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Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs + Laser treatment was superior to that of high-dose CPT, and PCRHNs + Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs + Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella, which may be attributed to diarrhea caused by CPT, thus leading to a reduction in microbial burden; additionally, Escherichia-Shigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea. PCRHNs + Laser treatment increased the abundance of Lactobacillus (probiotics), possibly due to the photothermal effect of the PCRHNs. This effect increased catalase activity, thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body, which is conducive to the growth of facultative anaerobic bacteria.

The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury. Label retaining cells (LRCs) expressing SRY-box transcription factor 9 (SOX9) promote epithelial repair by replenishing LGR5+ intestinal stem cells (ISCs). While, LRCs are also considered precursor cells for enteroendocrine cells (EECs) which exacerbate mucosal damage in inflammatory bowel disease (IBD). The factors that determine LRC-EEC differentiation and the effect of intervening in LRC-EEC differentiation on IBD remain unclear. In this study, we investigated the effects of a natural anthraquinone called aloe emodin (derived from the Chinese herb rhubarb) on mucosal healing in IBD models. Our findings demonstrated that aloe emodin effectively interfered with the differentiation to EECs and preserved a higher number of SOX9+ LRCs, thereby promoting mucosal healing. Furthermore, we discovered that aloe emodin acted as an antagonist of free fatty acid receptors (FFAR1), suppressing the FFAR1-mediated Gβγ/serine/threonine-protein kinase (AKT) pathway and promoting the translocation of forkhead box protein O1 (FOXO1) into the nucleus, ultimately resulting in the intervention of differentiation fate. These findings reveal the effect of free fatty acid accessibility on EEC differentiation and introduce a strategy for promoting mucosal healing in IBD by regulating the FFAR1/AKT/FOXO1 signaling pathway.

Abstract Ground subsidence caused by extraction of longwall panels has always been a great concern all over the world. Conventional longwall mining system (CLMS) gives rise to wavy subsidence causing great damage to surface structures. A coal mine in Shanxi, China, utilizes a split-level longwall layout (SLL) for a sub-horizontal No. 8 coal seam to improve the cavability of mudstone interlayer and top coal. This layout, however, also produced unexpectedly favorable surface subsidence. Subsidence of No. 6 and No. 8 longwall panels was monitored while mining was conducted. Field instrumentation and numerical simulation were carried out. It is demonstrated that an asymmetric subsidence profile with stepped subsidence and cracks occurred on the tailgate side but relatively mild and smooth deformation on the other. Due to elimination of conventional parallelepiped gate pillar, No. 6 and No. 8 gobs were connected. Extraction of two SLL panels acted as one supercritical panel. The maximum possible subsidence was reached which lowers the likelihood of potential future secondary subsidence as underground gob fractures and voids have closed. Therefore, SLL is more favorable for post-mining land reuse as gobs are more consolidated underground.

Based on existing triaxial compression experimental data, a new empirical failure criterion with wide applicability was proposed considering hydrostatic pressure, second stress invariance, and maximum shear stress. Four fitting evaluation indicators were used to verify the consistency of the new failure criterion, and the differences with the other 6 failure criteria were discussed. The characteristics of the new failure criteria in the principal stress space were finally analyzed. The results indicate that (1) the new failure criterion exhibits strong predictive ability for triaxial experiments and has good applicability for both intact and jointed rocks; (2) the influence of hydrostatic pressure on the failure surface exhibits a non-linear trend, and different hydrostatic pressure also exhibits different distribution patterns on the deviatoric stress plane, with a distribution characteristic pattern of hexagonal snowflake-regular hexagon. The maximum shear stress has a torsional effect on the new criterion, in the three-dimensional failure surface. The parameters a and b of the rock have an impact on the failure surface morphology of the new criterion function on the offset surface.

The coal industry is the ballast stone and stabilizer that supports the rapid development of China’s economy and society and ensures national energy security. It also undertakes the mission of ensuring energy supply and supporting the stable development of new energy. At present, the high-quality development of China’s coal industry has achieved some staged results, with remarkable achievements in energy supply, the continuous optimization of industrial structure, the significant improvement of scientific and technological innovation capabilities, and the continuous advance of green development and clean and efficient utilization. However, the current development level of the coal industry is far from meeting the national needs of Chinese-style modernization. The sustainable development is restricted by multiple factors. The digital technology and coal development and utilization have not yet been deeply integrated. The intelligent construction is still in the demonstration and cultivation stage. The green development is unbalanced and contradictory and prominent. The transformation and upgrading of the coal industry still has a long way to go. In view of the current development status and challenges of the coal industry, this paper proposes a synergistic development mode of digitalization, intelligentization and greenization (three -izations), clarifies the core connotation of new-quality coal productivity, constructs the overall framework of the synergistic development of new-quality coal productivity, and expounds the technical path for the transformation of the innovative allocation of production factors by digitalization, the breakthrough of key technologies led by intelligentization, and the deep transformation of traditional industries by greenization, i.e., by these three factors to generate new-quality coal productivity. Six major technical systems are proposed: through the research and development of the technical system of efficient data collection and in-depth governance of the whole industry chain, the data barriers among coal production, transportation, storage, marketing and use of the whole process are removed. Through the research and development of the knowledge map and intelligent decision-making and control technological system of the coal industry, the correlation relationship and value of the upstream and downstream business scenarios of the coal industry are deeply explored, so as to lay the foundation for the independent decision-making and intelligent control of the whole process of coal production and utilization. Also, the research should be carried out in terms of the intelligent-green-efficient development technological system of coal resources, the technical system of collaborative guarantee of safety in the coal industry, the technical system of ecological intelligent monitoring-early warning-restoration in mining areas, and the technical system of flexible development and clean and low-carbon utilization of coal, so as to realize the synergistic development of the whole industrial chain and the whole process of coal development and utilization, cultivate and form a new-quality coal productivity, and bring some fundamental changes and improvements to the overall image of the coal industry.

Background: Glucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear. Experimental approach: We designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats. Key results: The high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study. Conclusion: We compared the potential of the Fc fusion protein GLP-1/GCG dual receptor agonists with different receptor selectivity to provide the setting for future GLP-1/GCG dual receptor agonists to treat obesity and MASLD.

Abstract This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single‐center, randomized, open, single‐dose, parallel‐controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17‐day observation period after administration, and a 7‐day safety follow‐up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration‐time curve from zero time to the estimated infinite time (AUC0–∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0–∞ geometric mean ratios were 102.9%–122.0% and 97.1%–116.9%, respectively, which were both within the range of 80.00%–125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.

Bisphenol A (BPA) is one of the most widely used chemical products, which is discharged into rivers and oceans, posing great hazards to organisms such as reproductive toxicity, hormone imbalance and cardiopathy induction. With the expansion harm of BPA, people have paid more attention to the environmental effects. In this paper, the degradation of BPA from the synthetic wastewater using the immobilization of horseradish peroxidase membrane reactor (HPR) was investigated. The immobilized HRP microporous membrane was prepared by the porous calcium alginate method. In addition, the reuse of the immobilized HPR membrane and the measurement of membrane flux showed that the membrane has good activity and stability. Finally, the experimental parameters including reaction time, pH, the concentration of BPA and the dosage of H2O2 were optimized to remove the BPA, and about 78% degradation efficiency of BPA was achieved at the optimal condition as follows: H2O2 to BPA molar ratio of 1.50 with an initial BPA concentration of 0.1 mol/L, the HPR dosage of 3.84 u/mL, the initial solution pH of 7.0, a temperature of 20 °C and a contact time of 10 min. HIGHLIGHTS Horseradish peroxidase (HRP) can be effectively immobilized on the membrane.; The immobilized HRP can maintain high activity and be circulation utilization.; The optimum conditions for the mole rate of H2O2/BPA dosage and the pH value are 1.5 and 7, respectively.;

Abstract In order to deal with the global energy crisis and environmental problems, reducing carbon dioxide through artificial photosynthesis has become a hot topic. Lead halide perovskite is attracted people's attention because of its excellent photoelectric properties, but the toxicity and long‐term instability prompt people to search for new photocatalysts. Herein, a series of inorganic double perovskites Cs4Mn1‐xCuxSb2Cl12 microcrystals (x = 0, 0.1, 0.2, 0.3, 0.4, and 0.5) are synthesized and characterized. Among them, Cs4Mn0.7Cu0.3Sb2Cl12 microcrystals have the best photocatalytic performance, and the yields of CO and CH4 are 503.86 and 68.35 µmol g−1, respectively, after 3 h irradiation, which are the highest among pure phase perovskites reported so far. In addition, in situ Fourier transform infrared (FT‐IR) spectroscopy and electron spin resonance (ESR) spectroscopy are used to explore the mechanism of the photocatalytic reaction. The results highlight the potential of this class of materials for photocatalytic reduction reactions.

AbstractThe pathogenesis of rheumatoid arthritis (RA) is heavily impacted by the inflammation and activation of fibroblast-like synoviocytes (FLS). The objective of this investigation is to clarify the involvement of exosomes derived from FLS stimulated by tumour necrosis factor α (TNF-α) in angiogenesis and the underlying mechanisms. FLS cells were obtained from synovial fluid of RA patients and exosomes were obtained from FLS cell supernatant with TNF-α stimulation by ultracentrifugation. Exosomes were subsequently analysed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. The functional effects of exosomes with TNF-α stimulation on human umbilical vein endothelial cells (HUVEC) migration, invasion, and angiogenesis was evaluated using wound scratch healing test, transwell invasion assay, and tube formation assay. DNA nanoball-seq (DNBSEQ) sequencing platform was utilised to analysis different expression miRNA from exosomes, miRNA and mRNA from HUVEC. The expression level of miR-200a-3p was determined through quantitative real-time polymerase chain reaction (qRT-PCR). The quantification of KLF6 and VEGFA expression levels were performed by qRT-PCR and western blot analysis. The validation of the association between miR-200a-3p and KLF6 was established through a fluorescence enzyme reporting assay. In comparison to exosome induced by PBS, exosome induced by TNF-α exhibited a substantial exacerbation of invasion, migration, and angiogenesis in HUVEC. 4 miRNAs in exosomes and HUVEC cells, namely miR-1246, miR-200a-3p, miR-30a-3p, and miR-99b-3p was obtained. MiR-200a-3p maintained high consistency with the sequencing results. We obtained 5 gene symbols, and KLF6 was chose for further investigation. The expression of miR-200a-3p in exosomes induced by TNF-α and in HUVEC treated with these exosomes demonstrated a significantly increase. Additionally, HUVEC cells displayed a notable decrease in KLF6 expression and a significant elevation in VEGFA expression. This was further confirmed by the fluorescence enzyme report assay, which provided evidence of the direct targeting of KLF6 by miR-200a-3p. Exosomes induced by TNF-α have the ability to enhance the migration, invasion, and angiogenesis of HUVEC cells via the miR-200a-3p/KLF6/VEGFA axis.

Abstract This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar (RD12014) compared to reference liraglutide (Victoza) in healthy Chinese male subjects, so as to provide the basis for the similarity evaluation of the two drugs. Eligible subjects were randomized 1:1 to two sequences (RD12014‐Victoza or Victoza‐RD12014). Subjects received a single 0.6 mg dose of Victoza or RD12014 by abdominal subcutaneous injection during the first period. After a 7‐day washout period, subjects received the alternative drug during the second period. Blood samples were collected at predefined timepoints for PKs and immunogenicity assessment. The primary PK end points were maximum plasma concentration (Cmax) and area under the concentration‐time curve from time zero to the time of the last quantifiable concentration (AUC0−last). PK bioequivalence was achieved, if the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax and AUC0−last were within the range of 80.00–125.00%. Safety was assessed throughout the study. The 90% CIs of the GMR of RD12014 to Victoza for Cmax and AUC0−last were completely within the range of 80.00–125.00%. Thirteen treatment‐related adverse events (TRAEs) were reported in 11 subjects (22.4%) in the RD12014 group, compared to 12 TRAEs reported in 12 subjects (24.5%) in the Victoza group. The blood samples of 49 subjects were negative for anti‐drug antibody and the neutralizing antibody was not further detected. This study demonstrated PK similarity of RD12014 to Victoza in healthy Chinese male subjects. Safety and immunogenicity profiles were comparable between the two groups.

The tailwater of ion-type rare earth mines in southern Jiangxi has caused serious water pollution problems in small watersheds. In this study, seven physical and chemical indicators, namely, pH, TOC, dissolved oxygen, ammonia nitrogen, nitrate-nitrogen, salinity and redox potential were selected and spatial interpolation, principal component analysis, and geographic detector methods, were used to quantitatively analyze and evaluate the spatial heterogeneity of water quality in the small watersheds in this region. Tailwater pollution in the whole basin of the study area is serious. The spatial difference is manifested as east tributary > mainstream and reservoir area > southern tributary. Source pollution is the smallest, and water quality pollution is mainly manifested by excessive ammonia nitrogen, salinity, and TOC. The spatial differences in the physical and chemical properties of water bodies are significant. The distribution of ammonia nitrogen content is consistent with the spatial distribution of soil and water pollution, while nitrate-nitrogen is the opposite. Other indicators also show a certain spatial regularity, and the spatial regularity of dissolved oxygen content is not obvious. Water pollution in mining areas is mainly due to a large amount of ammonia nitrogen ions remaining in the mountains. As a result, the southern tributary ecological pool has an obvious purification effect on water quality. Salinity is extremely affected by ammonia nitrogen and TOC, oxidation-reduction potential is affected by pH and TOC, and TOC is influenced by ammonia nitrogen and pH. Salinity, ammonia nitrogen, and TOC are the potential risk factors of major pollution. The changes in the physical and chemical properties of the pollution index are not independent of each other. From the perspective of macro and micro, the comprehensive water pollution assessment system is adopted to provide a new idea for the prevention and control of rare earth industry tail water pollution, and further make exploratory efforts for the study of industrial wastewater pollution. HIGHLIGHTS Redox potential were selected and spatial interpolation, principal component analysis, and geographic detector methods.; Tailwater pollution in the whole basin of the study area is serious, and the spatial difference is manifested as east tributary > mainstream and reservoir area > southern tributary.;

Possible issues during mining of the upper coal seam in old goaf of nearby coal seams, including step subsidence, gas overflow in goaf, and roadway around rock fragmentation. Using the Hanjiawa Coal Mine’s upper coal seam mining, which takes place 28 m above the working face of the lower coal seam, as the research’s focal point. The paper focuses on the self-stability of the coal pillar in the old goaf, the failure form of the upper coal seam mining floor, the roof caving rule of the old goaf in the lower coal seam mining of the upper coal seam, and the bearing capacity of the interlayer rock strata using the pillar goaf stability evaluation system, field geological borehole electrical logging and borehole peeping, finite element difference numerical calculation, and other methods. The conclusion that the old goaf’s coal pillar can be completely stable and that the interlayer rock strata can bear the stress of upper coal seam mining is reached. The results show that the failure depth of the coal pillar in the lower coal seam old goaf is 1–3 m, the maximum failure depth accounting for 15% of the width of the coal pillar, and the failure depth of the roof in the old goaf is 0–3 m; After the mining of the upper coal seam, the floor above the coal pillar of the lower coal seam is plastic failure, and the failure depth is 1–10 m, and the failure depth of the roof of the old goaf of the lower coal seam is 3–15 m, which is 4 times greater than that before the mining. The maximum failure depth of the interlayer rock strata is 22 m, accounting for 78.6% of the rock strata spacing. The interlayer rock strata can bear the mining disturbance of the upper coal seam. The plastic zone of the floor of the upper coal seam is not connected with the plastic zone of the roof of the lower coal seam.

Aiming at the problems of time-varying topology,intermittent connection,and constrained resource in satellite network,a contact plan design (CPD) scheme based on bi-directional particle optimization (BPSO) algorithm was proposed.Firstly,the task-based time-expanded graph (TEG) model was constructed through the analysis of resource-constrained time-varying satellite network.Next,available contact plan (CP) in satellite network were generated through initialization,coding and repairing by considering the discreteness of network topology and the limitation of node resources.Then,an evaluation function was designed according to the characteristics of the execution task to distinguish whether the generated available CP was good or bad.Finally,the bits to be corrected in the worst location were determined according to the sparse characteristics of links in CP,and the CP was continuously modified by the proposed BPSO algorithm to optimize the performance of spatial data transmission.The simulation results show that the proposed BPSO-based CPD scheme can effectively reduce the task delivery time and increase the task arrival rate.

In order to obtain the analytical solution of the plastic area boundary of circular laneway surrounding rock in nonuniform stress field, we studied the evolution of the plastic area shapes of the circular laneway surrounding rock from circular to elliptical and derived the analytical solutions of the boundary radii in the elliptical shape. The results show that (1) with the increase of the confining pressure ratio from 1, the major axis radius of the plastic area increases gradually, the minor axis radius decreases gradually, and the shape of the plastic area gradually evolves from circular to elliptical; (2) on the basis of the Mohr–Coulomb strength criterion, the analytical expressions of major axis and minor axis radii of the elliptical plastic area are derived, and the elliptic equation of the plastic area boundary of circular laneway in nonuniform stress field is established; and (3) the confining pressure ratio is the key factor affecting the shape of the plastic area. When the confining pressure ratio is less than 1.6, the plastic area of the circular laneway surrounding rock is elliptical, and the elliptic boundary equation is applicable. When the confining pressure ratio is greater than 1.6, the plastic area is butterfly shaped, and the elliptic boundary equation is no longer applicable.

The distribution of a plastic zone ahead of a gateroad plays a significant role in maintaining the long-term stability of mining spaces. For a long time, the principal stress field such as the values, the direction, etc. have been observed to have impacts on plastic zone development, but has not been looked into deeply and systematically. To this end, the influence of principal stress field including the maximum principal stress (P1), the angle between the P1 direction and the Z-axis (α), the minimum principal stress (P3), and the ratio of maximum principal stress to minimum principal stress (P1/P3) on the expansion of the plastic zone ahead of the gateroad is investigated by the (Fast Lagrangian Analysis of Continua) FLAC3D models. The results show that: (1) The plastic zone volume increases first and then decreases with the increase of α, and the direction of butterfly-shaped plastic zone ahead of gateroad is rotating with the evolution of α. (2) The plastic zone volume ahead of excavation face increases gradually with the increase of P1/P3. Mutagenicity of butterfly-shaped plastic zone occurs ahead of the gateroad under a certain value of P1/P3. (3) With the increase of P1 and decrease of P3, the plastic zone volume is of exponential growth. The plastic zone volume approaches infinity when the critical value of maximum principal stress ([P1]) and the minimum principal stress ([P1]) is obtained. (4) The study of the effect of principal stress field on the expansion of plastic zone ahead of the gateroad is helpful for revealing the mechanisms of coal and gas outbursts. The critical stress state of butterfly-shaped plastic zone mutagenicity ahead of the gateroad can be used as an important indicator for assessing the risk of coal and gas outburst. The research can also guide the prevention of coal and gas outburst ahead of the gateroad.

Strata movement due to extraction of a longwall panel is of great significance both in terms of environment and ground control. Thick coal seam extraction is expected to severely disturb the overburden, which is critical. Most studies use only one or two methods to investigate strata movement that are not thorough or comprehensive. This paper presents a detailed comprehensive case study of strata movement in extraction of a longwall top coal caving panel of a composite coal seam with partings in the Baozigou Coal Mine. The caved zone and fractured zone development were captured through physical modeling by incorporating the digital image correlation method (DICM), universal distinct element code (UDEC) numerical modeling, and field observation with the method of high-pressure water injection. The result of the physical modeling is 90 m. The numerical modeling result is 84 m. Field data show that the fractured zone is 81 m. Therefore, it demonstrates that the results from different methods are consistent, which indicates that the results from this comprehensive study are reliable and scientific.

Factors leading to coal and gas outbursts are complicated, and the accuracy of predicting outbursts remains difficult to achieve. Therefore, coal and gas outburst risk are still a scientific challenge in the fields of mining, geology, safe engineering, and rock mechanics. Theories explaining and predicting coal and gas outbursts associated with restored strain and gas energy are hot topics. Based on numerical modelling, the evolution of a plastic zone ahead of an excavation face with change of direction and magnitude of regional pre-mining stress field were analyzed. A mechanical analysis model for the expansionary evolution process of the plastic zone ahead of the excavation face was constructed, and the expansionary evolution characteristics of plastic zone ahead of the excavation face were analyzed. The physical and mechanical process and basic conditions for the initiation and development of coal and gas outbursts induced by evolution of plastic zone were discussed. The research provides some new insights into the mechanism, prediction, and prevention of goal and gas outbursts.