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Abstract Background Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), can undergo erythroid differentiation, offering a potentially invaluable resource for generating large quantities of erythroid cells. However, the majority of erythrocytes derived from hPSCs fail to enucleate compared with those derived from cord blood progenitors, with an unknown molecular basis for this difference. The expression of vimentin (VIM) is retained in erythroid cells differentiated from hPSCs but is absent in mature erythrocytes. Further exploration is required to ascertain whether VIM plays a critical role in enucleation and to elucidate the underlying mechanisms. Methods In this study, we established a hESC line with reversible vimentin degradation (dTAG-VIM-H9) using the proteolysis-targeting chimera (PROTAC) platform. Various time-course studies, including erythropoiesis from CD34+ human umbilical cord blood and three-dimensional (3D) organoid culture from hESCs, morphological analysis, quantitative real-time PCR (qRT-PCR), western blotting, flow cytometry, karyotyping, cytospin, Benzidine-Giemsa staining, immunofluorescence assay, and high-speed cell imaging analysis, were conducted to examine and compare the characteristics of hESCs and those with vimentin degradation, as well as their differentiated erythroid cells. Results Vimentin expression diminished during normal erythropoiesis in CD34+ cord blood cells, whereas it persisted in erythroid cells differentiated from hESC. Depletion of vimentin using the degradation tag (dTAG) system promotes erythroid enucleation in dTAG-VIM-H9 cells. Nuclear polarization of erythroblasts is elevated by elimination of vimentin. Conclusions VIM disappear during the normal maturation of erythroid cells, whereas they are retained in erythroid cells differentiated from hPSCs. We found that retention of vimentin during erythropoiesis impairs erythroid enucleation from hPSCs. Using the PROTAC platform, we validated that vimentin degradation by dTAG accelerates the enucleation rate in dTAG-VIM-H9 cells by enhancing nuclear polarization. Graphical Abstract

Abstract Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier’s intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy. Graphical Abstract

Abstract The benefits of urban green space are socially widely recognized as a direct link between plant–microbe interactions and the maintenance of biodiversity, community stability, and ecosystem functioning. Nevertheless, there is a lack of knowledge about the factors influencing microbial communities in urban green spaces, especially those related to phyllosphere epiphytes and stem epiphytes. In this study, we analyzed the microbial community assembly in leaf and stem bark samples collected from Square, Road, Campus, and Park. Illumina sequecing of 16S amplicons was performed to characterize microbial diversity and composition. The α-diversity was significantly higher in the bark epiphytic community, compared to the phyllosphere. Moreover, urban greenspaces'type altered the way communities gathered. The main soil and air properties factors of the urban greenhouse (e.g. soil temperature, atmospheric moisture, air temperature) were shaping the characteristics of bacterial communities on the leaf surface and bark epiphytic. In addition, in the co-occurrence network analysis, keystone taxa were not mostly observed in abundant species, which may be necessary to maintain ecosystem functions. Finally, our findings provide a deeper understanding of the ecological dynamics and microbial interactions within plant phyllosphere and stem epiphytes microbiomes.

Abstract Background Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease. The aim of this research is to identify new biomarkers and therapeutic targets for the treatment of such deadly diseases. Methods Single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithms were used to identify distinct immune cell infiltration types between AAA and normal abdominal aortas. Single-cell RNA sequencing data were used to analyse the hallmark genes of AAA-associated macrophage cell subsets. Six macrophage-related hub genes were identified through weighted gene co-expression network analysis (WGCNA) and validated for expression in clinical samples and AAA mouse models. We screened potential therapeutic drugs for AAA through online Connectivity Map databases (CMap). A network-based approach was used to explore the relationships between the candidate genes and transcription factors (TFs), lncRNAs, and miRNAs. Additionally, we also identified hub genes that can effectively identify AAA and atherosclerosis (AS) through a variety of machine learning algorithms. Results We obtained six macrophage hub genes (IL-1B, CXCL1, SOCS3, SLC2A3, G0S2, and CCL3) that can effectively diagnose abdominal aortic aneurysm. The ROC curves and decision curve analysis (DCA) were combined to further confirm the good diagnostic efficacy of the hub genes. Further analysis revealed that the expression of the six hub genes mentioned above was significantly increased in AAA patients and mice. We also constructed TF regulatory networks and competing endogenous RNA networks (ceRNA) to reveal potential mechanisms of disease occurrence. We also obtained two key genes (ZNF652 and UBR5) through a variety of machine learning algorithms, which can effectively distinguish abdominal aortic aneurysm and atherosclerosis. Conclusion Our findings depict the molecular pharmaceutical network in AAA, providing new ideas for effective diagnosis and treatment of diseases.

Abstract The flow of fluid through the porous matrix of a reservoir rock applies a seepage force to the solid rock matrix. Although the seepage force exerted by fluid flow through the porous matrix of a reservoir rock has a notable influence on rock deformation and failure, its effect on hydraulic fracture (HF) propagation remains ambiguous. Therefore, in this study, we improved a traditional fluid–solid coupling method by incorporating the role of seepage force during the fracturing fluid seepage, using the discrete element method. First, we validated the simulation results of the improved method by comparing them with an analytical solution of the seepage force and published experimental results. Next, we conducted numerical simulations in both homogeneous and heterogeneous sandstone formations to investigate the influence of seepage force on HF propagation. Our results indicate that fluid viscosity has a greater impact on the magnitude and extent of seepage force compared to injection rate, and that lower viscosity and injection rate correspond to shorter hydraulic fracture lengths. Furthermore, seepage force influences the direction of HF propagation, causing HFs to deflect towards the side of the reservoir with weaker cementation and higher permeability.

Abstract In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.

Abstract Depression is a prevalent mental disorder with a complex biological mechanism. Following the rapid development of systems biology technology, a growing number of studies have applied proteomics and metabolomics to explore the molecular profiles of depression. However, a standardized resource facilitating the identification and annotation of the available knowledge from these scattered studies associated with depression is currently lacking. This study presents ProMENDA, an upgraded resource that provides a platform for manual annotation of candidate proteins and metabolites linked to depression. Following the establishment of the protein dataset and the update of the metabolite dataset, the ProMENDA database was developed as a major extension of its initial release. A multi-faceted annotation scheme was employed to provide comprehensive knowledge of the molecules and studies. A new web interface was also developed to improve the user experience. The ProMENDA database now contains 43,366 molecular entries, comprising 20,847 protein entries and 22,519 metabolite entries, which were manually curated from 1370 human, rat, mouse, and non-human primate studies. This represents a significant increase (more than 7-fold) in molecular entries compared to the initial release. To demonstrate the usage of ProMENDA, a case study identifying consistently reported proteins and metabolites in the brains of animal models of depression was presented. Overall, ProMENDA is a comprehensive resource that offers a panoramic view of proteomic and metabolomic knowledge in depression. ProMENDA is freely available at https://menda.cqmu.edu.cn .

Abstract Background As is known, CD4 cell count is a significant parameter predicting HIV progression, opportunistic infections and death in HIV-infected individuals, as well was an important indicator for initiating antiretroviral therapy (ART). In China’s National Free Antiretroviral Treatment Program, people with HIV (PWH) on ART can receive a CD4 count test at least once every six months. Importantly, the baseline CD4 count (before ART initiation) is significantly correlated with ART and even prognosis, but the influence of the peak CD4 cell count on ART and/or clinical outcomes is still unknown. Methods A retrospective study was conducted among 7965 PWH who received ART from October 2003 to September 2022 at Yunnan Infectious Disease Hospital. Clinical features and laboratory data were collected and analyzed by Chi-square test, univariate and multivariate Cox regression analysis. After elimination of confounding variables, multivariate Cox regression analysis was performed to identify survival-related factors. Results Of a total of 7965 PWH in the ART treatment cohort who met the inclusion and exclusion criteria, 7939 were finally included in the subsequent analyses. First, it was found that the proportion of clinical variables, including sex, age distribution, interval from diagnosis to ART initiation, marital status, and others, was significantly different between the living and dead groups (P

Introduction: Neuroinflammation and autophagy are implicated in stress-related major depressive disorder (MDD), but the underlying molecular mechanisms remain largely unknown. Objectives: Here, we identified that MDD regulated by HMGB1/STAT3/p65 axis mediated microglial activation and autophagy for the first time. Further investigations were performed to uncover the effects of this axis on MDD in vivo and in vitro. Methods: Bioinformatics analyses were used to re-analysis the transcriptome data from the dorsolateral prefrontal cortex (dlPFC) of post-mortem male MDD patients. The expression level of HMGB1 and its correlation with depression symptoms were explored in MDD clinical patients and chronic social defeat stress (CSDS)-induced depression model mice. Specific adeno-associated virus and recombinant (r)HMGB1 injection into the medial PFC (mPFC) of mice, and pharmacological inhibitors with rHMGB1 in two microglial cell lines exposed to lipopolysaccharide were used to analyze the effects of HMGB1/STAT3/p65 axis on MDD. Results: The differential expression of genes from MDD patients implicated in microglial activation and autophagy regulated by HMGB1/STAT3/p65 axis. Serum HMGB1 level was elevated in MDD patients and positively correlated with symptom severity. CSDS not only induced depression-like states in mice, but also enhanced microglial reactivity, autophagy as well as activation of the HMGB1/STAT3/p65 axis in mPFC. The expression level of HMGB1 was mainly increased in the microglial cells of CSDS-susceptible mice, which also correlated with depressive-like behaviors. Specific HMGB1 knockdown produced a depression-resilient phenotype and suppressed the associated microglial activation and autophagy effects of CSDS-induced. The effects induced by CSDS were mimicked by exogenous administration of rHMGB1 or specific overexpression of HMGB1, while blocked by STAT3 inhibitor or p65 knockdown. In vitro, inhibition of HMGB1/STAT3/p65 axis prevented lipopolysaccharide-induced microglial activation and autophagy, while rHMGB1 reversed these changes. Conclusion: Our study established the role of microglial HMGB1/STAT3/p65 axis in mPFC in mediating microglial activation and autophagy in MDD.

Tribbles pseudokinase 3 (TRIB3) expression significantly increases during terminal erythropoiesis in vivo. However, we found that TRIB3 expression remained relatively low during human embryonic stem cell (hESC) erythropoiesis, particularly in the late stage, where it is typically active. TRIB3 was expressed in megakaryocyte-erythrocyte progenitor cells and its low expression was necessary for megakaryocyte differentiation. Thus, we proposed that the high expression during late stage of erythropoiesis could be the clue for promotion of maturation of hESC-derived erythroid cells. To our knowledge, the role of TRIB3 in the late stage of erythropoiesis remains ambiguous. To address this, we generated inducible TRIB3 overexpression hESCs, named TRIB3tet-on OE H9, based on a Tet-On system. Then, we analyzed hemoglobin expression, condensed chromosomes, organelle clearance, and enucleation with or without doxycycline treatment. TRIB3tet-on OE H9 cells generated erythrocytes with a high proportion of orthochromatic erythroblast in flow cytometry, enhanced hemoglobin and related protein expression in Western blot, decreased nuclear area size, promoted enucleation rate, decreased lysosome and mitochondria number, more colocalization of LC3 with LAMP1 (lysosome marker) and TOM20 (mitochondria marker) and up-regulated mitophagy-related protein expression after treatment with 2 μg/mL doxycycline. Our results showed that TRIB3 overexpression during terminal erythropoiesis may promote the maturation of erythroid cells. Therefore, our study delineates the role of TRIB3 in terminal erythropoiesis, and reveals TRIB3 as a key regulator of UPS and downstream mitophagy by ensuring appropriate mitochondrial clearance during the compaction of chromatin.

Fourteen species of Cheiloneurus from China are studied. Cheiloneurus guangxiensis Zu, sp. nov., is described as new to science, and C. boldyrevi Trjapitzin & Agekyan, 1978, C. bouceki Anis & Hayat, 2002, C. gonatopodis Perkins, 1906, and C. hadrodorys Anis & Hayat, 2002 are newly recorded from China. A key to Chinese species based on females is also presented.

Abstract The inter-subspecific indica-japonica hybrid rice confer potential higher yield than the widely used indica-indica intra-subspecific hybrid rice. Nevertheless, the utilization of this strong heterosis is currently hindered by asynchronous diurnal floret opening time (DFOT) of indica and japonica parental lines. Here, we identify OsMYB8 as a key regulator of rice DFOT. OsMYB8 induces the transcription of JA-Ile synthetase OsJAR1, thereby regulating the expression of genes related to cell osmolality and cell wall remodeling in lodicules to promote floret opening. Natural variations of OsMYB8 promoter contribute to its differential expression, thus differential transcription of OsJAR1 and accumulation of JA-Ile in lodicules of indica and japonica subspecies. Furthermore, introgression of the indica haplotype of OsMYB8 into japonica effectively promotes DFOT in japonica. Our findings reveal an OsMYB8-OsJAR1 module that regulates differential DFOT in indica and japonica, and provide a strategy for breeding early DFOT japonica to facilitate breeding of indica-japonica hybrids.

Abstract Background Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. Results Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. Conclusion The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC. Graphical Abstract

Objective This study investigated the expression of TGF-β/Smad pathway-related indices in patients with isolated iliac artery aneurysms (IIAA) complicated with iliac arteriovenous fistula (IAVF) and their relationship with prognosis.Methods From January 2016 to June 2022, 83 patients with IIAA complicated with IAVF (Study group) and 54 patients with IIAA not complicated with IAVF (control group) were studied. The related indices of TGF-β/Smad pathway were evaluated, and the effects of each index on the formation of IAVF were analyzed. The patients were divided into the survival group (64 cases) and death group (19 cases), and the prognostic value of indices in combination was analyzed.Results TGF-β, p-Smad2, p-Smad3, p-JNK, and p-ERK in the study group were higher than those in the control group. Abnormal increase of pSmad3 expression was a risk factor for IAVF formation in patients with IIAA. TGF-β level in the death group was higher than that in the survival group, and p-Smad3 and p-JNK proteins were higher than those in the survival group. The AUC value of indices in the TGF-β/Smad pathway in combination was greater than that of each index alone. Abnormal increased expression of pSmad3 was a risk factor for prognosis of patients with IIAA complicated with IAVF.Conclusion The abnormal increase of TGF-β/Smad pathway-related indices is related to poor prognosis of patients with IIAA complicated with IAVF, and the combined detection of all indices has a predictive value for patients’ prognosis.

BackgroundThe causal associations between dietary intake and the risk and severity of Inflammatory Arthritis (IA) are currently unknown.ObjectiveIn this study, we aimed to investigate the causal relationship between nine dietary categories (30 types of diet) and IA using Mendelian randomization (MR).MethodsWe analyzed data from 30 diets and IA in a genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) that could influence the results of MR analyses were screened out through the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. SNPs were analyzed through two-sample bidirectional MR using inverse variance weighting, MR-Egger regression, and weighted median method. The multiplicity and heterogeneity of SNPs were assessed using MR-Egger intercept term tests and Cochran’s Q tests. FDR correction was used to correct the p-values.ResultsIVW results showed that Beef intake [Odds ratio (OR) = 2.862; 95% confidence interval (CI), 1.360–6.021, p = 0.006, p_fdr 0.05) was positively associated with psoriatic arthritis (PsA); Cheese intake (OR = 0.579; 95% CI, 0.367–0.914, p = 0.019, p_fdr > 0.05) was negatively associated with PsA; both were suggestive evidence. Processed meat intake (OR = 0.238; 95% CI, 0.100–0.565, p = 0.001, p_fdr 0.05) and no directional pleiotropy was detected. Leave-one-out analyses demonstrated the robustness of the causal relationship in the positive results.ConclusionOur study presents genetic evidence supporting a causal relationship between diet and an increased risk of IA. It also identifies a causal relationship between various dietary modalities and different types of IA. These findings have significant implications for the prevention and management of IA through dietary modifications.

Abstract Tumor‐infiltrating CD4+ T cells orchestrate the adaptive immune response through remarkable plasticity, and the expression patterns of exhaustion‐related inhibitory receptors in these cells differ significantly from those of CD8+ T cells. Thus, a better understanding of the molecular basis of CD4+ T cell exhaustion and their responses to immune checkpoint blockade (ICB) is required. Here, we integrated multiomics approaches to define the phenotypic and molecular profiles of exhausted CD4+ T cells in oropharyngeal squamous cell carcinoma (OPSCC). Two distinct immune‐promoting (Module 1) and immunosuppressive (Module 2) functional modules in tumor‐infiltrating CD4+ T cells were identified, and both the immune‐promoting function of Module 1 cells and immunosuppressive function of Module 2 cells were positively associated with their corresponding exhaustion states. Furthermore, the application of ICBs targeting effector CD4+ T cells in Module 1 (αPD‐1) and Treg cells in Module 2 (αCTLA‐4) in mouse models could help reinvigorate the effector function of Module 1‐exhausted CD4+ T cells and reduce the immunosuppressive function of Module 2‐exhausted CD4+ T cells, ultimately promoting OPSCC tumor regression. Taken together, our study provides a crucial cellular basis for the selection of optimal ICB in treating OPSCC.

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

An eco-friendly, mild and efficient acylation of various nucleophiles with alkenyl carboxylates via inorganic base catalysis is described. Among five inorganic base species examined, K2CO3 was proved to be the most efficient catalyst for the acylation. A broad variety of acylated products were achieved within 15 min at room temperature in high yields. In addition, we found that the 3-position of indoles should have a suitable substituent group under this procedure.

BackgroundThis study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments.MethodsWe conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1β, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed.ResultsA positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors.ConclusionO_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.

Summary: Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Effectively preventing and diagnosing laryngeal cancer is imperative for improving prognosis, particularly in high-risk populations. Early diagnosis in these individuals is crucial, offering timely interventions and higher survival rates. There is a growing demand for computer-assisted early prognosis with transparent and accountable interpretations. Methods and procedures: We present an interpretable classification framework based on radiomics for narrow-band imaging in contact endoscopy for laryngeal cancer. The framework aims to address the challenge of early prognosis with transparency and accountability by offering evidence-supported interpretation. Results: Performance metrics, including accuracy, precision, recall, F1 score, area under the curve (AUC), negative predict value (NPV), balanced accuracy(BA) and diagnostic odds ratio (DOR) were employed to analyze the results. The radiomics-based model demonstrated high recall rate (>94% in 3 out the 5 classifiers employed) and balanced accuracy (>89% in 3 classifiers) in distinguishing between benign and malignant cases. The interpretability analysis shed light on the framework’s behavior evidencing three features as main contributors for classification. Conclusion: Our interpretable classifying framework shows promise as a preliminary clinical diagnostic assistant for laryngeal cancer. Its commitment to transparency and accountability renders it an invaluable resource for conveying insightful information and assessing the framework’s effectiveness. Clinical impact: Our framework addresses the challenge of early diagnosis among high-risk populations, providing a transparent and accountable tool for clinicians and researchers.

The sliding mode observer (SMO) has the advantages of small influence by parameter changes and strong robustness, which is widely used in the sensorless control of permanent magnet synchronous motor (PMSM). However, when the sliding mode observer is used to observe the position and speed information of the PMSM, the problem of slow response and excessive chattering is always accompanied. In order to reduce the time of observation position and improve the anti-interference of the system, the super-twisting sliding mode observer(STSMO) is proposed, which can be used to reduce the chattering amplitude effectively, Additionally, the fast and terminal factors is added to the sliding mode surface so that it can converge quickly in a finite time. Then, an improved fast terminal super-twisting sliding mode observer (FTSTSMO) is proposed in the extended state. It can be proved that the observer can converge by Lyapunov stability, and the new observer can suppress chattering and improve the convergence speed. Finally, the experimental analysis is carried out on the 1kW permanent magnet synchronous motor experimental platform, and the SMO and STSMO are compared with FTSTSMO. The results show that FTSTSMO can effectively reduce the fluctuation of the system, improve the tracking effect of rotor speed and rotor position when the speed changes, and further make the whole control system of PMSM have stronger robustness and stability.

Abstract Background Chronic restraint stress (CRS) has iteratively been reported to be possibly implicated in the development of numerous cancer types. However, its role in oral squamous cell carcinoma (OSCC) has not been well elucidated. Here we intended to evaluate the role and mechanism. Methods The effects of CRS were investigated in xenograft models of OSCC by using transcriptome sequencing, LC–MS, ELISA and RT-PCR. Moreover, the role of CRS and ALDH3A1 on OSCC cells was researched by using Trans-well, flow cytometry, western blotting, immunofluorescence, ATP activity and OCR assay. Furthermore, immunohistochemical staining was employed to observe the cell proliferation and invasion of OSCC in xenotransplantation models. Results CRS promoted the progression of OSCC in xenograft models, stimulated the secretion of norepinephrine and the expression of ADRB2, but decreased the expression of ALDH3A1. Moreover, CRS changed energy metabolism and increased mitochondrial metabolism markers. However, ALDH3A1 overexpression suppressed proliferation, EMT and mitochondrial metabolism of OSCC cells. Conclusion Inhibition of ALDH3A1 expression plays a pivotal role in CRS promoting tumorigenic potential of OSCC cells, and the regulatory of ALDH3A1 on mitochondrial metabolism may be involved in this process.

Abstract Background Avian pathogenic Escherichia coli (APEC) causes tracheal damage and heterophilic granulocytic infiltration and inflammation in infected chicks. In this study, we infected chick tracheal tissue with strain AE17 and produced pathological sections with proteomic sequencing. We compared the results of pathological sections from the APEC-infected group with those from the PBS control group; the pathological sections from the experimental group showed hemorrhage, fibrinization, and infiltration of heterophilic granulocytes in the tracheal tissue. In order to explore the effect on proteomics on inflammation and to further search for the caus. Results The tandem mass tag-based (TMT) sequencing analysis showed 224 upregulated and 140 downregulated proteins after infection with the AE17 strain. Based on the results of KEGG in Complement and coagulation cascades, differential protein expression in the Protein export pathway was upregulated. Conclusions With these results, we found that chemokines produced by the Complement and coagulation cascades pathway may cause infiltration of heterophilic granulocytes involved in inflammation, as well as antimicrobial factors produced by the complement system to fight the infection together.These results suggest that APEC causes the infiltration of heterophilic granulocytes through the involvement of the complement system with serine protease inhibitors.

The tricarboxylic acid (TCA) cycle is a central route for generating cellular energy and precursors for biosynthetic pathways. Emerging evidences have shown that the aberrations of metabolic enzymes which affect the integrity of TCA cycle are implicated in various tumour pathological processes. Interestingly, several TCA enzymes exhibit the characteristics of RNA binding properties, and their long non-coding RNA (lncRNA) partners play critical regulatory roles in regulating the function of TCA cycle and tumour progression. In this review, we will discuss the functional roles of RNA binding proteins and their lncRNA partners in TCA cycle, with emphasis placed on the cancer progression. A further understanding of RNA binding proteins and their lncRNA partners in TCA cycle, as well as their molecular mechanisms in oncogenesis, will aid in developing novel layers of metabolic targets for cancer therapy in the near future. Abbreviations: CS: citrate synthase. AH: aconitase, including ACO1, and ACO2. IDH: isocitrate dehydrogenase, including IDH1, IDH2, and IDH3. KGDHC: α-ketoglutarate dehydrogenase complex, including OGDH, DLD, and DLST. SCS: succinyl-CoA synthase, including SUCLG1, SUCLG2, and SUCLA2. SDH: succinate dehydrogenase, including SDHA, SDHB, SDHC, and SDHD. FH: fumarate hydratase. MDH: malate dehydrogenase, including MDH1 and MDH2. PC: pyruvate carboxylase. ACLY: ATP Citrate Lyase. NIT: nitrilase. GAD: glutamate decarboxylase. ABAT: 4-aminobutyrate aminotransferase. ALDH5A1: aldehyde dehydrogenase 5 family member A1. ASS: argininosuccinate synthase. ASL: adenylosuccinate synthase. DDO: D-aspartate oxidase. GOT: glutamic-oxaloacetic transaminase. GLUD: glutamate dehydrogenase. HK: hexokinase. PK: pyruvate kinase. LDH: lactate dehydrogenase. PDK: pyruvate dehydrogenase kinase. PDH: pyruvate dehydrogenase complex. PHD: prolyl hydroxylase domain protein.

Abstract With the large-scale vaccination of lipid nanoparticles (LNP)-based COVID-19 mRNA vaccines, elucidating the potential polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant LNP has become imminent. However, inconsistent findings were observed across very limited population-based studies. Herein we initiated a study using LNP carrier of Comirnaty® as a representative, and simulated real-world clinical practice covering a series of time points and various doses correlated with approved LNP-delivered drugs in a rat model. We demonstrated the time- and dose-dependency of LNP-induced anti-PEG antibodies in rats. As a thymus-independent antigen, LNP unexpectedly induced isotype switch and immune memory, leading to rapid enhancement and longer lasting time of anti-PEG IgM and IgG upon re-injection in rats. Importantly, initial LNP injection accelerated the blood clearance of subsequent dosing in rats. These findings refine our understandings on LNP and possibly other PEG derivatives, and may promote optimization of related premarket guidelines and clinical protocols.

Homalotylus tianjinensis Zu, sp. nov., H. bicolor Zu, sp. nov. and H. guangxiensis Zu, sp. nov. are described as new to science; H. agarwali Anis & Hayat, 1998, H. hemipterinus (De Stefani, 1898) and H. varicolorus Krishnachaitanya & Manickavasagam, 2016 are newly recorded from China. A key to Chinese species based on females is also presented.

ABSTRACT: The type VI secretion system (T6SS) of avian pathogenic Escherichia coli (APEC) can affect the functions of eukaryotic cells by secreting or injecting effectors. Hemolysin co-regulatory protein (Hcp), one of the markers of the T6SS, is both a structural protein and an effector protein of the T6SS. According to previous studies, mitochondria in eukaryotic cells are targeted by pathogenic bacteria. However, little is known about the regulation of mitochondria in eukaryotic host cells by the T6SS effector protein Hcp of APEC. In our study, DF-1 cells co-incubated with Hcp2a protein for 6 h showed decreased mitochondrial membrane potential, increased Ca2+ concentration, and increased cellular reactive oxygen species (ROS) levels. We therefore conclude that Hcp2a protein causes dysfunction to mitochondria in DF-1 cells. To explain the mechanism that causes mitochondrial dysfunction, we reanalyzed the Hcp2a interaction protein dataset in DF-1 cells, and the Leucine zipper EF-hand-containing transmembrane protein 1 (LETM1), which is associated with mitochondria, was screened. The protein and molecular docking results showed that Hcp2a protein and LETM1 protein have better binding. Finally, subcellular localization results showed that Hcp2a was localized to mitochondria. In summary, Hcp2a effector proteins caused dysfunction to DF-1 cellular mitochondria, and we hypothesize that the interaction of Hcp2a protein with LETM1 protein induces mitochondrial dysfunction and promotes mitochondrial localization of Hcp2a in DF-1 cells.

Genetic diversity in endangered species is of special significance in the face of escalating global climate change and alarming biodiversity declines. Rhododendron platypodum Diels, an endangered species endemic to China, is distinguished by its restricted geographical range. This study aimed to explore genetic diversity and differentiation among its populations, gathering samples from all four distribution sites: Jinfo Mountain (JFM), Zhaoyun Mountain (ZYM), Baima Mountain (BMM), and Mao’er Mountain (MEM). We employed 18 pairs of Simple Sequence Repeat (SSR) primers to ascertain the genetic diversity and structural characteristics of these samples and further utilized 19 phenotypic data points to corroborate the differentiation observed among the populations. These primers detected 52 alleles, with the average number of observed alleles (Na) being 2.89, the average number of effective alleles (Ne) being 2.12, the average observed heterozygosity (Ho) being 0.57, and the expected heterozygosity (He) being 0.50. This array of data demonstrates the efficacy of the primers in reflecting R. platypodum’s genetic diversity. SSR-based genetic analysis of the populations yielded Ho, He, and Shannon index (I) values ranging from 0.47 to 0.65, 0.36 to 0.46, and 0.53 to 0.69, respectively. Notably, the ZYM population emerged as the most genetically diverse. Further analysis, incorporating molecular variance, principal component analysis, UPGMA cluster analysis, and structure analysis, highlighted significant genetic differentiation between the Chongqing (BMM, JFM, ZYM) and Guangxi (MEM) populations. Morphological data analysis corroborated these findings. Additionally, marked genetic and morphological distinctions were evident among the three Chongqing populations (BMM, JFM, and ZYM). This suggests that, despite the observed regional differentiation, R. platypodum’s overall genetic diversity is relatively constrained compared to other species within the Rhododendron genus. Consequently, R. platypodum conservation hinges critically on preserving its genetic diversity and protecting its distinct populations.

3D laser scanning is widely used in modeling industrial scenes, involving crucial steps like point cloud (PC) data preprocessing and extracting modeling targets from scattered points. Extracting target PC data from larger scenes is more challenging than from smaller settings. To efficiently obtain high-quality scene data and modeling targets, we introduce an innovative approach with the adaptive density-based voxel grid filtering algorithm and a probability statistics histogram method during preprocessing. We also propose a novel method for automatic extraction of target PC data using the adjacent feature plane constraint (AFPC) clustering technique. Initially, we capture height characteristics of the target object's PC through experiential and statistical height attributes. Points corresponding to each height are then clustered based on the PC's density distribution using the density-based spatial clustering of applications with noise algorithm. The intersection of these results optimizes the position of the target object's extraction bounding box, achieving seamless automatic object extraction. Experimental results validate the effectiveness of our preprocessing methodology, with F1 scores of 97.7 % and 97.3 % for the 220 kV and 500 kV areas, respectively. Furthermore, our novel extraction method demonstrates the ability to autonomously and directly extract electrical equipment from substation PC data.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease of the gastrointestinal tract. This study aimed to determine the effect of cathelicidin-related antimicrobial peptide (Cramp) on dextran sulfate sodium (DSS)-induced acute experimental colitis in mice and to investigate the underlying mechanisms. Acute UC was induced in C57BL/6 mice with 3% DSS for 7 days, 4 mg/kg b.w. synthetic Cramp peptide was administrated once daily starting on day 4 of the experimental period. Mice were evaluated for body weight, colon length, colon histopathology, and inflammatory cytokines in colon tissue. Using 16 s rRNA sequencing, the composition structure of gut microbiota was characterized. Metabolomic profiling of the serum was performed. The results showed that DSS treatment significantly induced intestinal damage as reflected by disease activity index, histopathological features, and colon length, while Cramp treatment significantly prevented these trends. Meanwhile, Cramp treatment decreased the levels of inflammatory cytokines in both serum and colonic tissue on DSS-induced colitis. It was also observed that DSS damaged the integrity of the intestinal epithelial barrier, whereas Cramp also played a protective role by attenuating these deteriorated effects. Furthermore, Cramp treatment reversed the oxidative stress by increasing the antioxidant enzymes of GSH-PX and decreasing the oxidant content of MDA. Notably, compared to the DSS group, Cramp treatment significantly elevated the abundance of Verrucomicrobiota at the phylum level. Furthermore, at the genus level, Parasutterella and Mucispirllum abundance was increased significantly in response to Cramp treatment, although Roseburia and Enterorhabdus reduced remarkably. Metabolic pathway analysis of serum metabolomics showed that Cramp intervention can regulate various metabolic pathways such as α-linolenic acid, taurine and hypotaurine, sphingolipid, and arachidonic acid metabolism. The study concluded that Cramp significantly ameliorated DSS-induced colonic injury, colonic inflammation, and intestinal barrier dysfunction in mice. The underlying mechanism is closely related to the metabolic alterations derived from gut microbiota.

Abstract Background Viburnum chinshanense is an endemic species found exclusively in the North-Central and South-Central regions of China. This species is a lush garden ornamental tree and is extensively utilized for vegetation restoration in rocky desertification areas. Results In this study, we obtained 13.96 Gb of Oxford Nanopore data for the whole genome, and subsequently, by combining Illumina short-reads, we successfully assembled the complete mitochondrial genome (mitogenome) of the V. chinshanense using a hybrid assembly strategy. The assembled genome can be described as a circular genome. The total length of the V. chinshanense mitogenome measures 643,971 bp, with a GC content of 46.18%. Our annotation efforts have revealed a total of 39 protein-coding genes (PCGs), 28 tRNA genes, and 3 rRNA genes within the V. chinshanense mitogenome. The analysis of repeated elements has identified 212 SSRs, 19 long tandem repeat elements, and 325 pairs of dispersed repeats in the V. chinshanense mitogenome. Additionally, we have investigated mitochondrial plastid DNAs (MTPTs) and identified 21 MTPTs within the mitogenome and plastidial genome. These MTPTs collectively span a length of 9,902 bp, accounting for 1.54% of the mitogenome. Moreover, employing Deepred-mt, we have confidently predicted 623 C to U RNA editing sites across the 39 protein-coding genes. Furthermore, extensive genomic rearrangements have been observed between V. chinshanense and the mitogenomes of related species. Interestingly, we have also identified a bacterial-derived tRNA gene (trnC-GCA) in the V. chinshanense mitogenome. Lastly, we have inferred the phylogenetic relationships of V. chinshanense with other angiosperms based on mitochondrial PCGs. Conclusions This study marks the first report of a mitogenome from the Viburnum genus, offering a valuable genomic resource for exploring the evolution of mitogenomes within the Dipsacales order.

The X-band medium distance microwave wireless power transmission (MWPT) system based on multilayer rectifier diode design is demonstrated in this paper. In order to pursuit highest rectification efficiency, the harmonic suppression rectifying circuit is proposed, which can acquire more than 60% rectification efficiency at the working frequency of 10 GHz. For the sake of longer distance, the Cassegrain antenna with an aperture of 1.6 m and the receiving planar array antenna with an area of 2 m × 2 m for the novel applications are designed. In the interest of improving the effective receiving area, the microwave rectifying antenna adopts the layered design of the receiving array antenna and the microwave rectifying circuit. Finally, this X-band medium distance MWPT system based on multilayer rectifier diode can achieve 400 W DC power with 10% RF-DC conversion efficiency for the distance of 70 m. The MWPT system can been applied in medium to long distance MWPT system, such as charging of various sensors, wireless power supplying and so on.

Abstract Although mRNA vaccines are known as potent activators of antigen-specific immune responses against infectious diseases, limited understanding of how they drive the functional commitment of CD8+ T cells in tumor microenvironment (TME) and secondary lymphoid organs hinders their broader application in cancer immunotherapy. Here, we systematically evaluated the immunological effects of a lipid nanoparticle (LNP)-encapsulated mRNA vaccine that encodes human papillomavirus E7 protein (HPV mRNA-LNP), a tumor-specific antigen of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). HPV mRNA-LNP vaccination activated overall and HPV-specific CD8+ T cells, as well as differentially drove the functional commitment of CD8+ T cells through distinct IFN-response and exhaustion trajectories in the spleen and TME, respectively. Combination therapies of HPV mRNA-LNP vaccination with immune checkpoint blockades boosted HPV-specific CD8+ T cells while maintaining their anti-tumor function, thus further promoting tumor regression. Our results showed that the HPV mRNA-LNP vaccination combined with immune checkpoint blockade is a promising approach for immunotherapy of HPV-positive OPSCC.

Under the influence of geological environment and engineering disturbance, elliptical hole-defects exist widely in engineering rock mass. Excavation unloading causes rebound tensile stress in rock mass. The tension-shear stress zone is formed under the hole defects, which induces the tension-shear failure of rock mass and greatly reduce the stability of engineering rock mass. In order to study the mechanical properties and failure behavior of the rock mass with an elliptical hole under tension and shear, the numerical model was built using discrete element numerical simulation based on the rock mechanics test results. Furthermore, the tension-shear numerical modelling tests of rock mass with an elliptical hole of different hole inclination angle α and the ratio of long to short axis k were carried out, and the meso-mechanism of crack evolution was revealed from the point of view of stress tensor. The results show that when k is constant, with the increase of α, the shear strength approximately shows a “W” shape under low normal tensile stress (1–3 MPa), and the minimum value is obtained when α is 120° or 150°, and the maximum value is obtained when α is 90°. Under high normal tensile stress (4–6 MPa), the shear strength increases at first and then decreases, and the minimum and maximum values are obtained when α is 0° and 90°, respectively. When α is constant, for the rock mass with an elliptical hole if α is not 90°, the shear strength decreases nonlinearly with the increase of k. The sensitivity of stress concentration of the elliptical hole to normal tensile stress decreases at first and then increases with the increase of α, and the sensitivity is the highest when α is 0°. The sensitivity is the lowest when α is 90°, and the sensitivity is higher when α is 120°and 150° than that when α is 30°and 60°. The strength of the rock mass with an elliptical hole is obviously worse than that of intact rock mass, and the degree of deterioration is positively related to the normal tensile stress. The level of crack initiation stress increases with the increase of normal tensile stress, and the crack initiation angle decreases with the increase of normal tensile stress. The failure type of the rock mass with an elliptical hole under tension and shear is the tensile failure caused by anti-wing crack penetration. Under the effect of tension and shear, the maximum tensile zone is formed by the coupling of tensile stress and compressive stress in the rock mass, and the boundary near the side of the shear loading surface is the crack propagation path. The crack starts from the plastic yield at the elliptical hole. After the crack initiation, the stress is released and redistributed by the particle contact fracture, and the crack propagates along the direction of the maximum principal stress after the redistribution, which shows the nonlinear propagation mode of the crack macroscopically.

Abstract Background Blueberries (Vaccinium corymbosum) are regarded as “superfoods” attributed to large amounts of anthocyanins, a group of flavonoid metabolites, which provide pigmentation in plant and beneficial effects for human health. MYB transcription factor is one of vital components in the regulation of plant secondary metabolism, which occupies a dominant position in the regulatory network of anthocyanin biosynthesis. However, the role of MYB family in blueberry responding to anthocyanin biosynthesis remains elusive. Results In this study, we conducted a comprehensive analysis of VcMYBs in blueberry based on the genome data, including phylogenetic relationship, conserved motifs, identification of differentially expressed MYB genes during fruit development and their expression profiling, etc. A total of 437 unique MYB sequences with two SANT domains were identified in blueberry, which were divided into 3 phylogenetic trees. Noticeably, there are many trigenic and tetragenic VcMYBs pairs with more than 95% identity to each other. Meanwhile, the transcript accumulations of VcMYBs were surveyed underlying blueberry fruit development, and they showed diverse expression patterns, suggesting various functional roles in fruit ripening. More importantly, distinct transcript profiles between skin and pulp of ripe fruit were observed for several VcMYBs, such as VcMYB437, implying the potential roles in anthocyanin biosynthesis. Conclusions Totally, 437 VcMYBs were identified and characterized. Subsequently, their transcriptional patterns were explored during fruit development and fruit tissues (skin and pulp) closely related to anthocyanin biosynthesis. These genome-wide data and findings will contribute to demonstrating the functional roles of VcMYBs and their regulatory mechanisms for anthocyanins production and accumulation in blueberry in the future study.

Abstract Background As one of the most common intestinal inflammatory diseases, celiac disease (CD) is typically characterized by an autoimmune disorder resulting from ingesting gluten proteins. Although the incidence and prevalence of CD have increased over time, the diagnostic methods and treatment options are still limited. Therefore, it is urgent to investigate the potential biomarkers and targeted drugs for CD. Methods Gene expression data was downloaded from GEO datasets. Differential gene expression analysis was performed to identify the dysregulated immune-related genes. Multiple machine algorithms, including randomForest, SVM-RFE, and LASSO, were used to select the hub immune-related genes (HIGs). The immune-related genes score (IG score) and artificial neural network (ANN) were constructed based on HIGs. Potential drugs targeting HIGs were identified by using the Enrichr platform and molecular docking method. Results We identified the dysregulated immune-related genes at a genome-wide level and demonstrated their roles in CD-related immune pathways. The hub genes (MR1, CCL25, and TNFSF13B) were further screened by integrating several machine algorithms. Meanwhile, the CD patients were divided into distinct subtypes with either high- or low-immunoactivity using single-sample gene set enrichment analysis (ssGSEA) and consensus clustering. By constructing IG score based on HIGs, we found that patients with high IG score were mainly attributed to high-immunoactivity subgroups, which suggested a strong link between HIGs and immunoactivity of CD patients. In addition, the novel constructed ANN model showed the sound diagnostic ability of HIGs. Mechanistically, we validated that the HIGs play pivotal roles in regulating CD's immune and inflammatory state. Through targeting the HIGs, we also found potential drugs for anti-CD treatment by using the Enrichr platform and molecular docking method. Conclusions This study unveils the HIGs and elucidates the networks regulated by these genes in the context of CD. It underscores the pivotal significance of HIGs in accurately predicting the presence or absence of CD in patients. Consequently, this research offers promising prospects for the development of diagnostic biomarkers and therapeutic targets for CD.

Deep learning-based 3D target detection methods need to solve the problem of insufficient 3D target detection accuracy. In this paper, the KM3D network is selected as the benchmark network after the experimental comparison of current mainstream algorithms, and the IAE-KM3D network algorithm based on the KM3D network is proposed. First, the Resnet V2 network is introduced, and the residual module is redesigned to improve the training capability of the new residual module with higher generalization. IBN NET is then introduced to carefully integrate instance normalization and batch normalization as building blocks to improve the model’s detection accuracy in hue- and brightness-changing scenarios without increasing time loss. Then, a parameter-free attention mechanism, Simam, is introduced to improve the detection accuracy of the model. After that, the elliptical Gaussian kernel is introduced to improve the algorithm’s ability to detect 3D targets. Finally, a new key point loss function is proposed to improve the algorithm’s ability to train. Experiments using the KITTI dataset conclude that the IAE-KM3D network model significantly improves detection accuracy and outperforms the KM3D algorithm regarding detection performance compared to the original KM3D network. The improvements for AP2D, AP3D, and APBEV are 5%, 12.5%, and 8.3%, respectively, and only a tiny amount of time loss and network parameters are added. Compared with other mainstream target detection algorithms, Monn3D, 3DOP, GS3D, and FQNet, the improved IAE-KM3D network in this paper significantly improves AP3D and APBEV, with fewer network parameters and shorter time consumption.

Recent decades have witnessed the increasing usage of deep cement mixing (DCM) mixers in the field of marine infrastructure construction. The mixing performance, including the torque history, can be helpful for structural safety evaluation, design, and the optimization of agitators, which is of engineering significance. However, to the best of the authors’ knowledge, there are no related publications that have reported the mixing behaviors of deep cement mixing agitators. In light of this, the present work conducts experimental and numerical investigations of the mixing behaviors of a DCM ship mixing agitator. To achieve this end, a model test device is established, and mixing experiments using two- and three-blade mixers are respectively conducted. Silt and clay soils are considered in the experiments with a three-blade mixer, while clay soils are used for those with a two-blade mixer. In addition, this work designs a torque transducer placed inside the rotating rod to accurately measure the torque history of the agitator during model test experiments. The experimental results show that, when mixing clay using agitators with different blades, the average torque value required for a two-blade agitator is slightly larger than that for a three-blade one. This study also presents a computational framework based on the arbitrary Lagrangian–Eulerian (ALE) method for an efficient and accurate modeling of the soil-mixing behaviors of the agitator. The numerical results are found to be in good agreement with the experimental data from model tests in terms of torque history, which demonstrates the effectiveness and capacity of our presented computational framework. The numerical results show that the average torque value is smaller at a higher rotational speed during the mixing of clay using a two-bladed agitator, but the effect of rotational speed on the torque history is small. The experimental and numerical methods introduced in the present work can act as a useful tool for investigations of mixing behaviors of DCM agitators.

Natural regeneration is deemed essential for maintaining biodiversity and ecosystem stability. Previous studies, however, have primarily concentrated on regions exhibiting limited environmental and climatic variability, overlooking the classification of natural regeneration based on age and source. Research conducted at the mesoscale, characterized by increased environmental variability and the incorporation of neighborhood competition and understory-associated vegetation, enhances our comprehension of the multifaceted influences on natural regeneration. To comprehend this issue, this study implemented 60 plots, each measuring 20 m × 20 m, across five distinct areas of Chongqing, China. Twenty explanatory variables were chosen from five diverse categories: understory vegetation, neighborhood competition, stand structure, climatic factors, and environmental factors. And the naturally regenerated species were classified into seedlings and saplings, as well as endogenous and exogenous species, based on their age and origin. We examined the response of the different categories of natural regeneration to various factors and constructed a structural equation model (SEM) for significant factors to investigate their direct and indirect effects on natural regeneration. A total of 61 regenerated tree species belonging to 29 families and 42 genera were found in the study area, and the naturally regenerating species with high importance values were Quercus fabri, Robinia pseudoacacia, Alangium chinense, Cunninghamia lanceolata, and Ligustrum lucidum. It was found that neighborhood competition and understory-associated vegetation explained the largest proportion (more than 50%) of the variation in the different categories of natural regeneration, and forests with clumped distribution (W), a high mingling index (M) and strong competition (H) had a reduced natural regeneration capacity. Understory-associated herbs significantly reduced natural regeneration and the crowdedness index (C) significantly inhibited the understory-associated herbs, thus indirectly promoting natural regeneration. The shrub cover is significantly and positively correlated with the number of naturally regenerated plants and can be used as an indicator of a forest community’s regeneration potential. Understanding the differences in the importance of various factors at the mesoscale, as well as their direct and indirect impacts, can help us further comprehend the mechanisms of natural regeneration and provide a foundation for the sustainable development of forests.

In this study, we designed a novel electrochemical sensor by modifying a glass carbon electrode (GCE) with Pd confined mesoporous carbon hollow nanospheres (Pd/MCHS) for the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA). The structure and morphological characteristics of the Pd/MCHS nanocomposite and the Pd/MCHS/GCE sensor are comprehensively examined using SEM, TEM, XRD and EDX. The electrochemical properties of the prepared sensor are investigated through CV and DPV, which reveal three resolved oxidation peaks for AA, DA, and UA, thereby verifying the simultaneous detection of the three analytes. Benefiting from its tailorable properties, the Pd/MCHS nanocomposite provides a large surface area, rapid electron transfer ability, good catalytic activity, and high conductivity with good electrochemical behavior for the determination of AA, DA, and UA. Under optimized conditions, the Pd/MCHS/GCE sensor exhibited a linear response in the concentration ranges of 300–9000, 2–50, and 20–500 µM for AA, DA, and UA, respectively. The corresponding limit of detection (LOD) values were determined to be 51.03, 0.14, and 4.96 µM, respectively. Moreover, the Pd/MCHS/GCE sensor demonstrated outstanding selectivity, reproducibility, and stability. The recovery percentages of AA, DA, and UA in real samples, including a vitamin C tablet, DA injection, and human urine, range from 99.8–110.9%, 99.04–100.45%, and 98.80–100.49%, respectively. Overall, the proposed sensor can serve as a useful reference for the construction of a high-performance electrochemical sensing platform.

A data-driven aerodynamic modeling method is proposed to address the problem that traditional modeling methods based on physical mechanisms cannot fully represent the special aerodynamic characteristics of tiltrotor evtol aircraft. By analyzing the uniquely complex aerodynamic characteristics of electric vertical take-off and landing (evtol) aircraft, an MLP neural network model has been constructed that reflects the coupling characteristics between influencing factors. Using the XV15 wind tunnel test data, a dataset was constructed, and the neural network model was trained and validated. Simulation results show that the selected data-driven method can accurately predict the aerodynamic characteristics of the longitudinal transition phase of the tiltrotor evtol.

Abstract The largest negative inorganic carbon isotope excursion in Earth’s history, namely the Ediacaran Shuram Excursion (SE), closely followed by early animal radiation, has been widely interpreted as a consequence of oceanic oxidation. However, the primary nature of the signature, source of oxidants, and tempo of the event remain contested. Here, we show that carbonate-associated sulfate (CAS) from three different paleocontinents all have conspicuous negative 17O anomalies (Δ′17OCAS values down to −0.53‰) during the SE. Furthermore, the Δ′17OCAS varies in correlation with its corresponding δ34SCAS and δ18OCAS as well as the carbonate δ13Ccarb, decreasing initially followed by a recovery over the ~7-Myr SE duration. In a box-model examination, we argue for a period of sustained water-column ventilation and consequently enhanced sulfur oxidation in the SE ocean. Our findings reveal a direct involvement of mass-anomalously 17O-depleted atmospheric O2 in marine sulfate formation and thus a primary global oceanic oxygenation event during the SE.

Abstract In recent years, cancer immunotherapy has emerged as an exciting cancer treatment. Immune checkpoint blockade brings new opportunities for more researchers and clinicians. Programmed cell death receptor-1 (PD-1) is a widely studied immune checkpoint, and PD-1 blockade therapy has shown promising results in a variety of tumors, including melanoma, non-small cell lung cancer and renal cell carcinoma, which greatly improves patient overall survival and becomes a promising tool for the eradication of metastatic or inoperable tumors. However, low responsiveness and immune-related adverse effects currently limit its clinical application. Overcoming these difficulties is a major challenge to improve PD-1 blockade therapies. Nanomaterials have unique properties that enable targeted drug delivery, combination therapy through multidrug co-delivery strategies, and controlled drug release through sensitive bonds construction. In recent years, combining nanomaterials with PD-1 blockade therapy to construct novel single-drug-based or combination therapy-based nano-delivery systems has become an effective mean to address the limitations of PD-1 blockade therapy. In this study, the application of nanomaterial carriers in individual delivery of PD-1 inhibitors, combined delivery of PD-1 inhibitors and other immunomodulators, chemotherapeutic drugs, photothermal reagents were reviewed, which provides effective references for designing new PD-1 blockade therapeutic strategies. Graphical Abstract

Abstract Objective To investigate the effectiveness of using a 3D-printed total skin bolus in total skin helical tomotherapy for the treatment of mycosis fungoides. Materials and methods A 65-year-old female patient with a 3-year history of mycosis fungoides underwent treatment using an in-house desktop fused deposition modelling printer to create a total skin bolus made of a 5-mm-thick flexible material, which increased the skin dose through dose building. The patient's scan was segmented into upper and lower sections, with the division line placed 10 cm above the patella. The prescription was to deliver 24 Gy over 24 fractions, given 5 times per week. The plan parameters consisted of a field width of 5 cm, pitch of 0.287 and modulation factor of 3. The complete block was placed 4 cm away from the planned target region to reduce the area of the internal organs at risk, especially the bone marrow. Dose delivery accuracy was verified using point dose verification with a "Cheese" phantom (Gammex RMI, Middleton, WI), 3D plane dose verification with ArcCHECK (Model 1220, Sun Nuclear, Melbourne, FL), and multipoint film dose verification. Megavoltage computed tomography guidance was also utilized to ensure the accuracy of the setup and treatment. Results A 5-mm-thick 3D-printed suit was used as a bolus to achieve a target volume coverage of 95% of the prescribed dose. The conformity index and homogeneity index of the lower segment were slightly better than those of the upper segment. As the distance from the skin increased, the dose to the bone marrow gradually decreased, and the dose to other organs at risk remained within clinical requirements. The point dose verification deviation was less than 1%, the 3D plane dose verification was greater than 90%, and the multipoint film dose verification was less than 3%, all of which confirmed the accuracy of the delivered dose. The total treatment time was approximately 1.5 h, which included 0.5 h of wearing the 3D-printed suit and 1 h with the beam on. Patients only experienced mild fatigue, nausea or vomiting, low-grade fever, and grade III bone marrow suppression. Conclusion The use of a 3D-printed suit for total skin helical tomotherapy can result in a uniform dose distribution, short treatment time, simple implementation process, good clinical outcomes, and low toxicity. This study presents an alternative treatment approach that can potentially yield improved clinical outcomes for mycosis fungoides.

Abstract The rapid development of blockchain technology has garnered increasing attention, particularly in the field of edge computing. It has become a significant subject of research in this area due to its ability to protect the privacy of data. Despite the advantages that blockchain technology offers, there are also security threats that must be addressed. Attackers may manipulate certain nodes in the blockchain network, which can result in tampering with transaction records or other malicious activities. Moreover, the creation of a large number of false nodes can be utilized to gain control and manipulate transaction records of the blockchain network, which can compromise the reliability and security of edge computing. This paper proposes a blockchain node detection method named $$T^2A2vec$$ T 2 A 2 v e c that provides a more secure, credible, and reliable solution to address these challenges. In order to achieve $$T^2A2vec$$ T 2 A 2 v e c , a transaction dataset that is evenly distributed in both space and time was collected. The transaction dataset is constructed as a transaction graph, where nodes represent accounts and edges describe transactions. BP neural network is used to extract account features, and a random walk strategy based on transaction time, type, and amount is used to extract transaction features. The obtained account features and transaction features are fused to obtain account representation. Finally, the obtained node representation is fed into different classifiers to identify malicious nodes.

Abstract. In the last decade, it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host. Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases, e.g., Parkinson's disease, Alzheimer's disease, and myasthenia gravis. However, the underlying molecular mechanisms are complex and remain unclear. Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation, indicating that the gut microbiota may be an important regulator of neurological diseases. However, further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases. Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders. In this review, we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases, and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.

Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an “AND” logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant H2O2 into O2, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin–DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.

With the rapid development of today’s society, the traffic environment has become more and more complex. As an essential part of intelligent vehicles, trajectory tracking has attracted significant attention for its stability and safety. It is prone to poor accuracy and instability in extreme working conditions like high speed. In this paper, a trajectory tracking control strategy to ensure lateral stability at a high speed and low attachment limit conditions is proposed for distributed drive vehicles. The model predictive controller (MPC) was used to control the front wheel angle, and the particle swarm optimization (PSO) algorithm was designed to optimize the MPC control parameters adaptively. The sliding mode controller controls the rear wheel angle, and the vehicle instability degree is judged by analyzing the β − β˙ phase plane. The controllers of different instability degrees are designed herein. Finally, a torque divider is designed to consider the actuation anti-slip. The designed controller is verified by Carsim and MATLAB-Simulink co-simulation. The results show that the trajectory tracking controller designed in this paper effectively improves the tracking accuracy under the premise of ensuring stability.

The power capacity of reflectarray antennas (RAs) is investigated through full-wave simulations and high-power microwave (HPM) experiments in this paper. In order to illustrate the results in detail, two RA elements are designed. The simulated power handling capacity of two RA elements are 7.17 MW/m2 and 2.3 GW/m2, respectively. To further study the HPM RA, two RA prototypes operating at 2.8 GHz are constructed with the aperture size of 1 m × 1 m. Simulations and experimental measurements are conducted for the two prototypes. The experimental results demonstrate that, even when subjected to 1 GW of power, the radiation beam of the RA with the second elements can still propagate in the intended direction. This research will establish a basis for advancing the practicality of RAs in HPM applications.