepM gene, the expression levels of related genes and proteins in clinical isolates, obtained prokaryotic expression and purification of mutated proteins, and analyzed the effect of the target mutations on the binding between SepM and CSP-21. Results We found that C482T, G533A, and G661A missense mutations were presented at significantly higher frequency in the inhibitory group relative to the non-inhibitory group. There was no significant difference in the expression of the sepM gene between selected clinical isolates harboring the G533A mutation and the control group. The expression levels of SepM, phosphorylated ComD, and ComE in the mutation group were significantly higher than those in the control group. SepM_control and SepM_D221N (G661A at the gene level) were found to contain two residues close to the active center while SepM_G178D (G533A at the gene level) contained three residues close to the active center. At 25 °C and a pH of 5.5, SepM_D221N (G661A) exhibited higher affinity for CSP-21 (KD = 8.25 µM) than did the SepM control (KD = 33.1 µM), and at 25 °C and a pH of 7.5, SepM_G178D (G533A) exhibited higher affinity (KD = 3.02 µM) than the SepM control (KD = 15.9 µM). It means that it is pH dependent. Conclusions Our data suggest that increased cleavage of CSP-21 by the the mutant SepM may be a reason for the higher inhibitory effect of S. mutans on S. gordonii .

Abstract Reconstruction of the neurovascular unit is essential for the repair of spinal cord injury (SCI). Nonetheless, detailed documentation of specific vascular changes following SCI and targeted interventions for vascular treatment remains limited. This study demonstrates that traumatic pathological vascular remodeling occurs during the chronic phase of injury, characterized by enlarged vessel diameter, disruption of blood‐spinal cord barrier, endothelial‐to‐mesenchymal transition (EndoMT), and heightened extracellular matrix deposition. After SCI, osteopontin (OPN), a critical factor secreted by immune cells, is indispensable for early vascular regeneration but also contributes to traumatic pathological vascular remodeling. This work further elucidates the mechanism by which OPN influences spinal cord microvascular endothelial cells, involving Akt‐mediated Foxo1 phosphorylation. This process facilitates the extranuclear transport of Foxo1 and decreases Smad7 expression, leading to excessive activation of the TGF‐β signaling pathway, which ultimately results in EndoMT and fibrosis. Targeted inhibition of Foxo1 phosphorylation through an endothelium‐specific aptamer‐liposome small molecule delivery system significantly mitigates vascular remodeling, thereby enhancing axon regeneration and neurological function recovery following SCI. The findings offer a novel perspective for drug therapies aimed at specifically targeting pathological vasculature after SCI.

Combining green warehousing with wind-solar-storage systems can enhance economic power consumption, energy saving, and emission reduction in green warehousing. To achieve efficient and stable operation of the wind-solar-storage microgrid, this paper proposes an optimal microgrid scheduling strategy based on the Improved Sparrow Algorithm (ISSA). Firstly, a comprehensive benefit model is established based on the economic and environmental benefits of microgrid daily operation. Then, an innovative improved sparrow search algorithm is proposed, which aims to improve the global search and local search capability of the microgrid scheduling problem by introducing improvements such as Logistic-Circle chaotic mapping, Bottle Sea Sheath swarm optimization algorithm, dynamic inertia weights, water wave dynamic factor, and Cauchy-Gaussian variational strategy. Finally, the microgrid optimal scheduling model is solved by the improved sparrow search algorithm and compared with other algorithms. In this paper, Matlab 2016b is used for simulation, and the simulation results show that the ISSA algorithm outperforms other algorithms in terms of solution stability and optimization search capability. Under three modes of operation, ISSA improves the microgrid operation revenue by 6.29%, 5.98%, and 6.31% at least. Therefore, the optimal scheduling scheme obtained based on ISSA improves the daily operating total revenue and the system operation stability of the microgrid.

For advanced aero-engine design and research, modeling and simulation in a digital environment is indispensable, especially for engines of complicated configurations, such as variable cycle engines (VCE) and adaptive cycle engines (ACE). Also, in the research of future smart engines, reliable real-time digital twins are paramount. However, the 2 dominant methods that used in solving the simulation models, Newton-Raphson (N-R) method and volume-based method, are not fully qualified for the study requirements, because neither of them reaches the satisfactory balance of convergence rate and calculating efficiency. In this study, by deeply analyzing the mathematical principle of these 2 methods, a novel modeling and solving method for aero-engine simulation, which integrates the advantages of both N-R and volume-based methods, is established. It has distributed architecture and local quadratic convergence rate. And a novel modeling method for variable area bypass injectors (VABI) is put forward. These facilitate simulation of various configurations of aero-engines. The modeling cases, including a high bypass-ratio (BPR) turbofan and an ACE, illustrate that the novel technique decreases the iterations by about two-thirds comparing with volume-based method, while the success rate of convergence remains over 99%. This proves its superiority in both convergence and calculating efficiency over the conventional ones. This technique can be used in advanced gas turbine engine design and control strategy optimization, and study of digital twins.

Microgrids comprising photovoltaic (PV), energy-storage systems and electric vehicles have received increasing attention. However, the increase in renewable energy sources, such as PVs, will introduce uncertainty factors to the frequency response, resulting in frequency fluctuations that can reduce power quality. Hence, we propose an outstanding learning-based control approach that combines a model of physical principles with a Gaussian Process (GP) learning approach. The learning model corrects the physical principles model and estimates its uncertainty. Simulations are performed by comparing the proposed controller with conventional model-predictive controllers. The results indicate that the learning-based controller proposed can adjust the frequency with less overshooting and a lower root mean square error compared to the conventional MPC control method.

Abstract Mineral dust plays an important role in Earth's climate system, yet it is difficult to identify dust imprints in paleofluvial sediments, especially on orbital timescales. Here, we present high‐resolution authigenic carbonate Ca–Mg–Sr compositions in a fluvial sequence under the transport pathway of Asian dust. The Mg/Ca, Sr/Ca, and Mg/Sr ratios exhibit distinct transitions in both secular trends and orbital cycles at ∼8 Ma. Before ∼8 Ma, given similar Mg and Sr partitioning behaviors during carbonate formation, hydroclimate changes yielded strong orbital signals in the Sr/Ca and Mg/Ca ratios but no detectable signals in the Mg/Sr ratios. After ∼8 Ma, given the strengthened input of Mg‐rich dust during cold‒dry periods, the Mg/Sr and Mg/Ca ratios clearly exhibited orbital signals, but the Sr/Ca ratio did not. Such transitions in carbonate composition corroborate the dust‐induced changes in fluvial hydrochemistry, offering an innovative methodology for detecting orbital dust cycles in paleofluvial systems.

Abstract Background Vascular endothelial cells are pivotal in the pathophysiological progression following spinal cord injury (SCI). The UTX (Ubiquitously Transcribed Tetratripeptide Repeat on Chromosome X) serves as a significant regulator of endothelial cell phenotype. The manipulation of endogenous neural stem cells (NSCs) offers a compelling strategy for the amelioration of SCI. Methods Two mouse models were used to investigate SCI: NSCs lineage-traced mice and mice with conditional UTX knockout (UTX KO) in endothelial cells. To study the effects of UTX KO on neural differentiation, we harvested extracellular vesicles (EVs) from both UTX KO spinal cord microvascular endothelial cells (SCMECs) and negative control SCMECs. These EVs were then employed to modulate the differentiation trajectory of endogenous NSCs in the SCI model. Results In our NSCs lineage-traced mice model of SCI, a marked decrease in neurogenesis was observed post-injury. Notably, NSCs in UTX KO SCMECs mice showed enhanced neuronal differentiation compared to controls. RNA sequencing and western blot analyses revealed an upregulation of L1 cell adhesion molecule (L1CAM), a gene associated with neurogenesis, in UTX KO SCMECs and their secreted EVs. This aligns with the observed promotion of neurogenesis in UTX KO conditions. In vivo administration of L1CAM-rich EVs from UTX KO SCMECs (KO EVs) to the mice significantly enhanced neural differentiation. Similarly, in vitro exposure of NSCs to KO EVs resulted in increased activation of the Akt signaling pathway, further promoting neural differentiation. Conversely, inhibiting Akt phosphorylation or knocking down L1CAM negated the beneficial effects of KO EVs on NSC neuronal differentiation. Conclusions In conclusion, our findings substantiate that EVs derived from UTX KO SCMECs can act as facilitators of neural differentiation following SCI. This study not only elucidates a novel mechanism but also opens new horizons for therapeutic interventions in the treatment of SCI. Video Abstract Graphical Abstract

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertkhi bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with the mitochondria, optimizing its targeting affinity for the injury site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated mitochondrial dysfunction, and attenuated pro-inflammatory profiles in macrophages, both in vitro and in vivo. The intravenously delivered mitochondrial compounds targeted the SCI epicenter, with macrophages being the primary recipients. Critically, they promoted tissue regeneration and bolstered functional recovery in SCI mice. This study heralds a transformative approach to mitochondrial transplantation in SCI, spotlighting the modulation of macrophage activity, phagocytosis, and phenotype.

Abstract Background Osteoking has been used for fracture therapy with a satisfying clinical efficacy. However, its therapeutic properties and the underlying mechanisms remain elusive. Method A bone defect rat model was established to evaluate the pharmacological effects of Osteoking by the dynamic observation of X-ray, micro-CT and histopathologic examination. Transcriptome profiling was performed to identify bone defect-related genes and Osteoking effective targets. Then, a “disease-related gene–drug target” interaction network was constructed and a list of key network targets were screened, which were experimentally verified. Results Osteoking effectively promoted bone defect repair in rats by accelerating the repair of cortical bone and the growth of trabeculae. Histopathologically, the bone defect rats displayed lower histopathologic scores in cortical bone, cancellous bone and bone connection than normal controls. In contrast, Osteoking exerted a favorable effect with a dose-dependent manner. The abnormal serum levels of bone turnover markers, bone growth factors and bone metabolism-related biochemical indexes in bone defect rats were also reversed by Osteoking treatment. Following the transcriptome-based network investigation, we hypothesized that osteoking might attenuate the levels of ZBP1–STAT1–PKR–MLKL-mediated necroptosis involved into bone defect. Experimentally, the expression levels of ZBP1, STAT1, PKR and the hallmark inflammatory cytokines for the end of necroptosis were distinctly elevated in bone defect rats, but were all effectively reversed by Osteoking treatment, which were also suppressed the activities of RIPK1, RIPK3 and MLKL in bone tissue supernatants. Conclusions Osteoking may promote bone formation and bone defect repair by regulating ZBP1–STAT1–PKR axis, leading to inhibit RIPK1/RIPK3/MLKL activation-mediated necroptosis.

Abstract Spinal cord injury (SCI) can prompt an immediate disruption to the blood–spinal cord barrier (BSCB). Restoring the integrity of this barrier is vital for the recovery of neurological function post-SCI. The UTX protein, a histone demethylase, has been shown in previous research to promote vascular regeneration and neurological recovery in mice with SCI. However, it is unclear whether UTX knockout could facilitate the recovery of the BSCB by reducing its permeability. In this study, we systematically studied BSCB disruption and permeability at different time points after SCI and found that conditional UTX deletion in endothelial cells (ECs) can reduce BSCB permeability, decrease inflammatory cell infiltration and ROS production, and improve neurological function recovery after SCI. Subsequently, we used RNA sequencing and ChIP-qPCR to confirm that conditional UTX knockout in ECs can down-regulate expression of myosin light chain kinase (MLCK), which specifically mediates myosin light chain (MLC) phosphorylation and is involved in actin contraction, cell retraction, and tight junctions (TJs) protein integrity. Moreover, we found that MLCK overexpression can increase the ratio of p-MLC/MLC, further break TJs, and exacerbate BSCB deterioration. Overall, our findings indicate that UTX knockout could inhibit the MLCK/p-MLC pathway, resulting in decreased BSCB permeability, and ultimately promoting neurological recovery in mice. These results suggest that UTX is a promising new target for treating SCI. Graphical Abstract

Abstract Background Synovial neovascularization promotes rheumatoid arthritis (RA) progression. Baihu guizhi decoction (BHGZD) has a potential in restricting this pathological change of RA. Purpose To identify bioactive compounds (BACs) of BHGZD and to elucidate the underlying mechanisms in restricting synovial neovascularization of RA. Method Through transcriptomic profiling, the chemical profiling of BHGZD and its effective transcriptomic profiling against RA were identified. Then, candidate targets and the corresponding BACs against synovial neovascularization were screened by “disease gene-drug target” interaction network analysis and in silico molecular docking. The binding affinities of candidate BAC-target pairs were verified using surface plasmon resonance, and the pharmacokinetic characteristics of BACs in vivo after BHGZD administration at different time points were detected by Ultra Performance Liquid Chromatography-Mass spectrum/Mass spectrum. After that, in vivo experiments based on adjuvant-induced arthritis (AIA-M) rats, and in vitro experiments based on human umbilical vein endothelial cells (HUVEC) and arthritic synovial fibroblasts (MH7A) were carried out to evaluate the pharmacological effects of BHGZD and the two-BACs-combination, and to verify the associated mechanisms. Result VEGFA/VEGFR2/SRC/PI3K/AKT signal axis was screened as one of the key network targets of BHGZD against synovial neovascularization in RA. Mangiferin (MG) and glycyrrhizic acid (GA) were identified as the representative BACs of BHGZD for their strong binding affinities with components of the VEGFA/VEGFR2/SRC/PI3K/AKT signal axis, and their high exposed quantity in vivo. Both BHGZD and the two-BAC combination of MG and GA were demonstrated to be effective in restricting disease severity, reducing synovial inflammation and decreasing the formation of vascular opacities in AIA-M rats, and also reducing the migrative and invasive activities of HUVEC and MH7A cells and attenuating the lumen formation ability of HUVEC cells significantly. Mechanically, both BHGZD and the two-BAC combination markedly reduced the expression of VEGFA in synovial tissues, the serum levels of VEGF and NO, and the enzymatic activity of eNOS, increased the content of endostatin, and also reversed the abnormal alterations in the VEGFA/VEGFR2/SRC/PI3K/AKT signal axis in vivo and in vitro. Conclusion MG and GA may be the representative BACs of BHGZD for restricting excessive synovial vascularization in RA via regulating VEGFA/VEGFR2/SRC/PI3K/AKT signal axis.

Flower and fruit abscission is a highly programmed physiological process, which is closely related to the yield of horticultural plants. The coordination of many regulatory factors associated with metabolic and signaling pathways plays a key role in the flower and fruit shedding. Hormones, peptides, carbohydrates, polyamines or cell wall modifying proteins regulate flower and fruit shedding. This article reviewed the recent studies of flower and fruit abscission, including the molecular regulation mechanism of abscission zone formation, typical structure and location of abscission zones, and other factors affecting flower and fruit abscission, such as stresses, hormones, peptides, carbohydrates, polyamines and cell wall modifying proteins. Overall, the review summarizes the developmental mechanism and the diversity of abscission zones, and the key factors affecting flower and fruit abscission of horticultural plants, aiming to provide guidance for studying the molecular regulatory mechanism of flower and fruit abscission.

Pyrolyzed organic matter, commonly referred to as biochar, generally has positive effects on plant growth and can enhance early seedling development. Biochar-based seed coatings may thus be beneficial, specifically under adverse soil conditions such as high soil salinity. Using a series of lab and greenhouse experiments, we evaluated germination and early plant development in radish (Raphinus sativa) seeds coated with conifer-feedstock slow-pyrolysis biochar. Following the precedent of prior studies, polyvinyl acetate (PVAc) was used as the binding agent. Biochar-based seed coatings reduced germination rates and radicle extension in Petri dish trials; however, leaching of coated seeds largely eliminated this effect. PVAc applied in solution inhibited seed germination to a similar extent, suggesting that toxicity of PVAc or chemical products derived from it is the main mechanism for germination inhibition. A meta-analysis of published literature also indicates negative effects of biochar-based seed coatings using PVAc. In greenhouse trials, the same biochar seed coatings improved aspects of plant growth and physiological status relative to controls, specifically enhancing root development. We conclude that biochar-based seed coatings have promise in promoting early seedling growth and potentially in combating salinity stress in agronomic and restoration applications. However, our findings contraindicate PVAc use as a binding agent. Further research is needed to test non-phytotoxic, readily biodegradable binding agents and to optimize biochars and seed coating processes for specific applications in agronomy and ecological restoration.

Abstract Background The ovarian reserve is a reservoir for reproductive potential. In clinical practice, early detection and treatment of premature ovarian decline characterized by abnormal ovarian reserve tests is regarded as a critical measure to prevent infertility. However, the relevant data are typically stored in an unstructured format in a hospital’s electronic medical record (EMR) system, and their retrieval requires tedious manual abstraction by domain experts. Computational tools are therefore needed to reduce the workload. Methods We presented RegEMR, an artificial intelligence tool composed of a rule-based natural language processing (NLP) extractor and a knowledge-based disease scoring model, to automatize the screening procedure of premature ovarian decline using Chinese reproductive EMRs. We used regular expressions (REs) as a text mining method and explored whether REs automatically synthesized by the genetic programming-based online platform RegexGenerator + + could be as effective as manually formulated REs. We also investigated how the representativeness of the learning corpus affected the performance of machine-generated REs. Additionally, we translated the clinical diagnostic criteria into a programmable disease diagnostic model for disease scoring and risk stratification. Four hundred outpatient medical records were collected from a Chinese fertility center. Manual review served as the gold standard, and fivefold cross-validation was used for evaluation. Results The overall F-score of manually built REs was 0.9444 (95% CI 0.9373 to 0.9515), with no significant difference (paired t test p > 0.05) compared with machine-generated REs that could be affected by training set sizes and annotation portions. The extractor performed effectively in automatically tracing the dynamic changes in hormone levels (F-score 0.9518–0.9884) and ultrasonographic measures (F-score 0.9472–0.9822). Applying the extracted information to the proposed diagnostic model, the program obtained an accuracy of 0.98 and a sensitivity of 0.93 in risk screening. For each specific disease, the automatic diagnosis in 76% of patients was consistent with that of the clinical diagnosis, and the kappa coefficient was 0.63. Conclusion A Chinese NLP system named RegEMR was developed to automatically identify high risk of early ovarian aging and diagnose related diseases from Chinese reproductive EMRs. We hope that this system can aid EMR-based data collection and clinical decision support in fertility centers.

Abstract Macrophages polarized to the M2 subtype after spinal cord injury (SCI) are beneficial for promoting neurological recovery. The crosstalk between endothelial cells (ECs) and macrophages is crucial for the imbalance between proinflammatory and pro-resolving responses caused by macrophage heterogeneity; however, this crosstalk is strengthened post-SCI, leading to inflammatory cascades and second damage. As a powerful means to regulate gene expression, epigenetic regulation of the interaction between immune cells and ECs in SCI is still largely unknown. Our previous research demonstrated that the histone demethylase UTX deletion in ECs (UTX−/− ECs) promotes neurological recovery, while the precise mechanism is unrevealed. Here, we discovered that UTX−/− ECs polarize macrophages toward the M2 subtype post-SCI. Macrophage deficiency could block the neurological recovery caused by the knockdown of UTX. The exosomes from UTX−/− ECs mediate this crosstalk. In addition, we found UTX, H3K27, and miR-467b-3p/Sfmbt2 promoters forming a regulatory complex that upregulates the miR-467b-3p in UTX−/− ECs. And then, miR-467b-3p transfers to macrophages by exosomes and activates the PI3K/AKT/mTOR signaling by decreasing PTEN expression, finally polarizing macrophage to the M2 subtype. This study reveals a mechanism by epigenetic regulation of ECs-macrophages crosstalk and identifies potential targets, which may provide opportunities for treating SCI. Graphical Abstract

Abstract Background Macrophage in the spinal cord injury (SCI) area imparts a chronic pro-inflammation effect that challenges the recovery of SCI. Previously, endothelial progenitor cell-produced exosomes (EPC-EXOs) have been noticed to facilitate revascularization and inflammation control after SCI. However, their effects on macrophage polarization remained unclear. This study aimed to investigate the EPC-EXOs' role in macrophage polarization and reveal its underlying mechanism. Methods We extracted the macrophages and EPC from the bone marrow suspension of C57BL/L mice by centrifugation. After cell identification, the EPC-EXOs were collected by ultra-high-speed centrifugation and exosome extraction kits and identified by transmission electron microscopy and nanoparticle tracking analysis. Then, macrophages were cultured with EPC-EXOs in different concentrations. We labeled the exosome to confirm its internalization by macrophage and detected the macrophage polarization marker level both in vitro and in vivo. We further estimated EPC-EXOs' protective effects on SCI by mice spinal cord tissue H&E staining and motor behavior evaluation. Finally, we performed RT-qPCR to identify the upregulated miRNA in EPC-EXOs and manipulate its expression to estimate its role in macrophage polarization, SOCS3/JAK2/STAT3 pathway activation, and motor behavior improvement. Results We found that EPC-EXOs decreased the macrophages’ pro-inflammatory marker expression and increased their anti-inflammatory marker expression on the 7 and 14 days after SCI. The spinal cord H&E staining results showed that EPC-EXOs raised the tissue-sparing area rate significantly after 28 days of SCI and the motor behavior evaluation indicated an increased BMS score and motor-evoked potential by EPC-EXOs treatment after SCI. The RT-qPCR assay identified that miR-222-3P upregulated in EPC-EXOs and its miRNA-mimic also decreased the pro-inflammatory macrophages and increased the anti-inflammatory macrophages. Additionally, miR-222-3P mimic activated the SOCS3/JAK2/STAT3 pathway, and SOCS3/JAK2/STAT3 pathway inhibition blocked miR-2223P’s effects on macrophage polarization and mouse motor behavior. Conclusion Comprehensively, we discovered that EPC-EXOs-derived miR-222-3p affected macrophage polarization via SOCS3/JAK2/STAT3 pathway and promoted mouse functional repair after SCI, which reveals EPC-EXOs’ role in modulation of macrophage phenotype and will provide a novel interventional strategy to induce post-SCI recovery.

Abstract Background Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation. Methods A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the “disease-related gene–drug effective target” interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro. Results PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats. Conclusions Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.

Superhydrophobic fabrics suggest tremendous potential in some emerging fields such as electronic skin, bioelectronic sensors and special clothing due to their excellent liquid repellency and self-cleaning properties. However, currently reported superhydrophobic materials are usually prepared using biologically toxic fluorinated compounds, which severely restricts their practical applications. Herein, we propose a two-step thiol-ene click reaction strategy to fabricate fluorine-free superhydrophobic cotton fibers (Fabric-SH-PB-SiO2). The 1,2-polybutadiene (1,2-PB) with flexible rubber molecular chains and low surface energy was coated by cotton fiber through thiol-ene click reaction. Subsequently, based on this reaction, the coated cotton fiber was used to establish chemical bonds with hydrophobic silica. The Fabric-SH-PB-SiO2 possesses a rich multi-level micro-nano structure that can form stable air layer on the surface of the fabric, which showed a high hydrophobic angle of 156° and exhibited some distinct advantages such as anti-fouling and self-cleaning characteristics, high buoyancy, and reduced drag. More remarkably, the Fabric-SH-PB-SiO2 could float on the water surface after carrying 34 times its weight. Compared with unmodified fabrics, the Fabric-SH-PB-SiO2 demonstrated a high drag reduction rate of up to 102 %, among the highest values for the reported hydrophobic materials. The strategy developed here provides insights towards fabricating high-buoyancy fluorine-free superhydrophobic cotton fibers.

ABSTRACTBackground We aimed to explore saliva microbiome alterations in dental fluorosis population.Methods The prevalence of dental fluorosis was examined in 957 college students. Dean’s fluorosis index was used to evaluate the dental fluorosis status. Changes in the composition of the salivary microbiome were assessed in a subset of these patients (100 healthy controls, 100 dental fluorosis patients).Results Dental fluorosis affected 47% of the student sample, and incidence was unrelated to gender. Compared with healthy controls, the microbiota of patients with dental fluorosis exhibited increased diversity, with increased abundance of Treponema lecithinolyticum, Vibrio metschnikovii, Cupriavidus pauculus, Pseudomonas, Pseudomonadaceae, Pseudomonadales, and decreased abundance of Streptococcus mutans, Streptococcus sanguinis, Gemella, and Staphylococcales. Function analyses showed increases in arginine biosynthesis in patients affected by dental fluorosis, together with reductions in amino sugar and nucleotide sugar metabolism, fructose and mannose metabolism, and starch and sucrose metabolism.Conclusions These results suggest that there are striking differences in salivary microbiome between healthy controls and dental fluorosis patients. Dental fluorosis may contribute to periodontitis and systemic lung diseases. There is a need for cohort studies to determine whether altering the salivary microbiota in dental fluorosis patients can alter the development of oral or systemic diseases.

Summary: Tianhe Zhuifeng Gao (TZG) shows a satisfying therapeutic efficacy in treating arthromyodynia, which shares similar etiology to myofascial pain syndrome (MPS). We herein aim to explore whether TZG could be a potential prescription for MPS therapy. An MPS rat model was successfully established presenting with reduced pain thresholds, abnormal local switch responses, etc., which was effectively reversed by TZG treatment externally. A transcriptome sequencing based on the active MTrPs samples of rats, combined with network analysis revealed that TZG might ameliorate the progression of MPS by impairing neutrophil extracellular traps (NETs) release through inhibiting PI3K-RAC2 signaling to reduce NADPH oxidase-originated ROS. Experimentally, the expression levels of inducers, biomarkers of NETs formation and vessel injury, and p-PI3K, p-P47, and RAC2 proteins were all significantly up-regulated in affected tissues, which were markedly reversed by TZG. Our results not only shed light into broadening the clinical indications of TZG, but benefit MPS therapy.

It is still a challenge to prepare flexible electromagnetic interference (EMI) shielding materials based on Ti3C2Tx MXene through a facial and scalable method. In this study, epoxied octamethyl-cyclotetrasiloxane (EPOSS) was self-assembled with Ti3C2Tx to construct EMI shielding composites via facial spraying coating. Because the EPOSS decreased the surface free energy of Ti3C2Tx in the acid-base component, the Ti3C2Tx/EPOSS suspension was able to be sprayed on carboxylated polybutadiene (CPB) uniformly. Molecular dynamics (MD) simulations were explored to demonstrate the interaction energy between EPOSS and CPB with different –COOH contents. The prepared EMI shielding composite has high abrasion resistance and good bending durability because EPOSS reinforced the interface interaction between Ti3C2Tx and CPB through covalent bonds. Based on a pre-stretching spray method, the prepared composite has high surface roughness, leading to a high specific EMI shielding effectiveness of 1800 dB cm2 g−1 at a low Ti3C2Tx loading of 8.5 wt%. Additionally, the physically protective effect of Si–O–Si cages in EPOSS provided good flame retardancy. Therefore, the proposed EPOSS-assisted Ti3C2Tx spraying strategy could prepare EMI shielding materials with high effectiveness, excellent abrasion resistance, and good flame retardancy, which has a broad prospect for the application of high-power, portable, and wearable flexible electronic devices.

Abstract Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

Abstract Tooth roots embedded in the alveolar bone do not typically undergo resorption while the bone continues remodeling in its physiological state. In this study, we analyzed genetically modified mice with the functional inactivation of nucleotide pyrophosphatase 1 (Npp1), encoded by ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). This mutation leads to the formation of ectopic cervical cementum vulnerable to external tooth root resorption. Cementoblasts with the inactivation of Enpp1 extensively expressed non-collagenous matrix proteins enriched with bone sialoprotein (Bsp), dentin matrix protein 1 (Dmp1), and osteopontin (Opn), which have roles in mineralization through nucleation and in cell adhesion through the Arg-Gly-Asp (RGD) motif. In cementoblasts with the inactivation of Enpp1, β-catenin was significantly activated and induced the expression of these non-collagenous matrix proteins. In addition, adenosine triphosphate (ATP), which is the most preferred substrate of Npp1, accumulated extracellularly and autocrinally induced the expression of the receptor activator of nuclear factor κB ligand (Rankl) in cementoblasts with inactivated Npp1. Consequently, these results strongly suggest that functional Npp1 preserves cervical cementum integrity and supports the anti-resorptive properties of tooth roots through ATP homeostasis in the physiological state of cervical cementum.

Abstract Clinical symptom‐based diagnosis and therapy play a crucial role in personalized medicine and drug discovery. The syndromes, distinctive groups of clinical symptoms summarized by traditional Chinese medicine (TCM) theories and clinical experiences, are used as the core diagnostic criteria and therapeutic guidance in TCM. However, there is still a lack of standardized data, information, and intrinsic molecular basis to help TCM syndromes better classify diseases and guide tailored medications. To address this problem, we built the first integrated web platform, SoFDA (http://www.tcmip.cn/Syndrome/front/), with a curated ontology of 319 TCM syndromes, 8045 diseases, and 1359 TCM herbal formulas and their relationships with genes, diseases, and formulas. This platform proposed an association measurement by calculating Jaccard/Cosine similarities between TCM syndromes and their related biomedical entities with case and control validations. On this basis, the SoFDA platform enables biomedical and pharmaceutical scientists to rank and filter the most promising associations for disease diagnosis and tailored interventions. Conversely, the targeted gene sets and symptom sets can also be associated with TCM syndromes, formulas, and diseases for function illustration. Notably, SoFDA explores the multi‐way associations among diseases, TCM syndromes, symptom genes, herbal formulas, drug targets, and pathways in heterogeneous biomedical networks with lots of customization. The protocol here implements all the analyses above using the SoFDA platform. Collectively, SoFDA may provide insights into the biological basis of disease‐specific TCM syndromes and the underlying molecular mechanisms, as well as a tailored treatment for single or multiple symptoms within a syndrome.

Light is an important regulator of most fungal life activities and transmits signals through certain photoreceptor proteins such as phytochromes and cryptochromes. However, the light response mechanism varies across different fungi. The WCC complex composed of white collar-1 (WC-1) and white collar-2 (WC-2) is considered to be the key factor regulating fungal albinism. The photoreceptor protein Vivid (VVD) is the negative regulator of the WCC complex. In this study, we discovered an albino mutant (Alb) generated by 60Co-γ-ray irradiation from Cordyceps militaris (C. militaris). This mutant showed albinism of the mycelia and fruiting bodies under light, and the fruiting bodies developed normally. However, this phenotype in Alb differed from that in the CmWC-1 mutant. This suggests that CmWC1 may not be mutated in Alb. A mutated polyketide synthase (CmPKS) was found through genome resequencing analysis. CmPKS was significantly induced by a light signal, and its mutation reduced melanin accumulation in C. militaris. In addition, we found that a zinc-finger domain-containing protein (CmWC-3) was induced by a light signal and interacted with CmWC-1 and CmVVD. Moreover, CmWC-2 also interacted with CmWC-1 to form the WCC complex and was inhibited by CmVVD. In addition, CmWC-3 directly bound with the CmPKS promoter, but CmWC1 did not. These results suggest that albinism and fruiting body development are two independent processes; the WCC complex of CmWC-1 with CmWC-3 regulates CmPKS expression to regulate color change, whereas CmWC-1 with CmWC-2 affects fruiting body development via the carotenoid pathway. These findings will help us to better understand the albinism mechanism of C. militaris.

Individuals with physical limb disabilities are often restricted to perform activities of daily life (ADLs). While efficacy of bilateral training has been demonstrated in improving physical coordination of human limbs, few robots have been developed in simulating people’s ADLs integrated with task-specific force field control. This study sought to develop a bilateral robot for better task rendering of general ADLs (gADLs), where gADL-consistent workspace is achieved by setting linear motors in series, and haptic rendering of multiple bimanual tasks (coupled, uncoupled and semi-coupled) is enabled by regulating force fields between robotic handles. Experiments were conducted with human users, and our results present a viable method of a single robotic system in simulating multiple physically bimanual tasks. In future, the proposed robotic system is expected to be serving as a coordination training device, and its clinical efficacy will be also investigated.

Abstract Background Growing clinical evidences show the potentials of Colquhounia root tablet (CRT) in alleviating diabetic kidney disease (DKD). However, its pharmacological properties and underlying mechanisms remain unclear. Methods ‘Drug target-Disease gene’ interaction network was constructed and the candidate network targets were screened through evaluating node genes' topological importance. Then, a DKD rat model induced by high-fat diet/streptozotocin was established and used to determine pharmacological effects and network regulatory mechanisms of CRT against DKD, which were also verified using HK2 cell model induced by high glucose. Results The candidate network targets of CRT against DKD were involved into various type II diabetes-related and nephropathy-related pathways. Due to the topological importance of the candidate network targets and the important role of the imbalance between immunity and inflammation in the pathogenesis of DKD, PI3K/AKT/NF-кB signaling-mediated immune-modulatory and anti-inflammatory actions of CRT were selected to be experimentally verified. On the basis of high-fat diet (HFD) / streptozotocin (STZ)-induced DKD rat model, CRT effectively reduced the elevated level of blood glucose, decreased the accumulation of renal lipid, suppressed inflammation and the generation of ECM proteins, and ameliorated kidney function and the renal histopathology through inhibiting the activation of PI3K, AKT and NF-кB proteins, reducing the nuclear accumulation of NF-кB protein and the serum levels of downstream cytokines, which were in line with the in vitro findings. Conclusions Our data suggest that CRT may be the promising candidate drug for treating DKD via reversing the imbalance of immune-inflammation system mediated by the PI3K/AKT/NF-кB/IL-1β/TNF-α signaling.

Abstract Zinc finger CCCH-type containing 15 (ZC3H15), a highly conserved protein involved in several cellular processes, which was responsible for tumorigenesis and may be a promising marker in myeloid leukemia (AML) and hepatocellular carcinoma (HCC). However, little is known about the biological significance and molecular mechanisms of ZC3H15 in GBM. In this study, we revealed that ZC3H15 was overexpressed in GBM and high ZC3H15 expression was associated with poor survival of patients with GBM. We found that ZC3H15 promoted the proliferation, migration, invasion, and tumorigenesis of GBM cells by activating the EGFR signaling pathway. We also revealed that ZC3H15 reduced EGFR ubiquitination, which was responsible for EGFR protein stabilization. In addition, we demonstrated that ZC3H15 inhibited the transcription of CBL, which was an E3 ubiquitin ligase for EGFR proteasomal degradation. And silencing of CBL could partly abrogate the inhibitory effects on cell proliferation, migration, and invasion of GBM cells induced by ZC3H15 knockdown. Thus, our research revealed the important roles of ZC3H15 in GBM development and provided a brand-new insight for improving the treatment of GBMs.

Abstract Zinc finger CCCH-type containing 15 (ZC3H15), a highly conserved eukaryotic protein, which was associated with several cellular processes and was ubiquitously expressed in various human tissues. Recent studies indicated that ZC3H15 was involved in tumorigenesis and may be a potential biomarker in hepatocellular carcinoma (HCC) and acute myeloid leukemia (AML). However, the biological function and molecular mechanism of ZC3H15 in gastric cancer (GC) have not been studied. In this study, we revealed that ZC3H15 was highly expressed in GC and high ZC3H15 expression was closely linked to poor survival of patients with GC. We found that ZC3H15 promoted cell proliferation, migration, and invasion by increasing c-Myc expression. Next, we found that ZC3H15 could modulate c-Myc protein stability by suppressing the transcription of FBXW7, which was mainly responsible for c-Myc degradation. Moreover, silencing of FBXW7 in ZC3H15-knockdown GC cells could partly abrogate the effects induced by ZC3H15 downregulation. Taken together, our data unearth the important roles of ZC3H15 in GC development and suggest that ZC3H15 may be a potential target for the treatment of GC.

Abstract The 0‐order natural frequency resonance is the main cause of electromagnetic vibration noise in integer slot multi‐pole pair permanent magnet synchronous motors (PMSMs) for electric vehicles. To study this phenomenon, this study proposes a finite element (FE) model of the stator system based on a 48‐slot 8‐pole permanent magnet synchronous motor for electric vehicles. Based on this model, the effects of winding, frame end cover and temperature on the natural frequencies of a stator system are analysed by using the equivalent stiffness method (ESM). The simulation results show that the 0‐order natural frequency of the stator core system decreases after considering the winding varnished, and the 0‐order natural frequency is almost unaffected after considering the frame and end cover. However, the other natural frequencies increase in different degrees. In addition, the natural frequencies of the stator core decrease with the increase of temperature. The accuracy of the finite element model is verified by the modal experiment of the hammer method (HM).

Background Streptococcus mutans is a major pathogen responsible for dental caries. Arginine is a promising potential caries preventive agent which can inhibit the growth of S. mutans. However, the mechanism whereby arginine inhibits S. mutans growth remains unclear. Aim To assess the impact of arginine-induced metabolomic perturbations on S. mutans under biofilm conditions. Methods We identified 5,933 and 7,413 ions in positive (ESI+) and negative (ESI-) electrospray ion modes, respectively, with a total of 11.05% and 11.58% differential ions subsequently detected in two respective modes. Further analyses of these metabolites led to identification of 8 and 22 metabolic pathways that were affected by arginine treatment in ESI+ and ESI- modes., Results Once or twice daily treatments of S. mutans biofilms with arginine resulted in reductions in biofilm biomass. Significant reductions in EPS production were observed following twice daily arginine treatments. Identified metabolites that were significantly differentially abundant following arginine treatment were associated with glycolysis metabolism, amino sugar and nucleotide sugar metabolism, and peptidoglycan synthesis. Conclusions Arginine can reduce S. mutans biofilm growth and acid production by inhibiting glycolysis, amino sugar and nucleotide sugar metabolism, and peptidoglycan synthesis.

Abstract RAN binding protein 10 (RANBP10), a ubiquitously expressed and evolutionarily conserved protein, as a RAN-GTP exchange factor (GEF) to regulate several factors involved in cellular progression. Previous studies showed that RANBP10 was overexpressed in prostate cancer cells and was responsible for androgen receptor (AR) activation. However, the biological function of RANBP10 in glioblastoma (GBM) has not been studied. Here, we found that RANBP10 was overexpressed in GBM, and high RANBP10 expression was closely linked to poor survival of patients with GBM. Downregulation of RANBP10 significantly inhibited cell proliferation, migration, invasion, and tumor growth of GBM cells. In addition, we revealed that RANBP10 could suppress the promoter activity of FBXW7, and thereby increase the protein stability of c-Myc in GBM cells. Silencing of FBXW7 in RANBP10-knockdown GBM cells could partly negate the effects induced by RANBP10 downregulation. Taken together, our findings established that RANBP10 significantly promoted GBM progression by control of the FBXW7–c-Myc axis, and suggest that RANBP10 may be a potential target in GBM.

Abstract Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin‐21 (IL‐21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL‐6 and IL‐21 receptors, thereby inhibiting the bindings of IL‐6 and IL‐21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides‐mediated immunomodulation.

Summary: The presence of anti-citrullinated protein autoantibodies (ACPA) is a hallmark feature of rheumatoid arthritis (RA), which causes chronic joint destruction and systemic inflammation. Based on ACPA status, RA patients can be sub-grouped into two major subsets: ACPA-positive RA (ACPA+ RA) and ACPA-negative RA (ACPA– RA). Accumulating evidence have suggested that ACPA+ RA and ACPA– RA are two distinct disease entities with different underlying pathophysiology. In contrast to the well-characterized pathogenic mechanisms of ACPA+ RA, the etiology of ACPA– RA remains largely unknown. In this review, we summarized current knowledge about the primary drivers of ACPA– RA, particularly focusing on the serological, cellular, and molecular aspects of immune mechanisms. A better understanding of the immunopathogenesis in ACPA– RA will help in designing more precisely targeting strategies, and paving the road to personalized treatment. In addition, identification of novel biomarkers in ACPA– RA will substantially promote early treatment and improve the outcomes.

Streptococcus mutans (S. mutans) is one of the primary pathogens responsible for dental caries. Streptococcus gordonii (S. gordonii) is one of the early colonizers of dental plaque and can compete with S. mutans for growth. In the present analysis, we explored key target genes against S. gordonii in S. mutans using 80 S. mutans clinical isolates with varying capabilities against S. gordonii. A principal coordinate analysis revealed significant genetic diversity differences between antagonistic and non-antagonistic groups. Genomic comparisons revealed 33 and 61 genes that were, respectively, positively and negatively correlated with S. mutans against S. gordonii, with RNA-sequencing (RNA-seq) highlighting 11 and 43 genes that were, respectively, upregulated and downregulated in the antagonistic group. Through a combination of these results and antiSMASH analysis, we selected 16 genes for qRT-PCR validation in which the expression levels of SMU_137 (malate dehydrogenase, mleS), SMU_138 (malate permease, mleP), SMU_139 (oxalate decarboxylase, oxdC), and SMU_140 (glutathione reductase) were consistent with RNA-seq results. SMU_1315c-1317c (SMU_1315c transport-related gene) and SMU_1908c-1909c were, respectively, downregulated and upregulated in the antagonistic group. The expression patterns of adjacent genes were closely related, with correlation coefficient values greater than 0.9. These data reveal new targets (SMU_137–140, SMU_1315c-1317c, and SMU_1908c-1909c) for investigating the critical gene clusters against S. gordonii in S. mutans clinical isolates.

Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine–threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

Growing evidence shows that Baihu-Guizhi decoction (BHGZD), a traditional Chinese medicine (TCM)-originated disease-modifying anti-rheumatic prescription, may exert a satisfying clinical efficacy for rheumatoid arthritis (RA) therapy. In our previous studies, we verified its immunomodulatory and anti-inflammatory activities. However, bioactive compounds (BACs) of BHGZD and the underlying mechanisms remain unclear. Herein, an integrative research strategy combining UFLC-Q-TOF-MS/MS, gene expression profiling, network calculation, pharmacokinetic profiling, surface plasmon resonance, microscale thermophoresis, and pharmacological experiments was carried out to identify the putative targets of BHGZD and underlying BACs. After that, both in vitro and in vivo experiments were performed to determine the drug effects and pharmacological mechanisms. As a result, the calculation and functional modularization based on the interaction network of the “RA-related gene–BHGZD effective gene” screened the TLR4/PI3K/AKT/NFκB/NLRP3 signaling-mediated pyroptosis to be one of the candidate effective targets of BHGZD for reversing the imbalance network of “immune-inflammation” during RA progression. In addition, both mangiferin (MG) and cinnamic acid (CA) were identified as representative BACs acting on that target, for the strong binding affinities between compounds and target proteins, good pharmacokinetic features, and similar pharmacological effects to BHGZD. Notably, both BHGZD and the two-BAC combination of MG and CA effectively alleviated the disease severity of the adjuvant-induced arthritis-modified rat model, including elevating pain thresholds, relieving joint inflammation and bone erosion via inhibiting NF-κB via TLR4/PI3K/AKT signaling to suppress the activation of the NLRP3 inflammasome, leading to the downregulation of downstream caspase-1, the reduced release of IL-1β and IL-18, and the modulation of GSDMD-mediated pyroptosis. Consistent data were obtained based on the in vitro pyroptosis cellular models of RAW264.7 and MH7A cells induced by LPS/ATP. In conclusion, these findings offer an evidence that the MG and CA combination identified from BHGZD may interact with TLR4/PI3K/AKT/NFκB signaling to inhibit NLRP3 inflammasome activation and modulate pyroptosis, which provides the novel representative BACs and pharmacological mechanisms of BHGZD against active RA. Our data may shed new light on the mechanisms of the TCM formulas and promote the modernization development of TCM and drug discovery.

Abstract Background As the key regulators in BR signaling, BES1 family genes regulate thousands of target genes involved in various development processes. So far, the functions of BES1 family are poorly understood in tomato, and a comprehensive genomic and expressional analysis is worth to conduct for this family. Results Here, nine SlBES1 family members were identified in tomato and classified into five groups based on the conserved motif, gene structure and phylogenetic analysis. Synteny among tomato, Arabidopsis, pepper and rice were further analyzed to obtain insights into evolutionary characteristics. Several cis-elements related to hormone, stress and plant development were exhibited in the promoter regions of SlBES1 family genes. Subcellular localization showed seven members localized both in the nucleus and cytoplasm, implying the presence of dephosphorylated and phosphorylated form of these seven proteins, furthermore, five of them possessed transcription activation activity whereas the left two functioned as transcriptional repressors. Another two members, however, neither localized in the nucleus nor had transactivation activity. Besides, SlBES1.8 showed flower-specific expression while other members expressed ubiquitously in all organs. Moreover, SlBES1 genes exhibited variational expression in response to nine principal plant hormones. Notably, the expression levels of SlBES1 genes presented a dominant downregulated trend in response to stresses. Conclusions In this study, we systematically analyzed the genomic characterization of SlBES1 family, together with the analyses of protein functional features and expression patterns, our results lay a foundation for the functional research of SlBES1 family.

Abstract In this study, we analyzed the complete mitochondrial genome (mitogenome) of Speiredonia retorta, which is a pest and a member of the Lepidoptera order. In total, the S. retorta mitogenome was found to contain 15,652 base pairs encoding 13 protein-coding genes (PCGs), 22 tRNAs, 2 rRNAs, as well as an adenine (A) + thymine (T)-rich region. These findings were consistent with the mitogenome composition of other lepidopterans, as we identified all 13 PCGs beginning at ATN codons. We also found that 11 PCGs terminated with canonical stop codons, whereas cox2 and nad4 exhibited incomplete termination codons. By analyzing the mitogenome of S. retorta using Bayesian inference (BI) and maximum likelihood (ML) models, we were able to further confirm that this species is a member of the Erebidae family.

Abstract As a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression, but its biological functions and molecular mechanisms in melanoma remain unknown. Our study showed that CSN6 expression was upregulated in melanoma patients and cells, and correlated with poor survival in melanoma patients. In melanoma cells, CSN6 knockdown remarkably inhibited cell proliferation, tumorigenicity, migration, and invasion, whereas CSN6 recovery rescued the proliferative and metastatic abilities. Notably, we identified that CSN6 stabilized CDK9 expression by reducing CDK9 ubiquitination levels, thereby activating CDK9-mediated signaling pathways. In addition, our study described a novel CSN6-interacting E3 ligase UBR5, which was negatively regulated by CSN6 and could regulate the ubiquitination and degradation of CDK9 in melanoma cells. Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5/CDK9 pathway to promote melanoma cell proliferation and metastasis. Thus, this study illustrates the mechanism by which the CSN6-UBR5-CDK9 axis promotes melanoma development, and demonstrate that CSN6 may be a potential biomarker and anticancer target in melanoma.

Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) have been reported in recent years across Asian countries and pose a serious threat to public health. Neutrophils represent the first line of defense against numerous infectious pathogens, such as CR-hvKP. Neutrophil extracellular traps (NETs) constitute one of the major antimicrobial defense mechanisms in neutrophils against invading pathogens, especially against hvKP. Interestingly, previous studies have demonstrated that patients with type 2 diabetes mellitus (T2D) display elevated levels of NETosis but are vulnerable to infections caused by hvKP. The discrepancy propels us to investigate the role of NETs in hvKP infections in the context of T2D. By utilizing a clinical-derived CR-hvKP strain and a combination of NETs complex detection, phagocytosis testing, NETs killing assay and immunofluorescence, and scanning electron microscope assays, we identified defective NETs-mediated killing of CR-hvKP strain in patients with T2D. Specifically, we show that the impaired NETs-mediated killing in T2D is not due to the decreased NETs formation, as the neutrophils isolated from T2D patients exhibited enhanced NETs formation compared to healthy controls. Further, we demonstrate that the reduced NETs activity does not result from the trapping failure of CR-hvKP, but likely associated with the deficient surface damage conferred by the NETs of T2D patients. Our data provide a novel insight into the defective innate immune response against CR-hvKP in T2D.

BackgroundBacillus Calmette–Guérin (BCG) is currently the most effective intravesical therapy for non-muscle-invasive bladder cancer (NMIBC) as it can prevent disease recurrence and progression and lower mortality. However, the response rates to BCG vary widely and are dependent on a multitude of factors.MethodsWe performed a systematic discovery by analyzing the whole exome sequence, expression profile, and immune repertoire sequence of treatment-naive and 5-year time-serial relapsed tumors from 24 NMIBC patients.ResultsBCG therapy showed bidirectional effects on tumor evolution and immune checkpoint landscape, along with a significant reduction of the percentage of neoantigen burden. In addition, a remarkable proportion of subclonal mutations were unique to the matched pre- or post-treatment tumors, suggesting the presence of BCG-induced and/or spatial heterogeneity. In the relapsed tumors, we identified and validated a shift in the mutational signatures in which mutations associated with aristolochic acid (AA) exposure were enriched, implying AA may be associated with tumor recurrence. Enhanced expressions of immune checkpoint regulation genes were found in the relapsed tumors, suggesting that the combination of immune checkpoint with BCG treatment may be an effective strategy to treat NMIBC. TCR sequencing revealed treatment-associated changes in the T-cell repertoire in the primary and relapsed tumors.ConclusionOur results provide insight into the genomic and immune dynamics of tumor evolution with BCG treatment, suggest new mechanisms of BCG resistance, and inform the development of clinically relevant biomarkers and trials of potential immune checkpoint inhibitor combination therapies.

APETALA2/ethylene responsive factors (AP2/ERF) are unique regulators in the plant kingdom and are involved in the whole life activity processes such as development, ripening, and biotic and abiotic stresses. In tomato (Solanum lycopersicum), there are 140 AP2/ERF genes; however, their functionality remains poorly understood. In this work, the 14th and 19th amino acid differences in the AP2 domain were used to distinguish DREB and ERF subfamily members. Even when the AP2 domain of 68 ERF proteins from 20 plant species and motifs in tomato DREB and ERF proteins were compared, the binding ability of DREB and ERF proteins with DRE/CRT and/or GCC boxes remained unknown. During fruit development and ripening, the expressions of 13 DREB and 19 ERF subfamily genes showed some regular changes, and the promoters of most genes had ARF, DRE/CRT, and/or GCC boxes. This suggests that these genes directly or indirectly respond to IAA and/or ethylene (ET) signals during fruit development and ripening. Moreover, some of these may feedback regulate IAA or ET biosynthesis. In addition, 16 EAR motif-containing ERF genes in tomato were expressed in many organs and their total transcripts per million (TPM) values exceeded those of other ERF genes in most organs. To determine whether the EAR motif in EAR motif-containing ERF proteins has repression function, their EAR motifs were retained or deleted in a yeast one-hybrid (YIH) assay. The results indicate that most of EAR motif-containing ERF proteins lost repression activity after deleting the EAR motif. Moreover, some of these were expressed during ripening. Thus, these EAR motif-containing ERF proteins play vital roles in balancing the regulatory functions of other ERF proteins by completing the DRE/CRT and/or GCC box sites of target genes to ensure normal growth and development in tomato.

Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by the production of abnormal autoantibodies and immune complexes that can affect the organ and organ systems, particularly the kidneys and the cardiovascular system. Emerging evidence suggests that dysregulated lipid metabolism, especially in key effector cells, such as T cells, B cells, and innate immune cells, exerts complex effects on the pathogenesis and progression of SLE. Beyond their important roles as membrane components and energy storage, different lipids can also modulate different cellular processes, such as proliferation, differentiation, and survival. In this review, we summarize altered lipid metabolism and the associated mechanisms involved in the pathogenesis and progression of SLE. Furthermore, we discuss the recent progress in the role of lipid metabolism as a potential therapeutic target in SLE.

ABSTRACTTigecycline is considered one of the last-resort antimicrobials for carbapenem-resistant K. pneumoniae. Plasmid-mediated tigecycline resistance remains largely unclear. Here, by utilizing whole genome sequencing, we report a plasmid-mediated tigecycline resistance mechanism, a 6,489 bp Resistance-nodulation-division family (RND) efflux pump (tmexCD1-toprJ1 pump), that confers transferable tigecycline resistance in K pneumoniae isolated from patients and chickens. In addition, we identified high prevalence of the plasmids co-harbouring both tmexCD1-toprJ1 pump and mcr (tmexCD1-mcr co-harbouring plasmid) from human in our nationwide collection. Even worse, the tmexCD1-toprJ1 and mcr co-harbouring plasmid was also co-existed with blaNDM-harbouring IncX3 plasmid in the same host, resulting in pandrug resistance. Phylogenetic analysis suggested that the plasmid-borne tmexCD1-toprJ1 originated from the chromosome of Aeromonas spp. through Tn5393-mediating translocation. Both plasmid-harbored tmexCD1-toprJ1 gene and mcr-8 likely originated from animal isolates and then spread to human. Our findings highlight a substantial threat of tmexCD1-toprJ1-mcr8 co-harbouring IncFIA/IncFII plasmid to public health due to their mobile resistance to both tigecycline and colistin, emphasizing an urgent need for further global surveillance on this plasmid.

Spinal cord injury (SCI) is a catastrophic event mainly involving neuronal apoptosis and axonal disruption, and it causes severe motor and sensory deficits. Due to the complicated pathological process of SCI, there is currently still a lack of effective treatment for SCI. Microglia, a type of immune cell residing in the central nervous system (CNS), need to respond to various stimuli to protect neuronal cells from death. It was also reported that microRNAs (miRNAs) had been identified in microglia-derived exosomes that can be taken up by neurons. However, the kinds of miRNAs in exosome cargo derived from microglia and the underlying mechanisms by which they contribute to neuroprotection after SCI remain unknown. In the present study, a contusive SCI mouse model and in vitro experiments were applied to explore the therapeutic effects of microglia-derived exosomes on neuronal apoptosis, axonal regrowth, and functional recovery after SCI. Then, miRNA analysis, rescue experiments, and luciferase activity assays for target genes were performed to confirm the role and underlying mechanism of microglia-derived exosomal miRNAs in SCI. We revealed that microglia-derived exosomes could promote neurological functional recovery by suppressing neuronal apoptosis and promoting axonal regrowth both in vivo and in vitro. MicroRNA-151-3p is abundant in microglia-derived exosomes and is necessary for mediating the neuroprotective effect of microglia-derived exosomes for SCI repair. Luciferase activity assays reported that P53 was the target gene for miR-151-3p and that p53/p21/CDK1 signaling cascades may be involved in the modulation of neuronal apoptosis and axonal regrowth by microglia-derived exosomal microRNA-151-3p. In conclusion, our data demonstrated that microglia-derived exosomes (microglia-Exos) might be a promising, cell-free approach for the treatment of SCI. MicroRNA-151-3p is the key molecule in microglia-derived exosomes that mediates the neuroprotective effects of SCI treatments.

Abstract With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1. Meanwhile, Self‐renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p‐Try1068 of EGFR, p‐Ser473 of AKT and p‐Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1‐promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.