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Abstract Background Mendelian randomization (MR) studies have an advantage over conventional observational studies when studying the causal effect of lifestyle-related risk factors on back pain. However, given the heterogeneous design of existing MR studies on back pain, the reported causal estimates of these effects remain equivocal, thus obscuring the true extent of the biological effects of back pain lifestyle-risk factors. Purpose The purpose of this study was to conduct a systematic review with multiple meta-analyses on the associations between various lifestyle factors and low back pain. Methods We conducted a PRISMA systematic review and specifically included MR studies to investigate the associations between lifestyle factors—specifically, BMI, insomnia, smoking, alcohol consumption, and leisure sedentary behavior—and various back pain outcomes. Each meta-analysis synthesized data from three or more studies to assess the causal impact of these exposures on distinct back pain outcomes, including chronic pain, disability, and pain severity. Quality of studies was assessed according to STROBE-MR guidelines. Results A total of 1576 studies were evaluated and 20 were included. Overall, the studies included were of high quality and had a low risk of bias. Our meta-analysis demonstrates the positive causal effect of BMI (OR IVW−random effects models: 1.18 [1.08–1.30]), insomnia(OR IVW−random effects models: 1.38 [1.10–1.74]), smoking(OR IVW−fixed effects models: 1.30 [1.23–1.36]), alcohol consumption(OR IVW−fixed effects models: 1.31 [1.21–1.42]) and leisure sedentary behaviors(OR IVW−random effects models: 1.52 [1.02–2.25]) on back pain. Conclusion In light of the disparate designs and causal effect estimates presented in numerous MR studies, our meta-analysis establishes a compelling argument that lifestyle-related risk factors such as BMI, insomnia, smoking, alcohol consumption, and leisure sedentary behaviors genuinely contribute to the biological development of back pain.

Abstract Background Since traditional germination test methods have drawbacks such as slow efficiency, proneness to error, and damage to seeds, a non-destructive testing method is proposed for full-process germination of radish seeds, which improves the monitoring efficiency of seed quality. Results Based on YOLOv8n, a lightweight test model YOLOv8-R is proposed, where the number of parameters, the amount of calculation, and size of weights are significantly reduced by replacing the backbone network with PP-LCNet, the neck part with CCFM, the C2f of the neck part with OREPA, the SPPF with FocalModulation, and the Detect of the head part with LADH. The ablation test and comparative test prove the performance of the model. With adoption of germination rate, germination index, and germination potential as the three vitality indicators, the seed germination phenotype collection system and YOLOv8-R model are used to analyze the full time-series sequence effects of different ZnO NPs concentrations on germination of radish seeds under varying degrees of salt stress. Conclusions The results show that salt stress inhibits the germination of radish seeds and that the inhibition effect is more obvious with the increased concentration of NaCl solution; in cultivation with deionized water, the germination rate of radish seeds does not change significantly with increased concentration of ZnO NPs, but the germination index and germination potential increase initially and then decline; in cultivation with NaCl solution, the germination rate, germination potential and germination index of radish seeds first increase and then decline with increased concentration of ZnO NPs.

The increasingly frequent and severe regional-scale compound heatwave‒drought extreme events (CHDEs), driven by global warming, present formidable challenges to ecosystems, residential livelihoods, and economic conditions. However, uncertainty persists regarding the future trend of CHDEs and their insights into regional spatiotemporal heterogeneity. By integrating daily meteorological data from observations in 1961–2022 and global climate models (GCMs) based on the Shared Socioeconomic Pathways, the evolution patterns of CHDEs were compared and examined among three sub-catchments of the Yangtze River Basin, and the return periods of CHDE in 2050s and 2100s were projected. The findings indicate that the climate during the 2022 CHDE period was the warmest and driest recorded in 1961–2022, with precipitation less than 154.5 mm and a mean daily maximum temperature 3.4 °C higher than the average of 1981–2010, whereas the characteristics in the sub-catchments exhibited temporal and spatial variation. In July–August 2022, the most notable feature of CHDE was its extremeness since 1961, with return periods of ∼200-year in upstream, 80-year in midstream, and 40-year in downstream, respectively. By 2050, the return periods witnessed 2022 CHDE would likely be reduced by one-third. Looking towards 2100, under the highest emission scenario of SSP585, it was projected to substantially increase the frequency of CHDEs, with return periods reduced to one-third in the upstream and downstream, as well as halved in the midstream. These findings provide valuable insights into the changing risks associated with forthcoming climate extremes, emphasizing the urgency of addressing these challenges in regional management and sustainable development.

Abstract Previous studies showed tacrolimus monotherapy and dual therapy with tacrolimus and prednisone as effective treatment modalities in managing membranous nephropathy. However, few studies have compared these therapeutic regimens. The patients were divided into two groups based on the treatment regimen: (1) tacrolimus and prednisone dual therapy (T + P group, n = 67) treatment group; and (2) tacrolimus monotherapy (T group, n = 65) or the control group. Propensity matching method and subgroup analysis to eliminate the bias in the relationship between the treatment regimen and the outcomes. The mean remission times were 20.33 ± 2.75 weeks at T group and 9.50 ± 1.81 weeks at T + P group. The T group had a remission rates of 73.33, 76.66 and 66.66% at 12weeks, 24weeks and 48weeks, while the T + P group had a remission rate of 81.66, 86.66, 91.66%; At the follow-up of 48 weeks, the relapse rate for the T group was 21.66%, and that for the T + P group was 5%. The anti-PLA2R ab is positive and therapy may be the independent risk factors for predicting remission. Tacrolimus and low-dose prednisone dual therapy is efficacious in managing MN and lowers the recurrence rate in clinical practice.

Abstract Fe–Mn oxide modified biochar (FMBC) was produced to explore its potential for remediation of Hg–Cd contaminated paddy soils. The results showed that the application of FMBC decreased the contents of bioavailable Hg and Cd by 41.49–81.85% and 19.47–33.02% in contrast to CK, while the amount of labile organic carbon (C) fractions and C-pool management index (CPMI) was increased under BC and FMBC treated soils, indicating the enhancement of soil C storage and nutrient cycling function. Dry weight of different parts of Oryza sativa L. was enhanced after the addition of BC and FMBC, and the contents of Fe and Mn in root iron–manganese plaques (IMP) were 1.46–2.06 and 6.72–19.35 times higher than those of the control groups. Hg and Cd contents in brown rice under the FMBC treatments were significantly reduced by 18.32–71.16% and 59.52–72.11% compared with the control. FMBC addition altered the composition and metabolism function of soil bacterial communities, especially increasing the abundance of keystone phyla, including Firmicutes, Proteobacteria and Actinobacteria. Partial least squares path modelling (PLSPM) revealed that the contents of Na2S2O3–Hg, DTPA–Cd and IMP were the key indicators affecting Hg and Cd accumulation in rice grains. These results demonstrate the simultaneous value of FMBC in remediation of Hg and Cd combined pollution and restoring soil fertility and biological productivity. Graphical Abstract

[Introduction] Pulse inductor is an important component of the oscillation discharge circuit in the quench protection system. In the oscillating discharge circuit, the pulse inductor and charging capacitor are used to oscillate and generate high pulse currents, causing the current flowing through the vacuum circuit breaker to reverse and create an artificial zero-crossing point, thus completing the switch breaking. However, under the condition of 120 kA current, due to the action of the electromagnetic force, the connecting bar below the pulse inductor will deform, causing equipment damage and greatly reducing the reliability of the auxiliary oscillation zero-crossing circuit. Therefore, it is necessary to conduct electromagnetic field analysis on the 120 kA pulse inductor and optimize the electromagnetic field distribution around it. [Method] Firstly, the commutation process of the auxiliary oscillation zero-crossing circuit was analyzed to establish a three-dimensional model of the pulse inductor, and the concept of magnetic field shielding percentage was introduced. Secondly, the influence of shielding plates with different materials and shapes on electromagnetic field distributions was calculated by using finite element simulation. Then the influence of different materials and shapes on shielding percentage was analyzed, and eddy current losses under different shapes were calculated. Finally, the deformation degree of the connecting bar under different shielding structures was calculated in the structural module. [Result] The results show that the use of different materials or structures in the shielding plates influences the magnetic induction intensity and electromagnetic force received by the connecting bar. [Conclusion] The circular aluminum shielding plate has a better optimization effect for the electromagnetic field distribution. This method also lays a foundation for the electromagnetic shield design of pulse inductors.

Abstract Time-stamped cross-sectional data, which lack linkage across time points, are commonly generated in single-cell transcriptional profiling. Many previous methods for inferring gene regulatory networks (GRNs) driving cell-state transitions relied on constructing single-cell temporal ordering. Introducing COSLIR (COvariance restricted Sparse LInear Regression), we presented a direct approach to reconstructing GRNs that govern cell-state transitions, utilizing only the first and second moments of samples between two consecutive time points. Simulations validated COSLIR’s perfect accuracy in the oracle case and demonstrated its robust performance in real-world scenarios. When applied to single-cell RT-PCR and RNAseq datasets in developmental biology, COSLIR competed favorably with existing methods. Notably, its running time remained nearly independent of the number of cells. Therefore, COSLIR emerges as a promising addition to GRN reconstruction methods under cell-state transitions, bypassing the single-cell temporal ordering to enhance accuracy and efficiency in single-cell transcriptional profiling.

Abstract Salt efflorescence is one of the critical problems for the preservation of immovable silicate relics. Salt efflorescence mainly comes from continuous cycles of crystallization/dissolution or hydration/dehydration of salts in confined pores in silicate relics. Many protocols have been developed in attempts to alleviate possible salt damages with minor success because of endless water and salt feed from underground. In this study, we propose and design a novel technique for salt damage prevention and protection of immovable relics. Materials with higher water-absorbing ability than matrix are applied to control the water and salt migration direction in simulated sand samples. The distribution of moisture content on the surface of sand is followed by hyperspectral imaging. It appears that water and salt molecules will preferentially transport towards positions containing higher water-absorbing material. Both organic and inorganic high water-absorbing materials show effective in controlling the water and salt migration direction, which provides a new approach for the prevention and protection of salt efflorescence in silicate cultural relics.

Abstract Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1β expression in the myocardial tissue of EAM mice. Notably, IL-1β expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1β expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Alkali stress is a significant challenge across the globe which is posing serious threat to crop production and food security. This study was carried out to study the effect of different levels of alkali stress on growth and physiological traits of Leymus chinensis. The study was comprised of different levels of alkali stress; control (CK; 0 mmol·L-1), 25 and 50 mmol·L-1. The results showed that imposition of 50 mmol·L-1 alkali stress substantially reduced the photosynthetic capacity, relative water contents and accumulation of carbon (C), nitrogen (N) and phosphorus (P) in plant parts. Further, 50 mmol·L-1 alkali stress also reduced the above and below ground biomass, and severely inhibited the root growth. Moreover, increase in concentration of alkali stress inhibited clone components, tillering, tillering bud, and internode bud of Leymus chinensis. In conclusion the increasing concentration of alkali stress can reduce the growth and biomass production and nutrient accumulation of Leymus chinensis.

Abstract Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)‐negative and early‐stage RA are still to be improved. We aimed to screen autoantibodies in ACPA‐negative patients and evaluated their diagnostic performance. The human genome‐wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti‐ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA‐negative RA, including anti‐ANAPC15, anti‐LSP1, anti‐APBB1, anti‐parathymosin, and anti‐UBL7. Anti‐parathymosin showed the highest prevalence of 46.2% (p = 0.016) in ACPA‐negative early stage (

BackgroundPostmenopausal osteoporosis (PMOP) increases fracture risk in women. Though traditional treatments are slow to act, combining romosozumab with conventional therapy shows promise. Despite its growing use, studies on effectiveness are limited. This study aims to systematically evaluate the combined therapy’s impact on pain relief, disease progression, and adverse reactions in PMOP patients.MethodsDatabases including PubMed, EMBASE, ScienceDirect, and the Cochrane Library were searched from their inception to September 2023 to identify randomized controlled trials (RCTs) evaluating the role of romosozumab in PMOP. Random or fixed effect models were employed for statistical analysis. Two reviewers independently assessed the quality of the included studies and extracted the data. The meta-analysis was conducted using RevMan 5.4 software.ResultsSix RCTs with a total sample size of 17,985 cases were included. The incidence of vertebral fractures was compared and analyzed after 12 and 24 months of treatment. Romosozumab significantly reduced the incidence of vertebral fractures at 24 months (OR = 0.36; 95% CI: 0.35–0.52) but not at 12 months (OR = 0.39; 95% CI: 0.14–1.05). It was also associated with a decreased incidence of nonvertebral fractures (OR = 0.79; 95% CI: 0.66–0.94) and clinical fractures at 24 months (OR = 0.70; 95% CI: 0.59–0.82) compared to standard therapy. Romosozumab demonstrated a significant improvement in percentage change in bone mineral density (BMD) [mean difference (MD) = 10.38; 95% CI: 4.62–16.14] and in hip joint BMD (MD = 4.24; 95% CI: 2.92–5.56). There was no notable difference in adverse reactions compared to standard care (p > 0.05). Funnel plots displayed a predominantly symmetrical pattern, suggesting no evidence of publication bias in the selected literature.ConclusionCombining romosozumab with conventional therapy effectively treats PMOP, significantly reducing vertebral, non-vertebral, and clinical fractures while increasing BMD in the hip, femoral neck, and lumbar spine. However, further high-quality studies are needed for validation.

Asthma is a common chronic inflammatory disease of the lungs and airway, yet its inflammatory subtypes and potential pathogenesis have not been completely elucidated and require further study. With advances in epigenetic development, methylation has emerged as a new direction for identifying and decoding the occurrence and subtype manifestations of asthma. N6-methyladenosine (m6A), an RNA methylation modification occurring in the N6-position of adenosine, is a prevalent epigenetic modification observed in eukaryotes. It exerts significant control over mRNA metabolism by regulating alternative splicing, stability, export, and translation. The dynamic process of m6A methylation plays a crucial role in the pathogenesis of asthma and is tightly regulated by three types of regulators: writers, readers, and erasers. This article provides a comprehensive review of the association between m6A regulators and the pathogenesis of inflammatory subtypes of asthma, such as involvement of inflammatory cells and related inflammatory response. Furthermore, the findings presented herein provide new insights and a solid foundation for further research on m6A mRNA methylation as biomarkers for the diagnosis and development of personalized treatment for different subtypes of asthma, particularly neutrophilic asthma and eosinophilic asthma.

Despite extensive research highlighting the pivotal role of MYB transcription factors in regulating anthocyanin biosynthesis, the interactive regulatory network involving these MYB factors in pear fruits remains inadequately characterized. In this study, the anthocyanin-regulatory gene PbrMYB114 was successfully cloned from ‘Yuluxiang’ pear (Pyrus bretschneideri) fruits, and its influence on anthocyanin accumulation was confirmed through transient expression assays. Specifically, the co-transformation of PbrMYB114 with its partner PbrbHLH3 in pears served to validate the functional role of PbrMYB114. Subsequently, PbrMYB114 was employed as bait in a yeast two-hybrid screening assay, using a ‘Yuluxiang’ pear protein library, which led to the identification of 25 interacting proteins. Further validation of the interactions between PbrMYB114 and PbrMT2/PbrMT3 was conducted. Investigations into the role of PbrMT2 and PbrMT3 in ‘Duli’ seedlings (Pyrus betulaefolia) revealed their potential to enhance anthocyanin accumulation. The outcomes of these studies provide novel insights into the protein network that regulates pear anthocyanin biosynthesis, particularly the functional interactions among PbrMYB114 and associated proteins.

The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and neurological diseases with high morbidity. Two distinct strains, NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), contribute to outbreaks in different geographical areas. Currently, there are no commercially licensed vaccines or drugs available for prevention or treatment. In response to this urgent need for protection against NiV and related henipaviruses infections, we developed a novel homotypic virus-like nanoparticle (VLP) vaccine co-displaying NiV attachment glycoproteins (G) from both strains, utilizing the self-assembling properties of ferritin protein. In comparison to the NiV G subunit vaccine, our nanoparticle vaccine elicited significantly higher levels of neutralizing antibodies and provided complete protection against a lethal challenge with NiV infection in Syrian hamsters. Remarkably, the nanoparticle vaccine stimulated the production of antibodies that exhibited superior cross-reactivity to homologous or heterologous henipavirus. These findings underscore the potential utility of ferritin-based nanoparticle vaccines in providing both broad-spectrum and long-term protection against NiV and emerging zoonotic henipaviruses challenges.

Abstract Background Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, and chemoresistance is a major obstacle in its treatment. Despite advances in therapy, the molecular mechanism underlying chemoresistance in CRC is not fully understood. Recent studies have implicated the key roles of long noncoding RNAs (lncRNAs) in the regulation of CRC chemoresistance. Methods In this study, we investigated the role of the lncRNA LINC01852 in CRC chemoresistance. LINC01852 expression was evaluated in multiple CRC cohorts using quantitative reverse transcription PCR. We conducted in vitro and in vivo functional experiments using cell culture and mouse models. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of LINC01852 in CRC. Results Our findings revealed that a lncRNA with tumor-inhibiting properties, LINC01852, was downregulated in CRC and inhibited cell proliferation and chemoresistance both in vitro and in vivo. Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis. Conclusions Our results demonstrate that LINC01852 plays an important role in repressing CRC malignancy and chemoresistance by regulating SRSF5-mediated alternative splicing of PKM, and that targeting the LINC01852/TRIM72/SRSF5/PKM2 signaling axis may represent a potential therapeutic strategy for CRC.

Abstract Ruthenium dioxide is the most promising alternative to the prevailing but expensive iridium-based catalysts for the oxygen evolution reaction in proton-exchange membrane water electrolyzers. However, the under-coordinated lattice oxygen of ruthenium dioxide is prone to over-oxidation, and oxygen vacancies are formed at high oxidation potentials under acidic corrosive conditions. Consequently, ruthenium atoms adjacent to oxygen vacancies are oxidized into soluble high-valence derivatives, causing the collapse of the ruthenium dioxide crystal structure and leading to its poor stability. Here, we report an oxyanion protection strategy to prevent the formation of oxygen vacancies on the ruthenium dioxide surface by forming coordination-saturated lattice oxygen. Combining density functional theory calculations, electrochemical measurements, and a suite of operando spectroscopies, we showcase that barium-anchored sulfate can greatly impede ruthenium loss and extend the lifetime of ruthenium-based catalysts during acidic oxygen evolution, while maintaining the activity. This work paves a new way for designing stable and active anode catalysts toward acidic water splitting.

Aggregation-Induced Emission luminogen (AIEgen) possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety. Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and penetration to tumor. Herein, we construct a delivery platform that Salmonella VNP20009 act as an activated bacteria vector loaded the as-prepared novel AIEgen (TBTP-Au, VNP@TBTP-Au), which showed excellent radio-immunotherapy. VNP@TBTP-Au could target and retain AIEgen at the tumor site and deliver it into tumor cells specially, upon X-ray irradiation, much ROS was generated to induce immunogenic cell death via cGAS-STING signaling pathway to evoke immune response, thus achieving efficient radioimmunotherapy of the primary tumor with good biosafety. More importantly, the radioimmunotherapy with VNP@TBTP-Au formatted good abscopal effect that was able to suppress the growth of distant tumor. Our strategy pioneer a novel and simple strategy for the organic combination of bacteria and imaging-guided radiotherapy, and also pave the foundation for the combination with immunotherapy for better therapeutic effects.

Abstract Spatially resolved omics technologies reveal the spatial organization of cells in various biological systems. Here we propose SLAT (Spatially-Linked Alignment Tool), a graph-based algorithm for efficient and effective alignment of spatial slices. Adopting a graph adversarial matching strategy, SLAT is the first algorithm capable of aligning heterogenous spatial data across distinct technologies and modalities. Systematic benchmarks demonstrate SLAT’s superior precision, robustness, and speed over existing state-of-the-arts. Applications to multiple real-world datasets further show SLAT’s utility in enhancing cell-typing resolution, integrating multiple modalities for regulatory inference, and mapping fine-scale spatial-temporal changes during development. The full SLAT package is available at https://github.com/gao-lab/SLAT .

Abstract Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that poses a severe threat to humans due to its high morbidity and the lack of viable countermeasures. Vaccines are the most crucial defense against NiV infections. Here, a recombinant chimpanzee adenovirus-based vaccine (AdC68-G) and a DNA vaccine (DNA-G) were developed by expressing the codon-optimized full-length glycoprotein (G) of NiV. Strong and sustained neutralizing antibody production, accompanied by an effective T-cell response, was induced in BALB/c mice by intranasal or intramuscular administration of one or two doses of AdC68-G, as well as by priming with DNA-G and boosting with intramuscularly administered AdC68-G. Importantly, the neutralizing antibody titers were maintained for up to 68 weeks in the mice that received intramuscularly administered AdC68-G and the prime DNA-G/boost AdC68-G regimen, without a significant decline. Additionally, Syrian golden hamsters immunized with AdC68-G and DNA-G via homologous or heterologous prime/boost immunization were completely protected against a lethal NiV virus challenge, without any apparent weight loss, clinical signs, or pathological tissue damage. There was a significant reduction in but not a complete absence of the viral load and number of infectious particles in the lungs and spleen tissue following NiV challenge. These findings suggest that the AdC68-G and DNA-G vaccines against NiV infection are promising candidates for further development.

Abstract Cerebral vessels are composed of highly complex structures that facilitate blood perfusion necessary for meeting the high energy demands of the brain. Their geometrical complexities alter the biophysical behavior of circulating tumor cells in the brain, thereby influencing brain metastasis. However, recapitulation of the native cerebrovascular microenvironment that shows continuities between vascular geometry and metastatic cancer development has not been accomplished. Here, we apply an in-bath 3D triaxial bioprinting technique and a brain-specific hybrid bioink containing an ionically crosslinkable hydrogel to generate a mature three-layered cerebrovascular conduit with varying curvatures to investigate the physical and molecular mechanisms of cancer extravasation in vitro. We show that more tumor cells adhere at larger vascular curvature regions, suggesting that prolongation of tumor residence time under low velocity and wall shear stress accelerates the molecular signatures of metastatic potential, including endothelial barrier disruption, epithelial–mesenchymal transition, inflammatory response, and tumorigenesis. These findings provide insights into the underlying mechanisms driving brain metastases and facilitate future advances in pharmaceutical and medical research.

Highlights The flower-like δ-MnO2 nanostructures with controlled oxygen vacancies as an extraordinary ZIBs cathode are innovatively developed. The cathode can present large capacity and high-rate zinc-ion storage. DFT analysis substantially unveils the effects of various vacancy concentrations on their electrochemical performances.

Abstract Single-atom catalysts (SACs) have become one of the most attractive frontier research fields in catalysis and energy conversion. However, due to the atomic heterogeneity of SACs and limitations of ensemble-averaged measurements, the essential active sites responsible for governing specific catalytic properties and mechanisms remain largely concealed. In this study, we develop a quantitative method of single-atom catalysis–fluorescence correlation spectroscopy (SAC-FCS), leveraging the atomic structure-dependent catalysis kinetics and single-turnover resolution of single-molecule fluorescence microscopy. This method enables us to investigate the oxidase-like single-molecule catalysis on unidentical iron-nitrogen (Fe-N) coordinated SACs, quantifying the active sites and their kinetic parameters. The findings reveal the significant differences of single sites from the average behaviors and corroborate the oxidase-like catalytic mechanism of the Fe-N active sites. We anticipate that the method will give essential insights into the rational design and application of SACs.

Weaning is a challenging period for piglets, characterized by stress-related growth checks, compromised immunity, and gut dysbiosis. Purslane (Portulaca oleracea L.), known for its rich content of antioxidants, has potential as a functional feed ingredient. This study investigates the effects of feeding fermented purslane (FP) on the growth performance, immune function, intestinal microbiota, and metabolic profiles of weaned piglets. Forty-eight weaned piglets were randomly divided into two groups, with eight pens in each group and three pigs in each pen: a control diet (CON group) and a diet supplemented with 0.20% FP (FP group). The experiment lasted 28 days. The results show that FP supplementation did not affect the average daily feed intake (ADFI) but significantly increased the average daily gain (ADG) during the initial 14 days post-weaning. FP supplementation decreased diarrhea occurrence, with a pronounced reduction from days 10 to 13 (p < 0.05). Immunologically, the FP group had a trend towards reduced serum IgA levels on day 14 (p < 0.10). Importantly, the serum concentrations of the pro-inflammatory cytokine IL-6 were significantly reduced on both days 14 and 28 post-weaning. The antioxidative analysis showed increased serum superoxide dismutase (SOD) and decreased catalase (CAT) activities on day 14 (p < 0.05). In addition, FP supplementation significantly decreased serum diamine oxidase (DAO) activity and D-lactate levels by day 28, indicating a potential improvement in gut integrity. Fecal microbiota assessment demonstrated a distinctive clustering of microbial communities between the FP and CON groups, with an increase in the abundance of Clostridium_sensu_stricto_1, Tyzzerella, and Prevotellaceae_NK3B31_group and a decrease in Lactobacillus, Bacillus, and Subdoligranulum in the FP group (p < 0.05). Functional predictions suggested that the relative abundance of microbial butyrate synthesis enzymes (EC 2.7.2.7 and EC 2.3.1.19) was significantly enhanced by FP treatment. This modulation was further corroborated by elevated fecal butyrate levels (p < 0.05). In summary, dietary supplementation with FP promotes early-growth performance and has beneficial effects on immune function and intestinal health in weaned piglets. The enhancements may be attributed to distinct microbiota compositional changes and targeted modulation of microbial butyrate metabolism, which are crucial for piglet post-weaning adaptation and overall health.

Abstract Corn straw is an abundant and renewable alternative for microbial biopolymer production. In this paper, an engineered Sphingomonas sanxanigenens NXG‐P916 capable of co‐utilising glucose and xylose from corn straw total hydrolysate to produce xanthan gum was constructed. This strain was obtained by introducing the xanthan gum synthetic operon gum as a module into the genome of the constructed chassis strain NXdPE that could mass produce activated precursors of polysaccharide, and in which the transcriptional levels of gum genes were optimised by screening for a more appropriate promoter, P916. As a result, strain NXG‐P916 produced 9.48 ± 0.34 g of xanthan gum per kg of fermentation broth (g/kg) when glucose was used as a carbon source, which was 2.1 times improved over the original engineering strain NXdPE::gum. Furthermore, in batch fermentation, 12.72 ± 0.75 g/kg xanthan gum was produced from the corn straw total hydrolysate containing both glucose and xylose, and the producing xanthan gum showed an ultrahigh molecular weight (UHMW) of 6.04 × 107 Da, which was increased by 15.8 times. Therefore, the great potential of producing UHMW xanthan gum by Sphingomonas sanxanigenens was proved, and the chassis NXdPE has the prospect of becoming an attractive platform organism producing polysaccharides derived from biomass hydrolysates.

In the realm of precise medicine, the advancement of manufacturing technologies is vital for enhancing the capabilities of medical devices such as nano/microrobots, wearable/implantable biosensors, and organ-on-chip systems, which serve to accurately acquire and analyze patients’ physiopathological information and to perform patient-specific therapy. Electrospinning holds great promise in engineering materials and components for advanced medical devices, due to the demonstrated ability to advance the development of nanomaterial science. Nevertheless, challenges such as limited composition variety, uncontrollable fiber orientation, difficulties in incorporating fragile molecules and cells, and low production effectiveness hindered its further application. To overcome these challenges, advanced electrospinning techniques have been explored to manufacture functional composites, orchestrated structures, living constructs, and scale-up fabrication. This review delves into the recent advances of electrospinning techniques and underscores their potential in revolutionizing the field of precise medicine, upon introducing the fundamental information of conventional electrospinning techniques, as well as discussing the current challenges and future perspectives.

As an on-demand mobility service, parking reservations can greatly alleviate the issue of parking challenges. There are currently three primary strategies for parking reservation: first-come-first-served, permit reservation, and auction. In contrast to the first-come-first-served and permit-reserved strategies, the auction strategy uses dynamic pricing to allocate parking supplies efficiently based on the auction, which attracts more scholars for the research. However, parking reservations based on the auction process may have an inequity issue because drivers’ age, gender, income level, and location of residence fluctuate. This inequity may limit the growth of reserved parking by influencing parking drivers’ acceptance of reserved parking. But currently, very few scholars focus on the issue of reserved parking equity, and even fewer measure this nebulous and personal issue. In consideration of this, the Lorenz curve of parking reservation and the vertical equity index of parking reservation are proposed in this paper along with the calculation method for the index, which enables the problem of reserved parking vertical equity to be visualized and made concrete. The numerical experimental method is used to analyze the vertical equity of drivers with varying income levels, utilizing the Vickrey–Clarke–Groves (VCG) auction process as an example. According to the research, loss-averse drivers are more than gain-neutral and gain-seeking drivers when the income levels of the drivers using reserved parking are the same. With the increasing number of high-income drivers involved in the parking reservation, medium to low-income drivers would lose their chances of successful reservations because of their uncompetitive bid price which leads to inequity issues when the number is less than the number of parking spaces. In contrast, the vertical equity index changes more for gain-seeking drivers while being generally steady when loss-averse and gain-neutral drivers participate. For instance, when the profit and loss coefficient is 3 and 15% of drivers with high-income levels use the parking reservation platform, the vertical equity index rises from 0.09128 to 0.45434. The reference price has a moderating influence on the vertical equity index when the number of driver participants at high-income levels remains constant. In general, within a reasonable range, the higher the reference price, the more equitable the parking reservation procedure and the lower the vertical equity index.

Abstract Background Poly-β-hydroxybutyrate (PHB), produced by a variety of microbial organisms, is a good substitute for petrochemically derived plastics due to its excellent properties such as biocompatibility and biodegradability. The high cost of PHB production is a huge barrier for application and popularization of such bioplastics. Thus, the reduction of the cost is of great interest. Using low-cost substrates for PHB production is an efficient and feasible means to reduce manufacturing costs, and the construction of microbial cell factories is also a potential way to reduce the cost. Results In this study, an engineered Sphingomonas sanxanigenens strain to produce PHB by blocking the biosynthetic pathway of exopolysaccharide was constructed, and the resulting strain was named NXdE. NXdE could produce 9.24 ± 0.11 g/L PHB with a content of 84.0% cell dry weight (CDW) using glucose as a sole carbon source, which was significantly increased by 76.3% compared with the original strain NX02. Subsequently, the PHB yield of NXdE under the co-substrate with different proportions of glucose and xylose was also investigated, and results showed that the addition of xylose would reduce the PHB production. Hence, the Dahms pathway, which directly converted D-xylose into pyruvate in four sequential enzymatic steps, was enhanced by overexpressing the genes xylB, xylC, and kdpgA encoding xylose dehydrogenase, gluconolactonase, and aldolase in different combinations. The final strain NX02 (ΔssB, pBTxylBxylCkdpgA) (named NXdE II) could successfully co-utilize glucose and xylose from corn straw total hydrolysate (CSTH) to produce 21.49 ± 0.67 g/L PHB with a content of 91.2% CDW, representing a 4.10-fold increase compared to the original strain NX02. Conclusion The engineered strain NXdE II could co-utilize glucose and xylose from corn straw hydrolysate, and had a significant increase not only in cell growth but also in PHB yield and content. This work provided a new host strain and strategy for utilization of lignocellulosic biomass such as corn straw to produce intracellular products like PHB.

Abstract Human skin is an organ located in the outermost part of the body; thus, it frequently exhibits visible signs of physiological health. Ethical concerns and genetic differences in conventional animal studies have increased the need for alternative in vitro platforms that mimic the structural and functional hallmarks of natural skin. Despite significant advances in in vitro skin modeling over the past few decades, different reproducible biofabrication strategies are required to reproduce the pathological features of diseased human skin compared to those used for healthy-skin models. To explain human skin modeling with pathological hallmarks, we first summarize the structural and functional characteristics of healthy human skin. We then provide an extensive overview of how to recreate diseased human skin models in vitro, including models for wounded, diabetic, skin-cancer, atopic, and other pathological skin types. We conclude with an outlook on diseased-skin modeling and its technical perspective for the further development of skin engineering.

Large-scale genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) studies have identified multiple non-coding variants associated with genetic diseases by affecting gene expression. However, pinpointing causal variants effectively and efficiently remains a serious challenge. Here, we developed CARMEN, a novel algorithm to identify functional non-coding expression-modulating variants. Multiple evaluations demonstrated CARMEN’s superior performance over state-of-the-art tools. Applying CARMEN to GWAS and eQTL datasets further pinpointed several causal variants other than the reported lead single-nucleotide polymorphisms (SNPs). CARMEN scales well with the massive datasets, and is available online as a web server at http://carmen.gao-lab.org.

α-Synuclein (α-syn) can form oligomers, protofibrils, and fibrils, which are associated with the pathogenesis of Parkinson’s disease and other synucleinopathies. Both the lipid peroxidation product 4-oxo-2-nonenal (ONE) and agitation can induce aggregation of α-syn and phosphorylated α-syn. Thus, clarification of the characteristics of different α-syn species could help to select suitable aggregates for diagnosis and elucidate the pathogenesis of diseases. Here, we characterized ONE-induced wild-type (WT) α-syn aggregates (OW), ONE-induced phosphorylated α-syn (p-α-syn) aggregates (OP), agitation-induced α-syn preformed fibrils (PFF), and agitation-induced p-α-syn preformed fibrils (pPFF). Thioflavin T (ThT) dying demonstrated that OW and OP had fewer fibrils than the PFF and pPFF. Transmission electron microscopy revealed that the lengths of PFF and pPFF were similar, but the diameters differed. OW and OP had more compact structures than PFF and pPFF. Aggregation of p-α-syn was significantly faster than WT α-syn. Furthermore, OW and OP were more sodium dodecyl sulfate-stable and proteinase K-resistant, suggesting greater stability and compactness, while aggregates of PFF and pPFF were more sensitive to proteinase K treatment. Both ONE- and agitation-induced aggregates were cytotoxic when added exogenously to SH-SY5Y cells with increasing incubation times, but the agitation-induced aggregates caused cell toxicity in a shorter time and more p-α-syn inclusions. Similarly, p-proteins were more cytotoxic than non-p-proteins. Finally, all four aggregates were used as standard antigens to establish sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the recognition efficiency of OW and OP was more sensitive than that of PFF and pPFF. The OW- and OP-specific ELISA for detection of p-α-syn and α-syn in plasma samples of Thy1-α-syn transgenic mice showed that the content of aggregates could reflect the extent of disease. ONE and agitation induced the formation of α-syn aggregates with distinct biophysical properties and biomedical applications.

The engineering of tubes with surface corrugations is recognized as an effective method for enhancing heat transfer within the tube. Yet the impact of surface corrugation on the flow and heat transfer around the tube’s exterior remains inadequately explored. This study investigates the crossflow and heat transfer characteristics in banks of periodically inward-corrugated tubes using computational fluid dynamics. Numerical simulations were performed for both in-line and staggered tube arrangements, covering Reynolds numbers from 1000 to 10,000. The aim was to examine how various corrugation parameters affect heat transfer and flow dynamics in tube banks configured in both in-line and staggered layouts. The results show that the heat transfer and the pressure drop in crossflow across tube banks are substantially influenced by changes in corrugation parameters. Specifically, in the in-line arrangement, both the Nusselt number and Euler number decrease significantly as the corrugation height increases. In contrast, in the staggered arrangement, the Nusselt number and Euler number exhibit less variation in response to surface corrugation. A comparative analysis of performance criteria suggests that a staggered arrangement is more advantageous for improving thermal–hydraulic efficiency in crossflow through corrugated tube banks.

Benzene is the typical volatile organic compound (VOC) of indoor and outdoor air pollution, which harms human health and the environment. Due to the stability of their aromatic structure, the catalytic oxidation of benzene rings in an environment without an external energy input is difficult. In this study, the efficient degradation of benzene at room temperature was achieved by constructing Ag and Ni bimetallic active site catalysts (AgNi/BCN) supported on boron–carbon–nitrogen aerogel. The atomic-scale Ag and Ni are uniformly dispersed on the catalyst surface and form Ag/Ni-C/N bonds with C and N, which were conducive to the catalytic oxidation of benzene at room temperature. Further catalytic reaction mechanisms indicate that benzene reacted with ·OH to produce R·, which reacted with O2 to regenerate ·OH. Under the strong oxidation of ·OH, benzene was oxidized to form alcohols, carboxylic acids, and eventually CO2 and H2O. This study not only significantly reduces the energy consumption of VOC catalytic oxidation, but also improves the safety of VOC treatment, providing new ideas for the low energy consumption and green development of VOC treatment.

Abstract Electrochemical CO2 reduction (CO2R) is an approach to closing the carbon cycle for chemical synthesis. To date, the field has focused on the electrolysis of ambient pressure CO2. However, industrial CO2 is pressurized—in capture, transport and storage—and is often in dissolved form. Here, we find that pressurization to 50 bar steers CO2R pathways toward formate, something seen across widely-employed CO2R catalysts. By developing operando methods compatible with high pressures, including quantitative operando Raman spectroscopy, we link the high formate selectivity to increased CO2 coverage on the cathode surface. The interplay of theory and experiments validates the mechanism, and guides us to functionalize the surface of a Cu cathode with a proton-resistant layer to further the pressure-mediated selectivity effect. This work illustrates the value of industrial CO2 sources as the starting feedstock for sustainable chemical synthesis.

In this work, a series of ZnxMg1.99-xSnO4:0.01Mn2+ (x = 0, 0.01, 0.02, 0.03, 0.04) green long afterglow phosphors are prepared by high-temperature solid-phase reaction. The photoluminescence and long afterglow performance of host material doped with Zn2+ are investigated. The results show that the emission peak of Mn2+ is red-shifted by 5 nm with increasing Zn2+ concentration. Zn0.03Mg1.96SnO4:0.01Mn2+ phosphor has the strongest green luminescence intensity with the chromaticity coordinates of (0.085 7, 0.608 3) under 270 nm, and Zn0.01Mg1.98SnO4:0.01Mn2+ phosphor has superior long afterglow performance with average lifetime of 102.41s. The afterglow decay and thermoluminescence curve of phosphor are used to explain the mechanism of long afterglow luminescence. Meanwhile, the afterglow intensity distribution of each pixel in Zn0.01Mg1.98SnO4:0.01Mn2+ coating samples is carried out by hyperspectral imaging, and the optimal luminescence intensity and uniformity of the sample are obtained at a phosphor/epoxy mass ratio of 0.002 5. Therefore, Zn0.01Mg1.98SnO4:0.01Mn2+ can be a potential candidate of novel long afterglow phosphors, and hyperspectral imaging also provides new research approaches for the rational proportioning of luminescent materials.

Abstract The outgrowth of epithelial bud followed by reiterated bifurcations during renal development is driven by the ligand-receptor interactions between the epithelium and the surrounding mesenchyme. Here, by exploring ligand-receptor interactions in E10.5 and E11.5 kidneys by single cell RNA-seq, we find that Isthmin1 (Ism1), a secreted protein, resembles Gdnf expression and modulates kidney branching morphogenesis. Mice deficient for Ism1 exhibit defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation in E11.5 embryos, attributable to the compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia. By HRP-induced proximity labelling, we further identify integrin α8β1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin α8β1, the receptor whose activation is responsible for Gdnf expression and mesenchyme condensation. Taken together, our work reveals Ism1 as a critical regulator of cell-cell interaction that modulates Gdnf/Ret signaling during early kidney development.

BackgroundGlioma is a prevalent and lethal brain malignancy; despite current treatment options, the prognosis remains poor. Therefore, immunotherapy has emerged as a promising therapeutic strategy. However, research trends and hotspots in glioma immunotherapy have not been systematically analyzed. This study aimed to elucidate global research trends and knowledge structures regarding immunotherapy for glioma using bibliometric analysis.MethodsPublications related to immunotherapy for glioma from 2000-2023 were retrieved from Web of Science Core Collection database (WoSCC). We conducted quantitative analysis and visualization of research trends using various tools, including VOSviewer (1.6.18), CiteSpace (5.7 R3), Microsoft Charticulator, and the Bibliometrix package in R.ResultsA total of 4910 publications were included. The number of annual publications exhibited an obvious upward trend since 2019. The USA was the dominant country in terms of publication output and centrality. Frontiers in Immunology published the most articles. Harvard Medical School ranked first in productivity among institutions. Sampson, John H. Ph.D. is the most prolific author in the field with 88 articles and a total of 7055 citations. Clinical Cancer Research has the largest total number and impact factor. Analysis of keywords showed immunotherapy, glioblastoma, immunotherapy, and clinical trials as hot topics. The tumor microenvironment, cell death pathways, chimeric antigen receptor engineering, tumor-associated macrophages, and nivolumab treatment represent indicating shifts in the direction of future glioma immunotherapy development.ConclusionThis bibliometric analysis systematically delineated global landscapes and emerging trends in glioma immunotherapy research. This study highlighted the prominence of Chimeric Antigen Receptor T-cell (CAR-T), Programmed Death-1 (PD-1), and nivolumab in current glioma immunotherapy research. The growing emphasis on specific neoantigens and prognostic tumor markers suggests potential avenues for future exploration. Furthermore, the data underscores the importance of strengthened international collaboration in advancing the field.

The accurate diagnosis and effective therapy of malignant tumors is still a challenge owing to its poor prognosis, recurrence, and drug resistance. In this study, a tumor microenvironment responsive and high O2-economic effect nano-theranostic agent GOx@NPs was constructed through the self-assembly of GOx and CDDO-Fe, which was synthesized by coupling natural chemotherapeutic drug CDDO-Me blocked by ferrocene (Fc) with near-infrared (NIR) fluorescence probe hemicyanine (I-CyOH) via redox-responsive linker dimercaptoisopropionyl, and then introducing tamoxifen (estrogen receptor target fragment) to hemicyanine to enhance the active targeting ability. The NIR fluorescence probe I-CyOH not only achieved an accurate diagnosis, but also possessed photodynamic therapy (PDT) effect. The active targeting fragment tamoxifen enhanced the accumulation of pathological site and alleviated the hypoxia microenvironment through the inhibition of mitochondrial respiratory to reinforce the PDT efficiency of I-CyOH. Moreover, the combination of Fc and GOx could achieve starvation therapy and enhance chemodynamic therapy (CDT). In vitro and vivo experiments exhibited that the effective dual sensitive synergistic therapy possessed significant therapy efficiency and lower side effects. This study provides a valuable strategy for constructing dual sensitization and high economic of intelligent nano-theranostic agents for tumor diagnosis and synergistic cancer therapy.

Abstract As the dominant component of the tumor microenvironment, cancer-associated fibroblasts (CAFs), play a vital role in tumor progression. An increasing number of studies have confirmed that CAFs are involved in almost every aspect of tumors including tumorigenesis, metabolism, invasion, metastasis and drug resistance, and CAFs provide an attractive therapeutic target. This study aimed to explore the feature genes of CAFs for potential therapeutic targets and reliable prediction of prognosis in patients with gastric cancer (GC). Bioinformatic analysis was utilized to identify the feature genes of CAFs in GC by performing an integrated analysis of single-cell and transcriptome RNA sequencing using R software. Based on these feature genes, a CAF-related gene signature was constructed for prognostic prediction by LASSO. Simultaneously, survival analysis and nomogram were performed to validate the prognostic predictive value of this gene signature, and qRT–PCR and immunohistochemical staining verified the expression of the feature genes of CAFs. In addition, small molecular drugs for gene therapy of CAF-related gene signatures in GC patients were identified using the connectivity map (CMAP) database. A combination of nine CAF-related genes was constructed to characterize the prognosis of GC, and the prognostic potential and differential expression of the gene signature were initially validated. Additionally, three small molecular drugs were deduced to have anticancer properties on GC progression. By integrating single-cell and bulk RNA sequencing analyses, a novel gene signature of CAFs was constructed. The results provide a positive impact on future research and clinical studies involving CAFs for GC.

Abstract It is of great significance to find new effective drugs for an adjuvant therapy targeting lung cancer to improve the survival rate and prognosis of patients with the disease. Previous studies have confirmed that certain Chinese herbal extracts have clear anti-tumor effects, and in our preliminary study, betulinaldehyde was screened for its potential anti-tumor effects. The current study thus aimed to confirm the anti-tumor effect of betulinaldehyde, using in vitro experiments to explore its underlying molecular mechanism. It was found that betulinaldehyde treatment significantly inhibited the viability, proliferation, and migration of A549 cells in a dose-dependent manner. In addition, betulinaldehyde inhibited the activation of Akt, MAPK, and STAT3 signaling pathways in A549 cells in a time-dependent manner. More importantly, betulinaldehyde also decreased the expression level of SQSTM1 protein, increased the expression level of LC3 II, and increased the autophagy flux in A549 cells. The pretreatment of A549 cells with the autophagy inhibitor, 3-methyladenine, could partially negate the anti-tumor effects of betulinaldehyde. These findings suggest that betulinaldehyde could significantly inhibit the oncological activity of A549 cells by regulating the intracellular autophagy level, making it a potentially effective option for the adjuvant therapy used to treat lung cancer in the future.

An integrated analysis of RNA editing events in human embryo development suggests that recurrent RNA edits might enhance maternal mRNA clearance.

With climate change and urbanization, the rainstorm disaster has become one of the major climate risks in constructing the Guangdong–Hong Kong–Macao Greater Bay Area (GBA). Based on daily precipitation, socio-economic data and a comprehensive evaluation method, the characteristics and risks of rainstorm disaster in the GBA at county level are investigated in this paper. Considering the hazard, vulnerability and exposure, the risks of rainstorm disasters are high (Level 3) and very high (Level 4) in Zhuhai, Zhongshan, Dongguan, Jiangmen and Shenzhen. From 1990 to 2018, the frequency and intensity of rainstorms in the GBA have increased by 10 times and 2 mm per decade, respectively. Moreover, the population, gross domestic product, and built-up areas have increased significantly in the GBA, while the vegetation coverage has decreased. The combination of these changes results in an increase in the frequency of rainstorm disasters by two times from 2005 to 2018 compared with that from 1990 to 2004. The findings of this study can provide a positive reference for local governments to improve the pertinence of the strategies for rainstorm disaster prevention and mitigation.

Context Folium Ginkgo extract and tetramethylpyrazine sodium chloride injection (Xingxiong injection) is a compound preparation commonly used for treating cerebral ischaemia/reperfusion injury in ischaemic stroke in China. However, its potential mechanisms on ischaemic stroke remain unknown. Objective This study explores the potential mechanisms of Xingxiong injection in vivo or in vitro. Materials and methods Sprague-Dawley (SD) rats were randomly assigned to five groups: the sham (normal saline), the model (normal saline) and the Xingxiong injection groups (12.5, 25 or 50 mL/kg). The rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by reperfusion for 14 d. Xingxiong injection was administered via intraperitoneal (i.p.) injection immediately after ischaemia induction for 14 d. Afterwards, rats were sacrificed at 14 d induced by administration of Xingxiong injection. Results Xingxiong injection significantly reduces infarct volume (23%) and neurological deficit scores (93%) compared with the MCAO/R group. Additionally, Xingxiong injection inhibits the loss in mitochondrial membrane potential (43%) and reduces caspase-3 level (44%), decreases NOX (41%), protein carbonyl (29%), 4-HNE (40%) and 8-OhdG (41%) levels, inhibits the expression of inflammatory factors, such as TNF-α (26%), IL-1β (34%), IL-6 (39%), MCP-1 (36%), CD11a (41%) and ICAM-1 (43%). Moreover, Xingxiong injection can increase p-Akt/Akt (35%) and Nrf2 (47%) protein expression and inhibit NLRP3 (42%) protein expression. Conclusions Xingxiong injection prevents cerebral ischaemia/reperfusion injury via activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome. These findings provide experimental evidence for clinical use of drugs in the treatment of ischaemic stroke.

Context Shengmai injection (SMI) has been used to treat heart failure.Objective This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX).Materials and methods In vivo, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. In vitro, H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed.Results SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group in vivo. Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway.Conclusions This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.

The hot spot extraction agent N,N,N′,N′-tetraoctyl-3-oxoglutaramide (TODGA) has the advantages of novelty, high efficiency and environmental protection in the separation of rare earths by tandem extraction. In this paper, the characteristic parameters for the separation of dysprosium, erbium, thulium and ytterbium ions in the TOGDA–kerosene/hydrochloric acid system for tandem extraction were calculated. Using a 10% TODGA–kerosene/5 mol·L−1 hydrochloric acid extraction system, the mixture containing Dy3+ 0.258 mol·L−1, Er3+ 0.252 mol·L−1, Tm3+ 0.248 mol·L−1 and Yb3+ 0.242 mol·L−1 can be separated by three separation steps, and four products of Dy3+, Er3+, Tm3+ and Yb3+ can be obtained. The purity of the four products was 99.80%, 99.20%, 99.70% and 99.70%, and the yields were 99.03%, 98.97%, 97.88% and 96.98%, in order. In this paper, the reasons were analyzed for the differences in the ability of the TODGA system to extract heavy rare earth ions (REEs) in terms of density functionality, complex structure and bond valence model. These will provide more basic data and guidance for the industrial application of TODGA.

Backgrounds Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are limited in solid tumors due to the hostile tumor microenvironment (TME). Combination therapy could be a promising approach to overcome this obstacle. Recent studies have shown that sphingosine 1-phosphate receptor (S1PR)3 has tremendous potential in regulating the immune environment. However, the functional significance of S1PR3 in T-cell-based immunotherapies and the molecular mechanisms have not been fully understood.Methods Here, we studied the combination of EpCAM-specific CAR T-cell therapy with pharmacological blockade of S1PR3 against solid tumor. We have applied RNA sequencing, flow cytometry, ELISA, cellular/molecular immunological technology, and mouse models of solid cancers.Results Our study provided evidence that S1PR3 high expression is positively associated with resistance to programmed cell death protein-1 (PD-1)-based immunotherapy and increased T-cell exhaustion. In addition, pharmacological inhibition of S1PR3 improves the efficacy of anti-PD-1 therapy. Next, we explored the possible combination of S1PR3 antagonist with murine EpCAM-targeted CAR-T cells in immunocompetent mouse models of breast cancer and colon cancer. The results indicated that the S1PR3 antagonist could significantly enhance the efficacy of murine EpCAM CAR-T cells in vitro and in vivo. Mechanistically, the S1PR3 antagonist improved CAR-T cell activation, regulated the central memory phenotype, and reduced CAR-T cell exhaustion in vitro. Targeting S1PR3 was shown to remodel the TME through the recruitment of proinflammatory macrophages by promoting macrophage activation and proinflammatory phenotype polarization, resulting in improved CAR-T cell infiltration and amplified recruitment of CD8+T cells.Conclusions This work demonstrated targeting S1PR3 could increase the antitumor activities of CAR-T cell therapy at least partially by inhibiting T-cell exhaustion and remodeling the TME through the recruitment of proinflammatory macrophages. These findings provided additional rationale for combining S1PR3 inhibitor with CAR-T cells for the treatment of solid tumor.

Abstract Tropical cyclones (TCs) constitute one of the major types of meteorological disasters in China, causing extensive damage. Based on the latest quality‐controlled provincial‐level TC disaster losses data over China from 2001 to 2020, the spatiotemporal variation in TC disaster and its link with TC activity in the form of prevailing track, precipitation, and intensity were investigated. Results showed that the areas impacted by TCs expanded significantly in the past decade (2011–2020) compared with the previous decade (2001–2010) throughout China, while the direct economic losses resulting from TCs did not increase significantly. Regionally, TC disaster losses increased in Northeast China but decreased in Fujian province. Causal analysis indicated that the increased influential TC (ITC) frequency and TC precipitation together led to the increase in damage for northern China. Also, more westward ITCs resulted in the increase in TC disasters for southwestern China. For southeastern China, the reduction in TC disasters was related to the northward shift in the northwestward ITC track. Although TC disasters increase with exposure, they are heavily influenced by TC track, precipitation, and intensity. Our findings suggest that more attention should be paid to TC prediction and early warning in northern China, especially Northeast China, where TC disasters are growing but there is greater vulnerability and insufficient capacity for TC prevention and mitigation.

Abstract Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).