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Abstract Background Gender is a significant risk factor for late-onset Alzheimer’s disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. Methods Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG’s cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. Results SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced β-amyloid (Aβ) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aβ-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. Conclusion These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral β-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.

Introduction: β-Elemene (β-ELE), derived from Curcuma wenyujin, has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how β-ELE modulates on this process are not clear. Objectives: To observe the action of β-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in β-ELE induced ferroptosis. Methods: Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of β-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by β-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549TFEB KO cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in β-ELE treated A549WT and A549TFEB KO cells, which was further studied in orthotopic NOD/SCID mouse model. Results: β-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. β-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, β-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised β-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model. Conclusion: This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to β-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy.

Tunnelling has increasingly become an essential tool in the exploration of underground space. A typical construction problem is the face instability during tunnelling, posing a great threat to associated infrastructures. Tunnel face instability often occurs with the soil arching collapse. This study investigates the combined effect of cutterhead opening ratio and soil non-uniformity on soil arching effect and face stability, via conducting random finite-element analysis coupled with Monte–Carlo simulations. The results underscore that the face stability is strongly associated with the evolution of stress arch. The obtained stability factors in the uniform soils can serve as a reference for the design of support pressure in practical tunnelling engineering. In addition, non-uniform soils exhibit a lower stability factor than uniform soils, which implies that the latter likely yields an underestimated probability of face failure. The tunnel face is found to have a probability of failure more than 50% if the spatial non-uniformity of soil is ignored. In the end, a practical framework is established to determine factor of safety (FOS) corresponding to different levels of probability of face failure considering various opening ratios in non-uniform soils. The required FOS is 1.70 to limit the probability of face instability no more than 0.1%. Our findings can facilitate the prediction of probability of instability in the conventionally deterministic design of face pressure.

Abstract Background Dysfunction of cholesterol metabolism may be associated with low skeletal muscle mass. This study aimed to explore the relationship between skeletal muscle mass and cholesterol metabolic disorders in adults. Methods The data of a total of 5949 people with complete medical history data, biochemical data and body composition analysis were recruited. According to the serum cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and nonHDL, the population was divided into a disorder group and a normal group. Independent sample t tests, chi-square tests, Pearson's correlation analyses and binary logistic regression analyses were used to study the effect of body composition on abnormal cholesterol metabolism. According to BMI and sex, the population was divided into different subgroups, and binary logistic regression analysis was used to study the effect of the skeletal mass ratio on cholesteral metabolic disorders in different subgroups. Results There were significant differences in sex, alcohol consumption, body weight, BMI, skeletal muscle mass index (SMI) [total skeletal muscle mass (kg)/height 2 (m2)] and skeletal muscle mass ratio (SMR) [total skeletal muscle mass (kg)/weight (kg) *100] between the disorder group (hypercholesterolemia, hyper-LDL, lower-HDL and hyper-nonHDL) and the normal group. Pearson correlation analysis revealed that the SMR was negatively correlated, while the SMI was positively correlated with cholesterol metabolic disorders in both sexes. The overweight group was older and had a greater SMI, abnormal cholesteral metabolism ratio and lower SMR than the normal-weight group. In the normal-weight group, the SMR was an independent protective factor against different kinds of cholesteral metabolic disorders in both sexes, while the SMI was a risk factor. In the overweight subgroup, the protective effect on HDL and nonHDL metabolism remained in the male subgroup but disappeared in the female subgroup. However, the SMI was an independent risk factor for different kinds of cholesteral metabolic disorders in both sexes. Conclusions SMR was an independent protective factor against cholesterol metabolic disorders in both males and females, especially in the normal weight group. SMI was an independent risk factor, especially in the overweight group.

Abstract Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Abstract Exploring the promiscuity of native enzymes presents a promising strategy for expanding their synthetic applications, particularly for catalyzing challenging reactions in non-native contexts. In this study, we explore the promiscuous potential of old yellow enzymes (OYEs) to facilitate the Morita-Baylis-Hillman reaction (MBH reaction), leveraging substrate similarities between MBH reaction and reduction reaction. Using mass spectrometry and spectroscopic techniques, we confirm promiscuity of GkOYE in both MBH and reduction reactions. By blocking H- and H+ transfer pathways, we engineer GkOYE.8, which loses its reduction ability but enhances its MBH activity. The structural basis of MBH reaction catalyzed by GkOYE.8 is obtained through mutation studies and kinetic simulations. Furthermore, enantiocomplementary mutants GkOYE.11 and GkOYE.13 are obtained by directed evolution, exhibiting the ability to accept various aromatic aldehydes and alkenes as substrates. This study demonstrates the potential of leveraging substrate similarities to unlock enzyme functionalities, enabling the catalysis of new-to-nature reactions.

Abstract Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Abstract Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases.

Abstract The mechanical properties of rocks in cold regions undergo significant changes as a result of decades of freeze‒thaw cycles with seasonal variations, which can lead to a series of geological disasters, such as collapse. This study investigates the evolution of the mechanical characteristics and internal progressive damage characteristics of mixed granite under freeze‒thaw cycling and axial loading. By measuring the mass, wave velocity, and uniaxial compressive strength of rock samples and combining these metrics with acoustic emission (AE) characteristics, the physical and mechanical properties and microfracture development of mixed granite after different numbers of freeze‒thaw cycles were investigated. The results indicate that as the number of freeze‒thaw cycles increases, the longitudinal wave velocity, uniaxial compressive strength, and elastic modulus of the mixed granite decrease nonlinearly, while the peak strain gradually increases. Combined with the stress‒strain curve, the AE characteristics can be divided into four stages. As the number of freeze‒thaw cycles increases, the AE cumulative count decreases, and the AE counts of the four stages are different. The low-frequency-high-amplitude signals first increases and then tends to stabilize, and they only appeared in the third and fourth stages. At the same time, the proportion of the low-frequency ratio gradually increases, and the proportion of the high-frequency ratio decreases. In addition, based on the rise time/amplitude (RA) and average frequency (AF) characteristics and failure modes, it was found that the internal crack types of mixed granite transition from shear cracks to tensile cracks, among which tensile cracks play a crucial role in rock failure.

Based on the latest results of near-source exploration in the Middle and Lower Jurassic of the Tuha Basin, a new understanding of the source rocks, reservoir conditions, and source-reservoir-cap rock combinations of the Jurassic Shuixigou Group in the Taibei Sag is established using the concept of the whole petroleum system, and the coal-measure whole petroleum system is analyzed thoroughly. The results are obtained in three aspects. First, the coal-measure source rocks of the Badaowan Formation and Xishanyao Formation and the argillaceous source rocks of the Sangonghe Formation in the Shuixigou Group exhibit the characteristics of long-term hydrocarbon generation, multiple hydrocarbon generation peaks, and simultaneous oil and gas generation, providing sufficient oil and gas sources for the whole petroleum system in the Jurassic coal-bearing basin. Second, multi-phase shallow braided river delta–shallow lacustrine deposits contribute multiple types of reservoirs, e.g. sandstone, tight sandstone, shale and coal rock, in slope and depression areas, providing effective storage space for the petroleum reservoir formation in coal-measure strata. Third, three phases of hydrocarbon charging and structural evolution, as well as effective configuration of multiple types of reservoirs, result in the sequential accumulation of conventional-unconventional hydrocarbons. From high structural positions to depression, there are conventional structural and structural-lithological reservoirs far from the source, low-saturation structural-lithological reservoirs near the source, and tight sandstone gas, coal rock gas and shale oil accumulations within the source. Typically, the tight sandstone gas and coal rock gas are the key options for further exploration, and the shale oil and gas in the depression area is worth of more attention. The new understanding of the whole petroleum system in the coal measures could further enrich and improve the geological theory of the whole petroleum system, and provide new ideas for the overall exploration of oil and gas resources in the Tuha Basin.

Abstract Renal cell carcinoma, a leading cause of death in urological malignancies, arises from the nephron. Its characteristics include diversity in disease biology, varied clinical behaviors, different prognoses, and diverse responses to systemic therapies. The term ‘organoids’ is used to describe structures resembling tissues created through the three-dimensional cultivation of stem cells in vitro. These organoids, when derived from tumor tissues, can retain the diversity of the primary tumor, mirror its spatial tissue structure, and replicate similar organ-like functions. In contrast to conventional two-dimensional cell cultures and the transplantation of tumor tissues into other organisms, organoids derived from tumors maintain the complexity and microenvironment of the original tumor tissue. This fidelity makes them a more reliable model for the development of cancer drugs, potentially accelerating the translation of these drugs to clinical use and facilitating personalized treatment options for patients. This review aims to summarize the recent advancements in the use of organoids for studying renal cell carcinoma, focusing on their cultivation, potential applications, and inherent limitations.

Abstract Background Mammalian intestine harbors a mass of phages that play important roles in maintaining gut microbial ecosystem and host health. Pig has become a common model for biomedical research and provides a large amount of meat for human consumption. However, the knowledge of gut phages in pigs is still limited. Results Here, we investigated the gut phageome in 112 pigs from seven pig breeds using PhaBOX strategy based on the metagenomic data. A total of 174,897 non-redundant gut phage genomes were assembled from 112 metagenomes. A total of 33,487 gut phage genomes were classified and these phages mainly belonged to phage families such as Ackermannviridae, Straboviridae, Peduoviridae, Zierdtviridae, Drexlerviridae, and Herelleviridae. The gut phages in seven pig breeds exhibited distinct communities and the gut phage communities changed with the age of pig. These gut phages were predicted to infect a broad range of 212 genera of prokaryotes, such as Candidatus Hamiltonella, Mycoplasma, Colwellia, and Lactobacillus. The data indicated that broad KEGG and CAZy functions were also enriched in gut phages of pigs. The gut phages also carried the antimicrobial resistance genes (ARGs) and the most abundant antimicrobial resistance genotype was diaminopyrimidine resistance. Conclusions Our research delineates a landscape for gut phages in seven pig breeds and reveals that gut phages serve as a key reservoir of ARGs in pigs. Video Abstract

Abstract Very high-resolution remote sensing images hold promising applications in ground observation tasks, paving the way for highly competitive solutions using image processing techniques for land cover classification. To address the challenges faced by convolutional neural network (CNNs) in exploring contextual information in remote sensing image land cover classification and the limitations of vision transformer (ViT) series in effectively capturing local details and spatial information, we propose a local feature acquisition and global context understanding network (LFAGCU). Specifically, we design a multidimensional and multichannel convolutional module to construct a local feature extractor aimed at capturing local information and spatial relationships within images. Simultaneously, we introduce a global feature learning module that utilizes multiple sets of multi-head attention mechanisms for modeling global semantic information, abstracting the overall feature representation of remote sensing images. Validation, comparative analyses, and ablation experiments conducted on three different scales of publicly available datasets demonstrate the effectiveness and generalization capability of the LFAGCU method. Results show its effectiveness in locating category attribute information related to remote sensing areas and its exceptional generalization capability. Code is available at https://github.com/lzp-lkd/LFAGCU .

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and Cmax, and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

An improved acetyl chloride-methanol method was established for the rapid and accurate determination of linoleic acid, α-linolenic acid, docosahexaenoic acid (DHA) and arachidonic acid (ARA) in infant foods for special medicinal purpose with deeply hydrolyzed milk proteins and amino acids. The results showed that the optimal pretreatment conditions were 6 mL of reaction reagent, reaction for 60 minutes, and use of isooctane as extraction solvent. The linear range of linolenic acid and α-linolenic acid were 0.8–8.0 and 0.2–2.0 mg/mL, respectively. The linear ranges of DHA and ARA were 0.02–0.40 mg/mL, and the determination coefficients for all analytes were greater than or equal to 0.999 7. The limits of detection (LOD) and limits of quantitation (LOQ) of the developed method were 2 and 5 mg/100 g, respectively. This method was characterized by good repeatability (relative standard deviation (RSD) ≤ 3.3%), high precision (RSD ≤ 3.8%), good stability (RSD ≤ 2.6%), and high spiked recovery (ranging from 93.1% to 101.7%). Compared with its original version, the developed method could effectively solve the problem of incomplete reaction due to caking, with an at least 100% higher working efficiency.

Abstract Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.

Abstract Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.

Abstract Introduction Post liver transplantation (LT) patients endure high morbidity rate of multi-organ ischemic symptoms following reperfusion. We hypothesize that enhanced external counterpulsation (EECP) as a typical non-invasive assisted circulation procedure, which can efficiently inhibit the relative ischemic symptoms via the systemic improvement of hemodynamics. Case presentation A 51-year-old male patient, 76 kg, 172 cm, received orthotopic LT surgery for viral hepatitis B induced acute-on-chronic liver failure hepatic failure. His medical records revealed ischemic symptoms in multi-organ at the time of hospital discharge, including headache, refractory insomnia, abdominal paralysis, and lower limb pain. The EECP treatment was introduced for assisted rehabilitation and to improve the postoperative quality of life. Doppler Ultrasound examination showed significant augmentation of blood flow volume in the carotid arteries, the hepatic artery, the portal vein and the femoral artery during EECP intervention. A standard 35-hour EECP treatment led to significant improvement in quality of life, e.g. sleep quality and walking ability. Conclusion We report a case of multi-organ ischemic symptoms in a post LT patient. EECP treatment can significantly improve the quality of life via the systematic promotion of hemodynamics.

Repetitive implant-related infections (IRIs) are devastating complications in orthopedic surgery, threatening implant survival and even the life of the host. Biofilms conceal bacterial-associated antigens (BAAs) and result in a ''cold tumor''-like immune silent microenvironment, allowing the persistence of IRIs. To address this challenge, an iron-based covalent organic framed nanoadjuvant doped with curcumin and platinum (CFCP) was designed in the present study to achieve efficient treatment of IRIs by inducing a systemic immune response. Specifically, enhanced sonodynamic therapy (SDT) from CFCP combined with iron ion metabolic interference increased the release of bacterial-associated double-stranded DNA (dsDNA). Immunogenic dsDNA promoted dendritic cell (DC) maturation through activation of the stimulator of interferon gene (STING) and amplified the immune stimulation of neutrophils via interferon-β (IFN-β). At the same time, enhanced BAA presentation aroused humoral immunity in B and T cells, creating long-term resistance to repetitive infections. Encouragingly, CFCP served as neoadjuvant immunotherapy for sustained antibacterial protection on implants and was expected to guide clinical IRI treatment and relapse prevention.

Abstract Background Severe burns may alter the stability of the intestinal flora and affect the patient’s recovery process. Understanding the characteristics of the gut microbiota in the acute phase of burns and their association with phenotype can help to accurately assess the progression of the disease and identify potential microbiota markers. Methods We established mouse models of partial thickness deep III degree burns and collected faecal samples for 16 S rRNA amplification and high throughput sequencing at two time points in the acute phase for independent bioinformatic analysis. Results We analysed the sequencing results using alpha diversity, beta diversity and machine learning methods. At both time points, 4 and 6 h after burning, the Firmicutes phylum content decreased and the content of the Bacteroidetes phylum content increased, showing a significant decrease in the Firmicutes/Bacteroidetes ratio compared to the control group. Nine bacterial genera changed significantly during the acute phase and occupied the top six positions in the Random Forest significance ranking. Clustering results also clearly showed that there was a clear boundary between the communities of burned and control mice. Functional analyses showed that during the acute phase of burn, gut bacteria increased lipoic acid metabolism, seleno-compound metabolism, TCA cycling, and carbon fixation, while decreasing galactose metabolism and triglyceride metabolism. Based on the abundance characteristics of the six significantly different bacterial genera, both the XGboost and Random Forest models were able to discriminate between the burn and control groups with 100% accuracy, while both the Random Forest and Support Vector Machine models were able to classify samples from the 4-hour and 6-hour burn groups with 86.7% accuracy. Conclusions Our study shows an increase in gut microbiota diversity in the acute phase of deep burn injury, rather than a decrease as is commonly believed. Severe burns result in a severe imbalance of the gut flora, with a decrease in probiotics and an increase in microorganisms that trigger inflammation and cognitive deficits, and multiple pathways of metabolism and substance synthesis are affected. Simple machine learning model testing suggests several bacterial genera as potential biomarkers of severe burn phenotypes.

Abstract Fast computational ghost imaging with high quality and ultra-high-definition resolution reconstructed images has important application potential in target tracking, biological imaging and other fields. However, as far as we know, the resolution (pixels) of the reconstructed image is related to the number of measurements. And the limited resolution of reconstructed images at low measurement times hinders the application of computational ghost imaging. Therefore, in this work, a new computational ghost imaging method based on saliency variable sampling detection is proposed to achieve high-quality imaging at low measurement times. This method physically variable samples the salient features and realizes compressed detection of computational ghost imaging based on the salient periodic features of the bucket detection signal. Numerical simulation and experimental results show that the reconstructed image quality of our method is similar to the compressed sensing method at low measurement times. Even at 500 (sampling rate $$0.76\%$$ 0.76 % ) measurement times, the reconstructed image of the method still has the target features. Moreover, the $$2160\times 4096$$ 2160 × 4096 (4K) pixels ultra-high-definition resolution reconstructed images can be obtained at only a sampling rate of $$0.11\%$$ 0.11 % . This method has great potential value in real-time detection and tracking, biological imaging and other fields.

Objective Dual‐plate fixation was thought to be the gold standard for treating complicated bicondylar tibial plateau fractures, yet it was found to be hard to accommodate the posterior column in three‐column fractures. Currently, column‐specific fixation is becoming more and more recognized, but no comprehensive investigation has been performed to back it up. Therefore, the objective of this study was to validate the importance of posterior column fixation in the three‐column tibial fractures by a finite element (FE) analysis and clinical study. Methods In FE analysis, three models were developed: the longitudinal triple‐plate group (LTPG), the oblique triple‐plate group (OTPG), and the dual‐plate group (DPG). Three loading scenarios were simulated. The distribution of the displacement and the equivalent von Mises stress (VMS) in each structure was calculated. The comparative measurements including the maximum posterior column collapse (MPCC), the maximum total displacement of the model (MTD), the maximum VMS of cortical posterior column (MPC‐VMS), and the maximum VMS located on each group of plates and screws (MPS‐VMS). The clinical study evaluated the indicators between the groups with or without the posterior plate, including operation time, blood loss volume, full‐weight bearing period, Hospital for Special Surgery Knee Scoring system (HSS), Rasmussen score, and common postoperative complications. Results In the FE analysis, the MPCC, the MPC‐VMS, and the MTD were detected in much lower amounts in LTPG and OTPG than in DPG. In comparison with DPG, the LTPG and OTPG had larger MPS‐VMS. In the clinical study, 35 cases were included. In the triple‐plate (14) and dual‐plate (21) groups, the operation took 115.6 min and 100.5 min (p

N6-methyladenosine (m6A) methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years. Cardiovascular diseases (CVDs) are a leading cause of death globally. Emerging evidence demonstrates that RNA modifications, such as the m6A modification, are associated with the development and progression of many diseases, including CVDs. An increasing body of studies has indicated that programmed cell death (PCD) plays a vital role in CVDs. However, the molecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood. Herein, elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs. There is great potential for clinical application.

PurposeGynecologic oncology laparotomy leads to severe postoperative pain. We aimed to evaluate the effects of preemptive multimodal analgesic regimen on postoperative opioid consumption for patients undergoing gynecologic oncology laparotomy.MethodsIn this prospective, randomized clinical trial, 80 female patients scheduled for gynecologic oncology laparotomy were randomized to receive preemptive multimodal analgesia consisted of transversus abdominis plane (TAP) block, cyclooxygenase−2 inhibitors, acetaminophen and intravenous morphine patient-controlled analgesia (PCA) (Study group) or conventional analgesia with cyclooxygenase−2 inhibitors and morphine PCA (Control group). The primary outcome was morphine consumption in the first 24 h after surgery. Secondary outcomes were pain scores, nausea, vomiting, time to ambulation and flatus, length of hospital stay, satisfaction score, the 40-item Quality of Recovery score (QoR-40) and the Short-Form Health Survey (SF-36) scale.ResultsMorphine consumption in the first 24 h was 6 (3–9.8) mg in the Study group and 7 (3.5–12.5) mg in the Control group (p = 0.222). The Study group showed lower morphine consumption up to 6 h, lower pain scores up to 48 h, and earlier time to ambulation and flatus. The global QoR-40 score at 48 h [182 (173–195) vs. 173.5 (154–185.5), p = 0.024], subdimension scores of physical dependence at 24 h, physical comfort and pain at 48 h were significantly improved in the Study group.ConclusionPreemptive multimodal analgesia was not superior to conventional analgesia in reducing 24 h morphine consumption; however, it showed a significantly improved pain control and early quality of recovery thus can be recommended for gynecologic oncology patients undergoing laparotomy.

BackgroundStable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI) represent two distinct subtypes of mild cognitive impairment (MCI). Early and effective diagnosis and accurate differentiation between sMCI and pMCI are crucial for administering targeted early intervention and preventing cognitive decline. This study investigated the intrinsic dysconnectivity patterns in sMCI and pMCI based on degree centrality (DC) and effective connectivity (EC) analyses, with the goal of uncovering shared and distinct neuroimaging mechanisms between subtypes.MethodsResting-state functional magnetic resonance imaging combined with DC analysis was used to explore the functional connectivity density in 42 patients with sMCI, 31 patients with pMCI, and 82 healthy control (HC) participants. Granger causality analysis was used to assess changes in EC based on the significant clusters found in DC. Furthermore, correlation analysis was conducted to examine the associations between altered DC/EC values and cognitive function. Receiver operating characteristic curve analysis was performed to determine the accuracy of abnormal DC and EC values in distinguishing sMCI from pMCI.ResultsCompared with the HC group, both pMCI and sMCI groups exhibited increased DC in the left inferior temporal gyrus (ITG), left posterior cerebellum lobe (CPL), and right cerebellum anterior lobe (CAL), along with decreased DC in the left medial frontal gyrus. Moreover, the sMCI group displayed reduced EC from the right CAL to bilateral CPL, left superior temporal gyrus, and bilateral caudate compared with HC. pMCI demonstrated elevated EC from the right CAL to left ITG, which was linked to episodic memory and executive function. Notably, the EC from the right CAL to the right ITG effectively distinguished sMCI from pMCI, with sensitivity, specificity, and accuracy of 0.5806, 0.9512, and 0.828, respectively.ConclusionThis study uncovered shared and distinct alterations in DC and EC between sMCI and pMCI, highlighting their involvement in cognitive function. Of particular significance are the unidirectional EC disruptions from the cerebellum to the temporal lobe, which serve as a discriminating factor between sMCI and pMCI and provide a new perspective for understanding the temporal-cerebellum. These findings offer novel insights into the neural circuit mechanisms involving the temporal-cerebellum connection in MCI.

IntroductionInsomnia is a common comorbidity symptom in major depressive disorder (MDD) patients. Abnormal brain activities have been observed in both MDD and insomnia patients, however, the central pathological mechanisms underlying the co-occurrence of insomnia in MDD patients are still unclear. This study aimed to explore the differences of spontaneous brain activity between MDD patients with and without insomnia, as well as patients with different level of insomnia.MethodsA total of 88 first-episode drug-naïve MDD patients including 44 with insomnia (22 with high insomnia and 22 with low insomnia) and 44 without insomnia, as well as 44 healthy controls (HC), were enrolled in this study. The level of depression and insomnia were evaluated by HAMD-17, adjusted HAMD-17 and its sleep disturbance subscale in all subjects. Resting-state functional and structural magnetic resonance imaging data were acquired from all participants and then were preprocessed by the software of DPASF. Regional homogeneity (ReHo) values of brain regions were calculated by the software of REST and were compared. Finally, receiver operating characteristic (ROC) curves were conducted to determine the values of abnormal brain regions for identifying MDD patients with insomnia and evaluating the severity of insomnia.ResultsAnalysis of variance showed that there were significant differences in ReHo values in the left middle frontal gyrus, left pallidum, right superior frontal gyrus, right medial superior frontal gyrus and right rectus gyrus among three groups. Compared with HC, MDD patients with insomnia showed increased ReHo values in the medial superior frontal gyrus, middle frontal gyrus, triangular inferior frontal gyrus, calcarine fissure and right medial superior frontal gyrus, medial orbital superior frontal gyrus, as well as decreased ReHo values in the left middle occipital gyrus, pallidum and right superior temporal gyrus, inferior temporal gyrus, middle cingulate gyrus, hippocampus, putamen. MDD patients without insomnia demonstrated increased ReHo values in the left middle frontal gyrus, orbital middle frontal gyrus, anterior cingulate gyrus and right triangular inferior frontal gyrus, as well as decreased ReHo values in the left rectus gyrus, postcentral gyrus and right rectus gyrus, fusiform gyrus, pallidum. In addition, MDD patients with insomnia had decreased ReHo values in the left insula when compared to those without insomnia. Moreover, MDD patients with high insomnia exhibited increased ReHo values in the right middle temporal gyrus, and decreased ReHo values in the left orbital superior frontal gyrus, lingual gyrus, right inferior parietal gyrus and postcentral gyrus compared to those with low insomnia. ROC analysis demonstrated that impaired brain region might be helpful for identifying MDD patients with insomnia and evaluating the severity of insomnia.ConclusionThese findings suggested that MDD patients with insomnia had wider abnormalities of brain activities in the prefrontal-limbic circuits including increased activities in the prefrontal cortex, which might be the compensatory mechanism underlying insomnia in MDD. In addition, decreased activity of left insula might be associated with the occurrence of insomnia in MDD patients and decreased activities of the frontal–parietal network might cause more serious insomnia related to MDD.

BackgroundThe systemic immune-inflammation index (SII) is a novel inflammatory marker used to assess the immune-inflammatory status of the human body. The systemic immune inflammation has an interplay and mutual relationship with neurological disorders. Serum neurofilament light chain (sNfL) is widely regarded as a potential biomarker for various neurological diseases. The study aimed to examine the association between SII and sNfL.MethodsThis cross-sectional investigation was conducted in a population with complete data on SII and sNfL from the 2013–2014 National Health and Nutrition Examination Survey (NHANES). The SII was calculated by dividing the product of platelet count and neutrophil count by the lymphocyte count. Multivariate linear regression models and smooth curves were used to explore the linear connection between SII and sNfL. Sensitivity analyses, interaction tests, and diabetes subgroup smoothing curve fitting were also performed.ResultsA total of 2,025 participants were included in our present research. SII showed a significant positive association with the natural logarithm-transformed sNfL (ln-sNfL) in crude model [0.17 (0.07, 0.28)], partially adjusted model [0.13 (0.03, 0.22)], and fully adjusted model [0.12 (0.02, 0.22)]. In all participants, the positive association between SII and ln-sNfL served as a linear relationship, as indicated by a smooth curve. Interaction tests showed that age, gender, BMI, hypertension, and diabetes did not have a significant impact on this positive association (p for interaction >0.05). The subgroup analysis of diabetes was conducted using smooth curve fitting. It was found that compared to the group without diabetes and the group in a pre-diabetic state, the effect was more pronounced in the group with diabetes.ConclusionOur findings suggest that there is a positive association between SII and sNfL. Furthermore, in comparison to individuals without diabetes and those in a pre-diabetic state, the positive association between SII and sNfL was more pronounced in individuals with diabetes. Further large-scale prospective studies are needed to confirm the association between SII and sNfL.

IntroductionEmergent crises can have a catastrophic impact on regional economic systems. The concurrent outbreaks of African Swine Fever (ASF) and the COVID-19 pandemic have severely affected Macau’s pork industry, making it an interesting case study for analyzing the effects of simultaneous emergent crises on food prices.MethodsThe study utilized a comprehensive dataset spanning from March 30, 2018, to April 15, 2022. The analysis employed the Ensemble Empirical Mode Decomposition (EEMD) method to decompose the pork price data into high-frequency, low-frequency, and trend components, while the Bai-Perron test pinpointed key events and regulatory interventions affecting pork prices.ResultsThe findings revealed that short-term market fluctuations had a limited impact on pork price dynamics, with primary drivers being long-term and low-frequency emergencies. The Bai-Perron test identified four significant emergencies or regulatory policies as critical turning points, segmenting the price series into five distinct phases. The results highlight the importance of considering long-cycle emergencies when assessing their impact on food prices and underline the need for more resilient agricultural supply chains.DiscussionThe study provides insights into how compounded emergent crisis threats impact market behavior and offers policy recommendations for enhancing market stability. Recommendations include strengthening cross-regional epidemic control, investing in vaccine research, optimizing cold chain logistics, updating legal frameworks, and improving emergency preparedness. The implications of these findings are relevant for similar regions facing concurrent health and economic crises, contributing to a better understanding of crisis management and market stability maintenance.

As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.

Background: Aging is characterized by a decline in the adaptability and resistance of the body. In this study, Bushen Kangshuai Granules (BKG), as a kind of Chinese herbal formula, was developed and shown to alleviate aging-related symptoms.Methods: Self-controlled study combined with RNA-seq and metabonomics were used to expound the efficacy and safety of BKG and revealed the regulation mechanism of BKG treating aging. In vitro experiments were used to confirm the analytical results. The aging cell model of AC16 cells were treated with D-galactose. The RT-qPCR was used to detect the impact of BKG on telomere length. The DCFH-DA staining was used for detecting intracellular ROS. The targeted signaling pathway was selected and verified using Western blot.Results: After 8 weeks of treatment, BKG significantly reduced SOD level (p = 0.046), TCM aging symptoms (p < 0.001) and TNF-α level (p = 0.044) in the elderly participants. High-throughput sequencing showed that BKG reversed the expression of 70 and 79 age-related genes and metabolites, respectively. Further enrichment analysis indicated that BKG downregulated the PI3K-AKT signaling pathway, extracellular matrix (ECM)-receptor interaction, and Rap1 signaling pathway, while up-regulating sphingolipid metabolism. The results of in vitro experiments show that, after D-gal treatment, the viability and telomere length of AC16 cells significantly decreased (p < 0.05), while the expression of ROS increased (p < 0.05), BKG significantly increased the telomere length of AC16 cells and reduced the level of ROS expression (p < 0.05). In addition, BKG decreased the expression of THBS1, PDGFRA, and EPS8L1(p < 0.05), consistent with the RNA-seq results. Our results also showed that BKG affects PI3K-AKT signaling pathway.Conclusion: BKG can significantly improve aging-related symptoms and increase SOD levels, which may be associated with the reversal of the expression of various aging-related genes. The PI3K-AKT signaling pathway and sphingolipid metabolism may be potential mechanisms underlying BKG anti-aging effects.