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Abstract Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What’s more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment. Graphical Abstract

Abstract Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.

Abstract Background Salvia miltiorrhiza Bunge, a significant and widely used medicinal herb, is also recognized in the US Pharmacopoeia as a dietary supplement. However, the decline in yield and quality limits its further development as a traditional herbal medicine. Therefore, a deeper understanding of how synthetic communities (SynCom) affect the quality and yield of S. miltiorrhiza and the underlying mechanisms is necessary. Results In this study, we selected S. miltiorrhiza as the research subject and designed two synthetic communities (SynCom 1 and SynCom 2) using five endophytic fungi without significantly growth-promoting effect. We conducted both greenhouse and field experiments to investigate their impact on the yield and quality of the herbal plants. Greenhouse experiments confirmed that SynCom 1 significantly increased the biomass of S. miltiorrhiza, whereas SynCom 2 had the opposite effect. Field experiments further demonstrated that the application of SynCom 1 promoted photosynthesis and enhanced carbon and nitrogen metabolism, steady and markedly promoted plant growth, and thus increased S. miltiorrhiza yield compared to the uninoculated. In contrast, SynCom 2 inhibited yield but increased the content of the main active components. Un-targeted metabolomics analysis showed that SynCom 1 mainly promoted tricarboxylic acid cycle and nitrogen assimilation process to increase yield, and SynCom 2 mainly increase substrate content in the salvianolic acid and tanshinone synthesis pathways to improve quality. Conclusion These beneficial qualities exhibited by SynComs composed of fungi without apparent growth-promoting abilities represent an untapped resource that can be leveraged to enhance crop productivity. This opens up new research avenues for precision manipulation of plant microbiomes. Graphical abstract

The study of the hydro-chemical characteristics of burnt rock aquifers helps to distinguish the hydraulic connections between different aquifers. Taking Zhangjiamao Coal Mine in Shenfu Mining Area as an example, 29 groups of water samples were collected from weathered bedrock, bedrock, 2−2 coal burned rock and 3−1 coal burned rock aquifers, and the hydro-chemical characteristics and control factors in the study area were analyzed by comprehensive use of statistical analysis, Piper trilinear diagram, Gibbs model and hybrid model, and the source of main ions was determined, based on which the contact relationship of each aquifer was identified. The results indicated that the total dissolved solids (TDS) of the weathered bedrock and the 2−2 coal burnt rock aquifer were close, slightly lower than the TDS of the bedrock aquifer, while the TDS of the 3−1 coal burnt rock aquifer was the highest, showing a trend of gradually increasing TDS with the increase of aquifer depth. The cations in the weathered bedrock and the 2−2 coal burnt rock aquifer were mainly Ca2+, while the cations in the bedrock and 3−1 coal burnt rock aquifer were mainly Na+; the anions in the weathered bedrock, 2−2 coal burnt rock, and 3−1 coal burnt rock aquifers were mainly HCO3−, while the bedrock aquifers were mainly HCO3−, and SO42−. The hydro-chemical types of weathered bedrock, 2−2 coal burnt rock, and 3−1 coal burnt rock aquifers were mainly HCO3−Ca type, HCO3−Ca and HCO3−Ca·Mg type, HCO3−Ca and HCO3−Na·Mg type. The hydro-chemical composition of weathered bedrock and 2−2 coal burnt rock aquifer was mainly controlled by water rock interaction, while the hydro-chemical composition of bedrock and 3−1 coal burnt rock aquifer was mainly influenced by both water rock interaction and concentration. The main ions of 3−1 coal burned rock, bedrock, weathered bedrock and 2−2 coal burned rock aquifer were respectively from the dissolution of silicate rock salt, the dissolution of silicate rock and evaporite rock salt, and the weathering dissolution of silicate rock and carbonate rock salt. At the same time, the reverse cation exchange interaction effect occurred in the groundwater disasters of each aquifer. Multiple indicator results showed that the ion composition of the weathered bedrock and the aquifer of the 2−2 coal fired rock was similar, and there was a strong hydraulic connection. There may be a direct contact relationship locally, which is different from the ion composition of the aquifer of the 3−1 coal fired rock. There is a certain barrier layer between them, and the hydraulic connection between them is weak.

Abstract This paper studies the problem of joint deployment, user association, channel, and resource allocation in unmanned aerial vehicle‐enabled access network. Since different user equipments performing different tasks and have different data rate requirements, the priority‐based traffic fairness problem is investigated. This problem, however, is a mixed integer nonlinear programming problem with NP‐hard complexity, making it challenging to be solved. To address this issue, a self‐organized and distributed framework “sense‐as‐you‐fly” based on the decomposition process, which divides the original problem into several subproblems, is proposed. Assuming without central controller, we derive the closed‐form resource allocation scheme and propose distributed many‐to‐one matching to optimize user association subproblem. Considering the coupled characteristics, the multi‐unmanned aerial vehicle deployment and channel allocation subproblems are modelled as a local altruistic game. The existence of Nash equilibrium is proved with the aid of exact potential game and efficient best response learning‐based algorithm is proposed. The original problem is finally addressed by solving the sub‐problems alternately and iteratively. Simulation results verify its effectiveness. By jointly optimizing multidimensional variables, the proposed algorithm unlocks network performance gains, especially in resource‐limited regimes.

In order to study the influence of cement content, comprehensive water-cement ratio, formation characteristics and other factors on the performance of equal thickness soil-cement cut-off curtain in coal mine, the principle analysis of equal thickness soil-cement curtain, the influencing factors of curtain performance analysis, the test and performance test of equal thickness soil-cement curtain were carried out, the key influencing factors were determined, the parameters of soil-cement of equal thickness in composite strata were obtained, and the field demonstration application was carried out. The results show that: the main factors affecting the performance of equal thickness soil-cement curtain were rock (soil) body properties, groundwater characteristics, cement cementitious materials, mixing process and curing conditions. Rock (soil) body properties and cement content were the direct factors affecting wall quality; water-cement ratio and curing period were the key factors to ensure wall quality. The ground layer had higher strength and better grain gradation, so the strength of soil-cement of equal thickness was higher and the permeability coefficient was smaller. According to the influencing factors, the cement content of the demonstration project was determined to be 25%, the comprehensive water-cement ratio was 1.2:1, and the formation was composite formation material. The treatment results of the complex formation leakage section of the gentle slope inclined shaft in Luotuoshan Coal Mine showed that the three-step construction process was used to construct the outer water cutting curtain wall of the inclined shaft with good quality. The 28 d compressive strength of the field samples was 5.3—31.8 MPa, and the permeability coefficient was 0.005×10−7—0.2403×10−7 cm/s. Wellbore water inflow decreased from 16.8 m3/h to about 1.6 m3/h, which was reduced by about 90.5% compared with before treatment.

Backgrounds: The functional recovery after peripheral nerve injury remains unsatisfactory. This study aims to perform a comprehensive evaluation of the efficacy of Fasudil Hydrochloride at treating the sciatic nerve transection injury in rats and the mechanism involved. Materials and methods: In animal experiments, 75 Sprague Dawley rats that underwent transection and repair of the right sciatic nerve were divided into a control, Fasudil, and Fas + LY group, receiving daily intraperitoneal injection of saline, Fasudil Hydrochloride (10 mg/kg), and Fasudil Hydrochloride plus LY294002 (5 mg/kg), respectively. At day 3 after surgery, the expression of ROCK2, p-PI3K, and p-AKT in L4-5 DRG and the lumbosacral enlargement was determined using Western blotting. At day 7 and 14, axon density in the distal stump was evaluated with immunostaining using the anti-Neurofilament-200 antibody. At day 30, retrograde tracing by injecting Fluoro-gold in the distal stump was performed. Three months after surgery, remyelination was analyzed with immostaining using the anti-MPZ antibody and the transmission electron microscope; Moreover, Motion-Evoked Potential, and recovery of sensorimotor functions was evaluated with a neuromonitor, Footprint, Hot Plate and Von Frey Filaments, respectively. Moveover, the Gastrocnemius muscles were weighed, and then underwent H＆E staining, and staining of the neuromuscular junction using α-Bungarotoxin to evaluate the extent of atrophy and degeneration of the endplates in the Gastrocnemius. In vitro, spinal motor neurons (SMNs) and dorsal root ganglia (DRG) were cultured to examine the impact of Fasudil Hydrochloride and LY294002 on the axon outgrowth. Results: Three days after injury, the expression of ROCK2 increased significantly (P＜0.01), and Fasudil application significantly increased the expression of p-PI3K and p-AKT in L4-6 DRG and the lumbosacral enlargement (P

Abstract Background Spermatogenesis is a highly regulated and complex process in which DNA methylation plays a crucial role. This study aimed to explore the differential methylation profiles in sperm DNA between patients with asthenospermia (AS) and healthy controls (HCs), those with oligoasthenospermia (OAS) and HCs, and patients with AS and those with OAS. Results Semen samples and clinical data were collected from five patients with AS, five patients with OAS, and six age-matched HCs. Reduced representation bisulfite sequencing (RRBS) was performed to identify differentially methylated regions (DMRs) in sperm cells among the different types of patients and HCs. A total of 6520, 28,019, and 16,432 DMRs were detected between AS and HC, OAS and HC, and AS and OAS groups, respectively. These DMRs were predominantly located within gene bodies and mapped to 2868, 9296, and 9090 genes in the respective groups. Of note, 12, 9, and 8 DMRs in each group were closely associated with spermatogenesis and male infertility. Furthermore, BDNF, SMARCB1, PIK3CA, and DDX27; RBMX and SPATA17; ASZ1, CDH1, and CHDH were identified as strong differentially methylated candidate genes in each group, respectively. Meanwhile, the GO analysis of DMR-associated genes in the AS vs. HC groups revealed that protein binding, cytoplasm, and transcription (DNA-templated) were the most enriched terms in the biological process (BP), cellular component (CC), and molecular function (MF), respectively. Likewise, in both the OAS vs. HC and AS vs. OAS groups, GO analysis revealed protein binding, nucleus, and transcription (DNA-templated) as the most enriched terms in BP, CC, and MF, respectively. Finally, the KEGG analysis of DMR-annotated genes and these genes at promoters suggested that metabolic pathways were the most significantly associated across all three groups. Conclusions The current study results revealed distinctive sperm DNA methylation patterns in the AS vs. HC and OAS vs. HC groups, particularly between patients with AS and those with OAS. The identification of key genes associated with spermatogenesis and male infertility in addition to the differentially enriched metabolic pathways may contribute to uncovering the potential pathogenesis in different types of abnormal sperm parameters.

Abstract Background Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. Methods Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. Results 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p

Abstract The biomechanical aspects of adjacent segment degeneration after Adult Idiopathic Scoliosis (AdIS) corrective surgery involving postoperative changes in motion and stress of adjacent segments have yet to be investigated. The objective of this study was to evaluate the biomechanical effects of corrective surgery on adjacent segments in adult idiopathic scoliosis by finite element analysis. Based on computed tomography data of the consecutive spine from T1–S1 of a 28-year-old male patient with adult idiopathic scoliosis, a three-dimensional finite element model was established to simulate the biomechanics. Two posterior long-segment fixation and fusion operations were designed: Strategy A, pedicle screws implanted in all segments of both sides, and Strategy B, alternate screws instrumentation on both sides. The range of motion (ROM), Maximum von Mises stress value of intervertebral disc (IVD), and Maximum von Mises stress of the facet joint (FJ) at the fixation adjacent segment were calculated and compared with data of the preoperative AdIS model. Corrective surgery decreased the IVD on the adjacent segments, increased the FJ on the adjacent segments, and decreased the ROM of the adjacent segments. A greater decrease of Maximum von Mises stress was observed on the distal adjacent segment compared with the proximal adjacent segment. The decrease of Maximum von Mises stress and increment of Maximum von Mises stress on adjacent FJ in strategy B was greater than that in strategy A. Under the six operation modes, the change of the Maximum von Mises stress on the adjacent IVD and FJ was significant. The decrease in ROM in the proximal adjacent segment was greater than that of the distal adjacent segment, and the decrease of ROM in strategy A was greater than that in strategy B. This study clarified the biomechanical characteristics of adjacent segments after AdIS corrective surgery, and further biomechanical analysis of two different posterior pedicle screw placement schemes by finite element method. Our study provides a theoretical basis for the pathogenesis, prevention, and treatment of adjacent segment degeneration after corrective surgery for AdIS.

The Asteraceae are widely distributed throughout the world, with diverse functions and large genomes. Many of these genes remain undiscovered and unstudied. In this study, we discovered a new gene ClNUM1 in Chrysanthemum lavandulifolium and studied its function. In this study, bioinformatics, RT-qPCR, paraffin sectioning, and tobacco transgenics were utilized to bioinformatically analyze and functionally study the three variable splice variants of the unknown gene ClNUM1 cloned from C. lavandulifolium. The results showed that ClNUM1.1 and ClNUM1.2 had selective 3′ splicing and selective 5′ splicing, and ClNUM1.3 had selective 5′ splicing. When the corresponding transgenic tobacco plants were subjected to abiotic stress treatment, in the tobacco seedlings, the ClNUM1.1 gene and the ClNUM1.2 gene enhanced salt and low-temperature tolerance and the ClNUM1.3 gene enhanced low-temperature tolerance; in mature tobacco plants, the ClNUM1.1 gene was able to enhance salt and low-temperature tolerance, and the ClNUM1.2 and ClNUM1.3 genes were able to enhance low-temperature tolerance. In summary, there are differences in the functions of the different splice variants and the different seedling stages of transgenic tobacco, but all of them enhanced the resistance of tobacco to a certain extent. The analysis and functional characterization of the ClNUM1 gene provided new potential genes and research directions for abiotic resistance breeding in Chrysanthemum.

Objective The talus is an important component in the ankle, and its treatment after injury is crucial. However, complications and adverse events due to incomplete traditional classifications may still occur, and these classifications fail to analyze the patterns and distribution of fractures from a three‐dimensional perspective. Therefore, in this study, we aimed to analyze the location and distribution of fracture lines in different types of talus fractures using three‐dimensional (3D) and heat mapping techniques. Additionally, we aimed to determine the surface area of the talus that can be utilized for different approaches of internal fixation, aiding in the planning of surgical procedures. Methods We retrospectively analyzed data from CT scans from 126 patients diagnosed with talus fractures at our two hospitals. We extracted the CT data of a healthy adult and created a standard talus model. We performed 3D reconstruction using patients' CT images and superimposed the fracture model onto the standard model for drawing fracture lines. Subsequently, we converted the fracture lines into a heat map for visualization. Additionally, we measured 20 specimens to determine the boundary for various ligaments attached to the talus. We determined the surface area of the talus available for different surgical approaches by integrating the boundary data with previously reported data on area of exposure. Results Without considering the displacement distance of the fracture, fracture types were classified as follows, by combining Hawkins and Sneppen classifications: talar neck, 41.3%; posterior talar tubercle, 22.2%; body for the talus and comminuted, 17.5%; lateral talar tubercle, 11.9%; and talar head, 7.1%. We established fracture line and heat maps using this classification. Additionally, we demonstrated the available area for anteromedial, anterolateral, posteromedial, posterolateral, and medial malleolus osteotomy and Chaput osteotomy approaches. Conclusion Fracture line and heat map analyses can aid surgeons in planning a single or combined surgical approach for the reduction and internal fixation of talus fractures. Demonstrating the different surgical approaches can help surgeons choose the most effective technique for individual cases.

Abstract Background Plant specialized (or secondary) metabolites (PSM), also known as phytochemicals, natural products, or plant constituents, play essential roles in interactions between plants and environment. Although many research efforts have focused on discovering novel metabolites and their biosynthetic genes, the resolution of metabolic pathways and identified biosynthetic genes was limited by rudimentary analysis approaches and enormous number of candidate genes. Results Here we integrated state-of-the-art automated machine learning (ML) frame AutoGluon-Tabular and multi-omics data from Arabidopsis to predict genes encoding enzymes involved in biosynthesis of plant specialized metabolite (PSM), focusing on the three main PSM categories: terpenoids, alkaloids, and phenolics. We found that the related features of genomics and proteomics were the top two crucial categories of features contributing to the model performance. Using only these key features, we built a new model in Arabidopsis, which performed better than models built with more features including those related with transcriptomics and epigenomics. Finally, the built models were validated in maize and tomato, and models tested for maize and trained with data from two other species exhibited either equivalent or superior performance to intraspecies predictions. Conclusions Our external validation results in grape and poppy on the one hand implied the applicability of our model to the other species, and on the other hand showed enormous potential to improve the prediction of enzymes synthesizing PSM with the inclusion of valid data from a wider range of species.

This study examines the nonlinear dynamic response of sandwich plates under low-velocity impacts (LVIs), which consist of a porous aluminum foam core with functionally graded (FG) graphene platelets (GPLs) reinforcement and two titanium alloy face sheets. The finite element method is employed to perform the numerical simulations and the Hertz contact theory is used to model the impact behavior. The generic Halpin-Tsai model, which incorporates the porosity effect, is adopted to estimate the mechanical properties of core made of the FG-GPLRC, based on the experimental data of the closed-cell aluminum alloy foam. The simulation results reveal that the FG-X configuration has the highest impact resistance, and that the addition of GPLs improves the impact performance. Moreover, a thicker core can reduce both the first contact time and the vibration period of plates, while a looser boundary condition can prolong the vibration time after the first impact. Additionally, a higher impactor velocity, mass and radius lead to a higher deflection and contact force. The oblique impact decreases the impact energy. This work provides a lighter and stiffer design for structure engineers when components suffer low-velocity impact.

Abstract Background The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. Methods Patients diagnosed with astrocytoma, IDH‐mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2–3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. Results A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki‐67 index (p

Infrared and visible image fusion is an effective solution for image quality enhancement. However, conventional fusion models require the decomposition of source images into image blocks, which disrupts the original structure of the images, leading to the loss of detail in the fused images and making the fusion results highly sensitive to matching errors. This paper employs Convolutional Sparse Representation (CSR) to perform global feature transformation on the source images, overcoming the drawbacks of traditional fusion models that rely on image decomposition. Inspired by neural networks, a multi-layer CSR model is proposed, which involves five layers in a forward-feeding manner: two CSR layers acquiring sparse coefficient maps, one fusion layer combining sparse maps, and two reconstruction layers for image recovery. The dataset used in this paper comprises infrared and visible images selected from public dataset, as well as registered images collected by an actual Unmanned Aerial Vehicle (UAV). The source images contain ground targets, marine targets, and natural landscapes. To validate the effectiveness of the proposed image fusion model in this paper, comparative analysis is conducted with state-of-the-art (SOTA) algorithms. Experimental results demonstrate that the proposed fusion model outperforms other state-of-the-art methods by at least 10% in SF, EN, MI and QAB/F fusion metrics in most image fusion cases, thereby affirming its favorable performance.