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Background Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. Methods A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson’s trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student’s t-test for two-group comparisons, and one-way ANOVA followed by Student–Newman–Keul test for multiple-group comparisons. Results We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis. Conclusions Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity. Graphical abstract

High-fat diet (HFD) promotes lung pre-metastatic niche formation and metastasis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrate that glycyrrhizic acid (GA) prevents HFD-enhanced pre-metastatic niche formation and metastasis through gut microbiota. GA reduced HFD-enhanced myeloid-derived suppressor cell recruitment, pro-metastatic protein S100A8/A9 expression and metastasis burden of 4T1 breast cancer and B16F10 melanoma, accompanied by gut microbiota alteration and colonic macrophage polarization far away the M1-like phenotype. These parameters were greatly decreased by treatment with antibiotics, recolonization of Desulfovibrio vulgaris and Clostridium sordellii, and administration of lipopolysaccharide or deoxycholic acid. Macrophage depletion attenuated HFD-enhanced pre-metastatic niche formation and metastasis, but failed to further affect the effects of GA. Mechanistically, counteraction of HFD-enhanced gut microbiota dysbiosis by GA inhibited Gr-1+ myeloid cell migration and S100A8/A9 expression through decreasing the proportion of M1-like macrophages and their production of CCL2 and TNF-α in the colons via LPS/HMGB1/NF-κB signaling inactivation. Together, targeting the gut microbiota by GA to modulate colonic macrophages could be a novel strategy for the prevention of HFD-enhanced pre-metastatic niche formation and metastasis.

Pulverized coal mass concentration in the primary air pipe is one of the essential parameters for promoting furnace combustion efficiency. However, attaining accurate, real-time, and online detection for pulverized coal mass concentration remains challenging due to factors such as large pipe diameter and high flow rate. This study introduces a quasi-open microwave resonant cavity sensor. The principle and model were analyzed using the perturbation method, and the design and optimization were conducted with the simulation. A prototype and its test system were constructed, and the test results demonstrated good agreement between the simulations and experiments. The simulation revealed that the resonant frequency decreased monotonically from 861 to 644 MHz as mass concentration increased within 20%~80%, resulting in a change of about 3.62 MHz/1% under static mixture. The resonant frequency showed a drop from 21 MHz to 9 MHz with an increase in mass concentration under pulverized coal flow. Prediction models were developed and validated, showing the absolute values of the relative errors to be within 4% under operational scenarios. Additionally, the impact of the sensor on pulverized coal flow was evaluated, and it was found that the sensor structure had minimal impact on the flow in terms of velocity and the distribution of continuous flow. Finally, the long-term stability was assessed by examining the wear of the antennas and barriers. With inner barriers experiencing up to 2/3d wear, the resonant frequency drift ratio remained below 1.5%, corresponding to a mass concentration deviation of less than 3.2%.

Newcastle disease virus (NDV) belongs to Paramyxoviridae, which contains lethal human and animal pathogens. NDV RNA genome is replicated and transcribed by a multifunctional 250 kDa RNA-dependent RNA polymerase (L protein). To date, high-resolution structure of NDV L protein complexed with P protein remains to be elucidated, limiting our understanding of the molecular mechanisms of Paramyxoviridae replication/transcription. Here, we used cryo-EM and enzymatic assays to investigate the structure-function relationship of L-P complex. We found that C-terminal of CD-MTase-CTD module of the atomic-resolution L-P complex conformationally rearranges, and the priming/intrusion loops are likely in RNA elongation conformations different from previous structures. The P protein adopts a unique tetrameric organization and interacts with L protein. Our findings indicate that NDV L-P complex represents elongation state distinct from previous structures. Our work greatly advances the understanding of Paramyxoviridae RNA synthesis, revealing how initiation/elongation alternates, providing clues for identifying therapeutic targets against Paramyxoviridae. Newcastle disease virus (NDV) belongs to Paramyxoviridae and encodes a large protein (L) and phosphoprotein (P) for viral RNA synthesis. Here the authors present cryo-EM structures of the L-P complex, and propose a model of how RNA initiation/elongation alternates during viral RNA synthesis.

Junin virus (JUNV) causes Argentine hemorrhagic fever, a debilitating human disease of high mortality rates and a great risk to public health worldwide. Studying the L protein that replicates and transcribes the genome of JUNV, and its regulator Z protein should provide critical clues to identify therapeutic targets for disrupting the life cycle of JUNV. Here we report the 3.54 Å cryo-EM structure of the JUNV L protein complexed with regulator Z protein. JUNV L structure reveals a conserved architecture containing signature motifs found in other L proteins. Structural analysis shows that L protein is regulated by binding of Z protein at the RNA product exit site. Based on these findings, we propose a model for the role of Z protein as a switch to turn on/off the viral RNA synthesis via its interaction with L protein. Our work unveils the mechanism of JUNV transcription, replication and regulation, which provides a framework for the rational design of antivirals for combating viral infections. Junin virus (JUNV) causes Argentine hemorrhagic fever and encodes the large protein (L) of the RNA dependent RNA polymerase (RdRp) and its regulator, the matrix zinc-binding protein (Z). Here, the authors present the 3.54 Å cryo-EM structure of the complex of JUNV L with Z, and they propose a model of how JUNV L is regulated by Z during the viral life cycle and RNA synthesis.

Background Arachidonic acid (AA) metabolic enzymes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1) and cytochrome P450 (CYP) 4A11 play important roles in glioma angiogenesis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Methods A homology model of human CYP4A11 was constructed using SYBYL-X 2.0. Structure-based virtual screening against COX-2, mPGES-1 and CYP4A11was performed using the Surflex-Dock of the SYBYL suite. The candidates were further evaluated their antiangiogenic activities in a zebrafish embryo and rabbit corneal angiogenesis model. Laser doppler analysis was used to measure tumor perfusion. The expression of CD31 and α-SMA was measured by immunofluorescence. Western blot was used to measure the expression of HIF-1, Akt and p-Akt. The gene expression of FGF-2, G-CSF, PDGF, TGF-β, Tie-2, VEGF, lncRNA NEAT1 and miR-194-5p were determined using qPCR. The production of FGF-2, TGF-β and VEGF were analyzed using ELISA. Bioinformatic analysis and luciferase reporter assays confirmed the interaction between lncRNA NEAT1 and miR-194-5p. Results The nearly 36,043 compounds from the Traditional Chinese Medicine (TCM) database were screened against COX-2, mPGES-1 and CYP4A11 3D models, and the 17 top flavonoids were identified. In zebrafish screening, isoliquiritigenin (ISL) exhibited the most potent antiangiogenic activities with the EC 50 values of 5.9 μM. Conversely, the antiangiogenic effects of ISL in the zebrafish and rabbit corneal models were partly reversed by 20-hydroxyeicosatetraenoic acid (20-HETE) or prostaglandin E2 (PGE 2 ). ISL normalized glioma vasculature and improved the efficacy of temozolomide therapy in the rat C6 glioma model. Inhibition of COX-2, mPGES-1 and CYP4A by ISL decreased FGF-2, TGF-β and VEGF production in the C6 and U87 glioma cells with p-Akt downregulation, which was reversed by Akt overexpression. Furthermore, ISL downregulated lncRNA NEAT1 but upregulated miR-194-5p in the U87 glioma cell. Importantly, lncRNA NEAT1 overexpression reversed ISL-mediated increase in miR-194-5p expression, and thereby attenuated FGF-2, TGF-β and VEGF production. Conclusions Reprogramming COX-2, mPGES-1 and CYP4A mediated-AA metabolism in glioma by flavonoid ISL inhibits the angiogenic Akt- FGF-2/TGF-β/VEGF signaling through ceRNA effect of miR-194-5p and lncRNA NEAT1, and may serve as a novel therapeutic strategy for human glioma.

Due to accelerated urbanization, modern urban residents are facing increasing life pressures. Many citizens are experiencing situational aversion in daily commuting, and the deterioration in the traffic environment has led to psychological distress of varying degrees among urban dwellers. Cyclists, who account for about 7% of urban commuters, lack a sense of belonging in the urban space and experience significant deficiencies in the corresponding urban infrastructure, which causes more people to face significant barriers to choosing cycling as a mode of transportation. To address the aforementioned issues, this study proposes a bionic intelligent interaction helmet (BIIH) designed and validated based on the principles of bionics, which has undergone morphological design and structural validation. Constructed around the STM32-embedded development board, the BIIH is an integrated smart cycling helmet engineered to perceive environmental conditions and enable both human–machine interactions and environment–machine interactions. The system incorporates an array of sophisticated electronic components, including temperature and humidity sensors; ultrasonic sensors; ambient light sensors; voice recognition modules; cooling fans; LED indicators; and OLED displays. Additionally, the device is equipped with a mobile power supply, enhancing its portability and ensuring operational efficacy under dynamic conditions. Compared with conventional helmets designed for analogous purposes, the BIIH offers four distinct advantages. Firstly, it enhances the wearer’s environmental perception, thereby improving safety during operation. Secondly, it incorporates a real-time interaction function that optimizes the cycling experience while mitigating psychological stress. Thirdly, validated through bionic design principles, the BIIH exhibits increased specific stiffness, enhancing its structural integrity. Finally, the device’s integrated power and storage capabilities render it portable, autonomous, and adaptable, facilitating iterative improvements and fostering self-sustained development. Collectively, these features establish the BIIH as a methodological and technical foundation for exploring novel research scenarios and prospective applications.

For the gob-side entry retained by roof cutting, the roof pre-splitting depth is directly related to its stability, especially under the condition of fully mechanized mining in 4.5 m thick coal seam underneath 13.7 m thick limestone roof. Due to insufficient investigation, the Yongning coal mine 10202 gob-side entry retained by roof cutting experienced large rock pressure, causing severe prop deformation and sharp reduction in the cross-section of the entry, which greatly affects its reuse. Extensive field measurements were conducted to analyze the severe rock pressure in the 10202 gob-side entry retained. Two typical models of overburden structure after roof pre-splitting were established, and they were used to study the effect of pre-splitting depth on the stability of gob-side entry retained in terms of the roof subsidence and the support resistance, respectively. A numerical investigation of the effect of roof pre-splitting depth on the stress distribution near the gob-side entry retained was carried out. Afterwards, the roof pre-splitting parameters for the 10204 gob-side entry retained were optimized, and they were validated through field experiments. The results indicated that insufficient pre-splitting depth is the main factor causing the severe rock pressure of the 10202 gob-side entry retained. The roof subsidence and support resistance after main roof pre-splitting were reduced by 35.2% and 24.8% compared with immediate roof pre-splitting, respectively. As pre-splitting depth increased, the stress-relaxation area expanded, but the pressure-relief effect weakened beyond 20 m. As the roof pre-splitting depth increased, the weighting interval increased, but the working resistance decreased, which indicates that the goaf is almost densely filled by the collapsed roof and the main roof has no space for subsidence movement. Thus, the rock pressure behaviors of the 10204 gob-side entry retained were milder than that of the 10202 gob-side entry retained.

The great success of fully mechanized mining with a large mining height of 8 m and above in Mongolia and Shaanxi proves the feasibility of this technology. Although fully mechanized mining with a large mining height significantly increases the production capacity of mining areas, there are higher requirements for mining safety. Due to the special conditions of the 8 m coal seam in Huoxi Coalfield, the adoption of fully mechanized mining with a large mining height faces a serious problem of spalling. The key to whether complete equipment for fully mechanized mining with a large mining height can be adopted lies in the possibility to reduce such risks. In this paper, the mechanism of spalling on the 8 m fully mechanized mining face in Huoxi Coalfield is analyzed through theoretical analysis, numerical calculations and comparison of on-site data, and a “one point four zone” comprehensive evaluation method for coal seam at the front end of the working face is established based on the failure characteristics of the coal seam; according to the numerical simulation test results, it is believed that the presence of a dirt band in the middle and upper parts of the coal seam has a positive effect on the control of spalling; the overburden structure of Huoxi Coalfield exhibits the changes in “cantilever-instability-hinge”, and there is a risk of caving before the mining face, which exacerbates spalling; the advance blasting roof cutting of the working face has a significant effect on controlling the spalling of production coal faces. This research provides a theoretical basis and engineering reference for the treatment of spalling in fully mechanized mining with a large mining height in Huoxi Coalfield.

In order to alleviate the risk of landslides on high and steep slopes during excavation, slope protection coal pillars are commonly increased at the site to maintain slope stability, which causes a considerable waste of coal. In roof cutting for pressure relief at quarries, the movement of the overburden structure is artificially regulated by blasting. However, there is a lack of theoretical research on the impact on the slope movement. In order to explore how blasting roof cutting affects the deformation and fracture of slopes, a case study of the 10101 working face of Xinyuan Coal Mine was carried out. The particle flow code numerical simulation of the mining with different heights of roof cutting was performed to analyze the impact of the height of roof cutting on the movement of overlaying rock formation, the development of slope fractures, stress distribution, collapse angle, slope deformation and fracture, etc. The research results are as follows: the overlaying rock formation can be divided into the stable zone, the rotary zone and the subsidence area by displacement; a reasonable roof-cutting height allows the cutting and crushing of the overlaying rock formation, as a result of which the movement boundary is offset to cutting line and the slope is within the stable area; at the same time, the horizontal displacement of the rock formation in the rotary zone, the collapse angle and the stress at slope bottom are reduced, which controls the deformation and failure of slope by inhibiting the development of cracks at slope bottom and reducing the rotation of the rotary zone to the goaf zone. The research results provide certain references for controlling ground sedimentation and slopes in blasting roof cutting.