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Abstract Cancer immunotherapy harnesses the body’s immune system to combat malignancies, building upon an understanding of tumor immunosurveillance and immune evasion mechanisms. This therapeutic approach reactivates anti-tumor immune responses and can be categorized into active, passive, and combined immunization strategies. Active immunotherapy engages the immune system to recognize and attack tumor cells by leveraging host immunity with cytokine supplementation or vaccination. Conversely, passive immunotherapy employs exogenous agents, such as monoclonal antibodies (anti-CTLA4, anti-PD1, anti-PD-L1) or adoptive cell transfers (ACT) with genetically engineered chimeric antigen receptor (CAR) T or NK cells, to exert anti-tumor effects. Over the past decades, CAR-T cell therapies have gained significant traction in oncological treatment, offering hope through their targeted approach. However, the potential adverse effects associated with CAR-T cells, including cytokine release syndrome (CRS), off-tumor toxicity, and neurotoxicity, warrant careful consideration. Recently, CAR-NK cell therapy has emerged as a promising alternative in the landscape of tumor immunotherapy, distinguished by its innate advantages over CAR-T cell modalities. In this review, we will synthesize the latest research and clinical advancements in CAR-NK cell therapies. We will elucidate the therapeutic benefits of employing CAR-NK cells in oncology and critically examine the developmental bottlenecks impeding their broader application. Our discussion aims to provide a comprehensive overview of the current status and future potential of CAR-NK cells in cancer immunotherapy.

Abstract PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor microenvironment remains unclear. The expression profiles of PTBP1 across various cancers were derived from the TCGA, as well as the GTEx and CGGA databases. The CGGA mRNA_325, CGGA mRNA_301, and CGGA mRNA_693 datasets were utilized as validation cohorts. Immune cell infiltration scores were approximated using the TIMER 2.0 tool. Functional enrichment analysis for groups with high and low PTBP1 expression was conducted using Gene Set Enrichment Analysis (GSEA). Methylation data were predominantly sourced from the SMART and Mexpress databases. Linked-omics analysis was employed to perform functional enrichment analysis of genes related to PTBP1 methylation, as well as to conduct protein functional enrichment analysis. Single-cell transcriptome analysis and spatial transcriptome analysis were carried out using Seurat version 4.10. Compared to normal tissues, PTBP1 is significantly overexpressed and hypomethylated in various cancers. It is implicated in prognosis, immune cell infiltration, immune checkpoint expression, genomic variation, tumor neoantigen load, and tumor mutational burden across a spectrum of cancers, with particularly notable effects in low-grade gliomas. In the context of gliomas, PTBP1 expression correlates with WHO grade and IDH1 mutation status. PTBP1 expression and methylation play an important role in a variety of cancers. PTBP1 can be used as a marker of inflammation, progression and prognosis in gliomas.

ObjectiveTo mine and analyze adverse events (AEs) related to proteasome inhibitors in multiple myeloma based on the FDA Adverse Event Reporting System (FAERS), providing references for rational clinical medication.MethodsAE data related to multiple myeloma proteasome inhibitors were collected from the FAERS from the first quarter of 2010 to the first quarter of 2024. Signal mining of AEs was conducted using the reporting odds ratio method and Bayesian confidence propagation neural network method.ResultsA total of 8,805 reports for bortezomib, 5,264 for carfilzomib, and 8,771 for ixazomib were collected, with corresponding AE signals of 474, 279, and 287, respectively, involving 23, 21, and 22 System Organ Classes (SOCs). The report information for the three drugs tended to be consistent: more cases were reported in males than in females; the majority of patients were 65 years and over; AEs mostly occurred within 6 months of medication; the outcomes primarily consisted of hospitalization, prolonged hospital stay, and other serious adverse events; the primary reporting country was the United States. The most affected SOCs were infections and infestations, general disorders and administration site conditions, and blood and lymphatic system disorders.ConclusionThe overall distribution of AEs for the three multiple myeloma proteasome inhibitors was consistent, but there were certain differences in specific AE signal characteristics, which should be noted in clinical applications.

ObjectiveHyperuricaemia and gout are common metabolic disorders. However, the causal relationships between blood metabolites and serum urate levels, as well as gout, remain unclear. A systematic evaluation of the causal connections between blood metabolites, hyperuricemia, and gout could enhance early screening and prevention of hyperuricemia and gout in clinical settings, providing novel insights and approaches for clinical treatment.MethodsIn this study, we employed a bidirectional two-sample Mendelian randomization analysis utilizing data from a genome-wide association study involving 7,286 participants, encompassing 486 blood metabolites. Serum urate and gout data were sourced from the Chronic Kidney Disease Genetics consortium, including 288,649 participants for serum urate and 9,819 African American and 753,994 European individuals for gout. Initially, LDSC methodology was applied to identify blood metabolites with a genetic relationship to serum urate and gout. Subsequently, inverse-variance weighting was employed as the primary analysis method, with a series of sensitivity and pleiotropy analyses conducted to assess the robustness of the results.ResultsFollowing LDSC, 133 blood metabolites exhibited a potential genetic relationship with serum urate and gout. In the primary Mendelian randomization analysis using inverse-variance weighting, 19 blood metabolites were recognized as potentially influencing serum urate levels and gout. Subsequently, the IVW p-values of potential metabolites were corrected using the false discovery rate method. We find leucine (IVW P FDR = 0.00004), N-acetylornithine (IVW P FDR = 0.0295), N1-methyl-3-pyridone-4-carboxamide (IVW P FDR = 0.0295), and succinyl carnitine (IVW P FDR = 0.00004) were identified as significant risk factors for elevated serum urate levels. Additionally, 1-oleoylglycerol (IVW P FDR = 0.0007) may lead to a substantial increase in the risk of gout. Succinyl carnitine exhibited acceptable weak heterogeneity, and the results for other blood metabolites remained robust after sensitivity, heterogeneity, and pleiotropy testing. We conducted an enrichment analysis on potential blood metabolites, followed by a metabolic pathway analysis revealing four pathways associated with serum urate levels.ConclusionThe identified causal relationships between these metabolites and serum urate and gout offer a novel perspective, providing new mechanistic insights into serum urate levels and gout.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway. Resumen: El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory reactions and tissue damage in the joints. Long-term drug use in clinical practice is often accompanied by adverse reactions. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy with few side effects, offering a potential and safe therapeutic alternative for RA through the induction of immune tolerance. This study aimed to investigate the therapeutic effects of ECP on RA using a collagen-induced arthritis (CIA) murine model, as well as to explore its immunomodulatory effects in vivo. Additionally, particular attention was given to the significant role of monocytes during the ECP process. Methods A murine model of rheumatoid arthritis was established by administering two injections of bovine type II collagen to DBA/1J mice. ECP, ECP-MD (mononuclear cells were depleted during the ECP), MTX, and PBS treatment were applied to the CIA mice. During the treatment process, clinical scores and body weight changes of CIA mice were closely monitored. After six treatment sessions, micro-CT images of the hind paws from live mice were captured. Ankle joints and paws of the mice were collected and processed for histological evaluation. Spleen samples were collected to measure the Th17/Treg cells ratio, and serum samples were collected to assess cytokine and anti-type II collagen IgG levels. Monocytes and dendritic cells populations before and after ECP in vitro were detected by flow cytometry. Result ECP therapy significantly attenuated the progression of CIA, alleviated the severity of clinical symptoms in CIA mice and effectively suppressed synovial hyperplasia, inflammation, and cartilage damage. There was an expansion in the percentage of CD3 + CD4 + CD25 + FoxP3 + Tregs and a decrease in CD3 + CD4 + IL17A + Th17 cells in vivo. Furthermore, ECP reduced the serum levels of pro-inflammatory cytokines IL-6 (53.47 ± 7.074 pg/mL vs 5.142 ± 1.779 pg/mL, P

Rosa roxburghii fruit is rich in flavonoids, but little is known about their biosynthetic pathways. In this study, we employed transcriptomics and metabolomics to study changes related to the flavonoids at five different stages of R. roxburghii fruit development. Flavonoids and the genes related to their biosynthesis were found to undergo significant changes in abundance across different developmental stages, and numerous quercetin derivatives were identified. We found three gene expression modules that were significantly associated with the abundances of the different flavonoids in R. roxburghii and identified three structural UDP-glycosyltransferase genes directly involved in the synthesis of quercetin derivatives within these modules. In addition, we found that RrBEH4, RrLBD1 and RrPIF8 could significantly increase the expression of downstream quercetin derivative biosynthesis genes. Taken together, these results provide new insights into the metabolism of flavonoids and the accumulation of quercetin derivatives in R. roxburghii.

AbstractThe mitogenome of Bauhinia variegate was assembled and characterized in this study. The mitogenome size was 437,271 bp, and its GC content was 45.5%. 36 protein-coding genes, 17 tRNAs and 3 rRNAs were annotated in the mitogenome. A total of 12 MTPTs, ranging from 71 bp to 3562 bp, were identified in the mitogenome and covered 1.46% (6373 bp) of the mitogenome. Phylogenetic analysis of 15 species of Leguminosae based on 23 core protein-coding genes showed that B. variegata was sister to Tylosema esculentum, another member from the subfamily Cercidoideae. The mitogenome of B. variegata provides a valuable genetic resource for further phylogenetic studies of this family.

Abstract Background To develop and validate a preoperative nomogram model combining the radiomics signature and clinical features for preoperative prediction of visceral pleural invasion (VPI) in lung nodules presenting as part‐solid density. Methods We retrospectively reviewed 156 patients with pathologically confirmed invasive lung adenocarcinomas after surgery from January 2016 to August 2019. The patients were split into training and validation sets by a ratio of 7:3. The radiomic features were extracted with the aid of FeAture Explorer Pro (FAE). A CT‐based radiomics model was constructed to predict the presence of VPI and internally validated. Multivariable regression analysis was conducted to construct a nomogram model, and the performance of the models were evaluated with the area under the receiver operating characteristic curve (AUC) and compared with each other. Results The enrolled patients were split into training (n = 109) and validation sets (n = 47). A total of 806 features were extracted and the selected 10 optimal features were used in the construction of the radiomics model among the 707 stable features. The AUC of the nomogram model was 0.888 (95% CI: 0.762–0.961), which was superior to the clinical model (0.787, 95% CI: 0.643–0.893; p = 0.049) and comparable to the radiomics model (0.879, 95% CI: 0.751–0.965; p > 0.05). The nomogram model achieved a sensitivity of 90.5% and a specificity of 76.9% in the validation dataset. Conclusions The nomogram model could be considered as a noninvasive method to predict VPI with either highly sensitive or highly specific diagnoses depending on clinical needs.

ABSTRACTGut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Abstract Objectives To assess cigarette smoking’s effects on efficacy of the preferential Janus kinase (JAK) 1 inhibitor filgotinib and drug persistence in patients with rheumatoid arthritis (RA). Methods Efficacy in non-smokers, former smokers, and current smokers from phase 3 filgotinib trials was analyzed, including patients with inadequate response (IR) to methotrexate (MTX) or biologic disease-modifying antirheumatic drugs (bDMARDs) or who were MTX-naïve. Proportions achieving Disease Activity Score in 28 joints with C-reactive protein (DAS28[CRP]) ≤ 3.2 were compared using logistic regression. Retrospective claims-based switching data were reviewed. Results Week 12 (W12) DAS28(CRP) ≤ 3.2 was achieved by 50, 61, and 62% of MTX-IR non-smokers, former smokers, and current smokers taking filgotinib 200 mg (FIL200) + MTX vs. 23, 16, and 32% taking placebo + MTX (p

Objective To investigate the preventive effects of early apoptotic splenic mononuclear cells induced by extracorporeal photopheresis (ECP) on acute graft versus host disease (aGVHD) in mice and explore the underlying mechanisms. Methods 1) Splenic mononuclear cells were extracted from C57BL/6 mice and treated with different concentrations of 8-MOP (50 ng/mL, 100 ng/mL, 200 ng/mL, 300 ng/mL, 600 ng/mL). After treatment, irradiate the cells with 2 J/cm2 of ultraviolet light. Then, use the Annexin V-FITC/PI apoptosis detection kit to assess the early apoptosis rate of the cells and determine the optimal concentration of 8-MOP for the experiment.2) There were 35 SPF-grade female BALB/C mice (H-2Kd) aged 6-8 weeks. After whole-body irradiation with 8Gy X-rays, the mice were divided into five groups: sham irradiation group received intravenous infusion of 0.2 mL of normal saline, the syngeneic bone marrow transplantation group received intravenous infusion of 0.2 mL of BALB/C mouse bone marrow nucleated cell suspension (including a cell count of 1×107), the allogeneic bone marrow transplantation group received intravenous infusion of 0.2 mL of C57BL/6 mouse bone marrow nucleated cell suspension (including a cell count of 1×107), the aGVHD group received intravenous injection of a mixture of C57BL/6 mouse bone marrow nucleated cells (including a cell count of 1×107) and splenic mononuclear cells (including a cell count of 1×107) in 0.2 mL, the ECP prevention group received pre-transplant intravenous infusion of 0.2 mL of ECP-treated splenic mononuclear cells of C57BL/6 mice (including a cell count of 1×107 ) 48 hours before transplantation, and on the day of transplantation, intravenous injection of a mixture of C57BL/6 mouse bone marrow nucleated cells (including a cell count of 1×107) and splenic mononuclear cells (including a cell count of 1×107 ) in 0.2 mL.The preventive effects of ECP on aGVHD were observed, and the concentrations of IFN-γ, IL-2, TNF, IL-4 and IL-6 in mouse serum were measured using CBA. Th1 cell counts were determined by flow cytometry. Results Different concentrations of 8-MOP (50 ng/mL,100 ng/mL, 200 ng/mL, 300 ng/mL, 600 ng/mL) were used to treat mouse splenic mononuclear cells. The early apoptosis rates (%), observed after treatment were as follows: (14.18±0.865) vs (16.76±0.407) vs (18.83±0.404) vs (19.27±0.404) vs (14.5±0.529). The appropriate concentration of 8-MOP was determined to be 200 ng/mL.In vivo experiment, the results showed that the aGVHD group had decreased survival rate, reduced body weight, and increased clinical scores compared to the syngeneic and allogeneic bone marrow transplantation groups (P

Myopia has become a serious global burden of visual impairment and blindness, and the World Health Organization has included the prevention and treatment of myopia in its global blindness prevention program. Many ocular pathological alterations that follow from advanced myopia could cause visual impairment and even blindness in severe situations. Myopia is becoming more prevalent and has a greater impact on young people. Myopia's social repercussions are becoming more widely known. One of the several fundus alterations linked to myopia is tessellated fundus, which is the earliest lesion in the natural course of myopic fundus lesions and an important clinical marker for the development of retinopathy. Currently, there are several different methods of grading fundus tessellation, all of which are graded subjectively by fundus color photography. One can investigate the morphological characteristics and functional status of the tessellated fundus with ophthalmoscope, fundus photography, optical coherence tomography, electroretinogram, microperimetry and other modal images. In this study, the imaging properties and common applications of the tessellated fundus are reviewed to provide appropriate resources for clinical ophthalmology.

As an important gelling material, cementitious materials are widely used in civil engineering construction. Currently, research on these materials is conducted using experimental and numerical image processing methods, which enable the observation and analysis of structural changes and mechanical properties. These methods are instrumental in designing cementitious materials with specific performance criteria, despite their resource-intensive nature. The material genome approach represents a novel trend in material research and development. The establishment of a material gene database facilitates the rapid and precise determination of relationships between characteristic genes and performance, enabling the bidirectional design of cementitious materials’ composition and properties. This paper reviews the characteristic genes of cementitious materials from nano-, micro-, and macro-scale perspectives. It summarizes the characteristic genes, analyzes expression parameters at various scales, and concludes regarding their relationship to mechanical properties. On the nanoscale, calcium hydrated silicate (C-S-H) is identified as the most important characteristic gene, with the calcium–silicon ratio being the key parameter describing its structure. On the microscale, the pore structure and bubble system are key characteristics, with parameters such as porosity, pore size distribution, pore shape, air content, and the bubble spacing coefficient directly affecting properties like frost resistance, permeability, and compressive strength. On the macroscale, the aggregate emerges as the most important component of cementitious materials. Its shape, angularity, surface texture (grain), crushing index, and water absorption are the main characteristics influencing properties such as chloride ion penetration resistance, viscosity, fluidity, and strength. By analyzing and mapping the relationship between these genes and properties across different scales, this paper offers new insights and establishes a reference framework for the targeted design of cementitious material properties.

Objective To evaluate the effect of the uncertainty training on improvement of students’ diagnostic ability. Methods Data were collected on 70 fifth-year medical students enrolled in the Case Discussion courses on Obstetrics and Gynecology in the spring of 2020. Of these students, 36 were in the uncertainty training group and 34 in the control group. The effect of training was evaluated by cognitively diagnostic assessment which mapped exam questions to 4 attributes assessing clinical reasoning and basic science knowledge. Results Uncertainty training was able to improve students’ ability to use basic science concepts for inference and problem solving, and the ability to integrate complex clinical information to arrive at a diagnosis. But it could not improve students’ ability on the basic recall of foundational concepts and the ability to use basic science concepts in clinical reasoning. Medical students could do well in integrating complex clinical information although they didn’t recall basic science knowledge well. Conclusion Uncertainty training could be used as an effective teaching method in Case Discussion course on Obstetrics and Gynecology. However, students still need to improve their basic knowledge besides the training.

Exosomes have been demonstrated to exert momentous roles in autism spectrum disorder (ASD). However, few studies have reported a correlation between exosomal microRNAs (miRNAs) and ASD. To date, our understanding of crucial competing endogenous RNA (ceRNA) networks in ASD remains limited. Herein, the exosomal miRNA profile in the peripheral blood of children with ASD and healthy controls was investigated and the level of immune cell infiltration in ASD was evaluated to determine the distribution of immune cell subtypes. Exosomes were isolated from the peripheral blood of ten children with ASD and ten healthy controls, and further identified using transmission electron microscopy and western blot analysis. RNA sequencing was conducted to investigate exosomal miRNA profiles in patients with ASD. The mRNA and circular RNA (circRNA) expression profiles were acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified and ceRNA regulatory networks were constructed. Furthermore, the immune cell infiltration levels in patients with ASD were evaluated. Exosomes were spherical, approximately 100 nm in size, and were confirmed via western blot analysis using exosome-associated markers CD9, CD63, and CD81. Thirty-five DEmRNAs, 63 DEmiRNAs, and 494 DEcircRNAs were identified in patients with ASD. CeRNA regulatory networks, including 6 DEmRNAs, 14 DEmiRNAs, and 86 DEcircRNAs, were established. Correlation analysis indicated that leucine-rich glioma inactivated protein 1 (LGI1) expression was significantly positively correlated with the content of CD8+ T cells. Our findings may be conducive to offering novel insights into this disease and providing further evidence of transcriptomic abnormalities in ASD.

Background Although head elevation is an early first-line treatment for elevated intracranial pressure (ICP), the use of the head-down or prone position in managing neurocritical patients is controversial because a change in a position directly affects the intracranial and cerebral perfusion pressure, which may cause secondary brain injury and affect patient outcomes. This study compared the effects of two postural drainage positions (30° head-up tilt and 0° head flat) on the prognosis of neurocritical care patients with complicated pneumonia and a clinical pulmonary infection score (CPIS) ≥5 points to provide a reference for selecting appropriate postural drainage positions for patients with pneumonia in neurocritical care units. Methods A prospective randomized controlled study was conducted with 62 neurocritical care patients with complicated pneumonia. The patients were categorized into control (=31) and experimental (=31) groups in a 1:1 ratio using a simple randomized non-homologous pairing method. Emphasis was placed on matching the baseline characteristics of the two groups, including patient age, sex, height, weight, Glasgow Coma Scale score, heart rate, mean arterial pressure, cough reflex, and mechanical ventilation usage to ensure comparability. Both groups received bundled care for artificial airway management. The control group maintained a standard postural drainage position of 0° head-flat, whereas the experimental group maintained a 30° head-up tilt. The efficacy of the nursing intervention was evaluated by comparing the CPIS and other therapeutic indicators between the two groups after postural drainage. Results After the intervention, the within-group comparison showed a significant decrease in the CPIS (P

Few work have been performed regarding the quantitative characterization of three-dimensional (3D) pitting corrosion process directly, although the corrosion behaviors and the passivation film stability of metals in various solutions have been studied heavily. The reported work quantitatively characterized the 3D pitting corrosion of the Fe-based amorphous alloy coating (Fe-based AAC) via X-ray micro-computed tomography (X-ray micro-CT) and further elucidated the mechanism of its pitting corrosion. Moreover, the microstructure and electrochemical performance of the Fe-based AAC have also been explored. The results showed that the targeted thermal sprayed Fe43Cr20Mo10W4C15B6Y2 coating was prone to be corroded with the increase of the hydrogen ion concentration, i.e. higher hydrogen ion concentration leads to poorer corrosion performance of the Fe-based AAC. The X-ray micro-CT results revealed that the pits in the Fe-based AAC initially nucleated below the pitting potential, and they also generated in the over-passivation stage. Furthermore, it was found that the corrosive medium does not penetrate into the coating/substrate interface, and the deduced corrosion mechanism from the findings was also discussed.

Abstract Background The aim of this study is to investigate the profiles of gut microbiota and metabolites in acute myelocytic leukemia (AML) patients treated with/without chemotherapy. Methods Herein, high‐throughput 16S rRNA gene sequencing was performed to analysis gut microbiota profiles, and liquid chromatography and mass spectrometry were performed to analysis metabolites profiles. The correlation between gut microbiota biomarkers identified by LEfSe and differentially expressed metabolites were determined by spearman association analysis. Results The results showed the distinguished gut microbiota and metabolites profiles between AML patients and control individuals or AML patients treated with chemotherapy. Compared to normal populations, the ratio of Firmicutes to Bacteroidetes was increased at the phylum level than that in AML patients, and LEfSe analysis identified Collinsella and Coriobacteriaceae as biomarkers of AML patients. Differential metabolite analysis indicated that, compared to AML patients, numerous differential amino acids and analogs could be observed in control individuals and AML patients treated with chemotherapy. Interestingly, spearman association analysis demonstrated that plenty of bacteria biomarkers shows statistical correlations with differentially expressed amino acid metabolites. In addition, we found that both Collinsella and Coriobacteriaceae demonstrate remarkable positive correlation with hydroxyprolyl‐hydroxyproline, prolyl‐tyrosine, and tyrosyl‐proline. Conclusion In conclusion, our present study investigated the role of the gut‐microbiome–metabolome axis in AML and revealed the possibility of AML treatment by gut‐microbiome–metabolome axis in the further.

Abstract To investigate whether the combination scheme of deep learning score (DL-score) and radiomics can improve preoperative diagnosis in the presence of micropapillary/solid (MPP/SOL) patterns in lung adenocarcinoma (ADC). A retrospective cohort of 514 confirmed pathologically lung ADC in 512 patients after surgery was enrolled. The clinicoradiographic model (model 1) and radiomics model (model 2) were developed with logistic regression. The deep learning model (model 3) was constructed based on the deep learning score (DL-score). The combine model (model 4) was based on DL-score and R-score and clinicoradiographic variables. The performance of these models was evaluated with area under the receiver operating characteristic curve (AUC) and compared using DeLong's test internally and externally. The prediction nomogram was plotted, and clinical utility depicted with decision curve. The performance of model 1, model 2, model 3 and model 4 was supported by AUCs of 0.848, 0.896, 0.906, 0.921 in the Internal validation set, that of 0.700, 0.801, 0.730, 0.827 in external validation set, respectively. These models existed statistical significance in internal validation (model 4 vs model 3, P = 0.016; model 4 vs model 1, P = 0.009, respectively) and external validation (model 4 vs model 2, P = 0.036; model 4 vs model 3, P = 0.047; model 4 vs model 1, P = 0.016, respectively). The decision curve analysis (DCA) demonstrated that model 4 predicting the lung ADC with MPP/SOL structure would be more beneficial than the model 1and model 3 but comparable with the model 2. The combined model can improve preoperative diagnosis in the presence of MPP/SOL pattern in lung ADC in clinical practice.

Abstract Background The plant hormone auxin is widely involved in plant growth, development, and morphogenesis, and the TIR1/AFB and AUX/IAA proteins are closely linked to rapid auxin response and signal transmission. However, their evolutionary history, historical patterns of expansion and contraction, and changes in interaction relationships are still unknown. Results Here, we analyzed the gene duplications, interactions, and expression patterns of TIR1/AFBs and AUX/IAAs to understand their underlying mechanisms of evolution. The ratios of TIR1/AFBs to AUX/IAAs range from 4:2 in Physcomitrium patens to 6:29 in Arabidopsis thaliana and 3:16 in Fragaria vesca. Whole-genome duplication (WGD) and tandem duplication have contributed to the expansion of the AUX/IAA gene family, but numerous TIR1/AFB gene duplicates were lost after WGD. We further analyzed the expression profiles of TIR1/AFBs and AUX/IAAs in different tissue parts of Physcomitrium patens, Selaginella moellendorffii, Arabidopsis thaliana and Fragaria vesca, and found that TIR1/AFBs and AUX/IAAs were highly expressed in all tissues in P. patens, S. moellendorffii. In A. thaliana and F. vesca, TIR1/AFBs maintained the same expression pattern as the ancient plants with high expression in all tissue parts, while AUX/IAAs appeared tissue-specific expression. In F. vesca, 11 AUX/IAAs interacted with TIR1/AFBs with different interaction strengths, and the functional specificity of AUX/IAAs was related to their ability to bind TIR1/AFBs, thus promoting the development of specific higher plant organs. Verification of the interactions among TIR1/AFBs and AUX/IAAs in Marchantia polymorpha and F. vesca also showed that the regulation of AUX/IAA members by TIR1/AFBs became more refined over the course of plant evolution. Conclusions Our results indicate that specific interactions and specific gene expression patterns both contributed to the functional diversification of TIR1/AFBs and AUX/IAAs.

Abstract Background Metastasis is the leading cause of death among patients with colorectal cancer (CRC). Therefore, it is important to explore the molecular mechanisms of metastasis to develop effective therapeutic targets for CRC. In the present study, ribosomal protein L21 (RPL21) was considered as being involved in promoting CRC metastasis, yet the underlying mechanism requires further investigation. Methods Immunohistochemistry, western blotting, and quantitative reverse transcription polymerase chain reaction were performed to measure the expression of RPL21 and lysosome-associated membrane protein 3 (LAMP3) in CRC tissues and cells. Wound healing, transwell migration, and invasion assays were performed to study the migration and invasion of cultured CRC cells. An orthotopic CRC mouse model was developed to investigate the metastatic ability of CRC. Transcriptome sequencing was conducted to identify the genes related to RPL21. The dual-luciferase reporter gene assay was performed to determine the transcriptional activity of transcription factor EB (TFEB). The GST/His pull-down assay was performed to investigate the specific binding sites of RPL21 and LAMP3. The cell adhesion assay was performed to determine the adhesion ability of CRC cells. Immunofluorescence staining was performed to observe focal adhesions (FAs). Results RPL21 was highly expressed in CRC, contributing to tumor invasiveness and poor patient prognosis. Functionally, RPL21 promoted the migration and invasion of CRC cells in vitro and tumor metastasis in vivo. Moreover, LAMP3 was identified as being highly related to RPL21 and was essential in promoting the migration and invasion of CRC cells. Mechanistically, RPL21 activated the transcriptional function of TFEB to upregulate LAMP3 expression. RPL21 directly bound to the aa 341–416 domain of LAMP3 via its aa 1–40 and aa 111–160 segments. The combination of RPL21 and LAMP3 enhanced the stability of the RPL21 protein by suppressing the degradation of the ubiquitin–proteasome system. Furthermore, RPL21 and LAMP3 promoted the formation of immature FAs by activating the FAK/paxillin/ERK signaling pathway. Conclusions RPL21 promoted invasion and metastasis by regulating FA formation in a LAMP3-dependent manner during CRC progression. The interaction between RPL21 and LAMP3 may function as a potential therapeutic target against CRC.

ObjectiveObservational studies have suggested an increased risk of cardiovascular disease in individuals with ankylosing spondylitis. However, these studies are prone to confounding factors and reverse causality. To address these limitations, we conducted a Mendelian randomization study to assess the causal relationship between AS and CVD.MethodsThe study population comprises 9,069 individuals with ankylosing spondylitis and 509,093 individuals with either of six common cardiovascular diseases and a related indicator. Causal analysis using summary effect estimates and inverse variance weighting were employed as the main methods.ResultsThe CAUSE analysis showed no evidence of a causal relationship between AS and CVD. The odds ratios for total CVD, heart failure, myocardial infarction, valvular heart disease, ischemic heart disease, and venous thromboembolism, Arterial stiffness index, were as follows: OR, 1.01; 95% confidence interval, 0.96–1.05; P = 0.91; OR, 1.03; 95% CI, 0.99–1.08; P = 0.50; OR, 0.94; 95% CI, 0.86–1.03; P = 0.53; OR, 0.99; 95% CI, 0.94–1.04; P = 0.99; OR, 0.98; 95% CI, 0.91–1.04; P = 0.94; OR, 0.98; 95% CI, 0.91–1.04; P = 0.99; β, −0.0019; 95% CI, 0.97–1.01; P = 0.99. The IVW and weighted median methods also yielded consistent results, and no heterogeneity or pleiotropy was found. Likewise, a reverse Mendelian randomization analysis did not uncover a heritable causal relationship between AS and CVD.ConclusionThis Mendelian randomization study does not support a causal relationship between AS and CVD. Further research is needed to confirm this association.

Beta-alanine is an important amino acid involved in several metabolic reactions in the body. The study aimed to investigate the effect of β-alanine supplementation on intestinal development and the immune performance of weaned piglets. Thirty-two 21-day-old healthy weaned piglets (half female and half male; Duroc × Landrace × Yorkshire) with an initial body weight of 8.11 ± 0.21 kg were randomly divided into 4 groups with 8 replicates of 1 pig each. The control group was fed a basal diet and the three experimental treatment groups were fed diets supplemented with 300, 600 and 1,200 mg/kg β-alanine, respectively. The trial lasted 28 days and the diets fed were divided into 2 phases: the late lactation period (day 1 to 14) and the nursery period (day 15 to 28), during which the weaned piglets had free access to food and water. The regulatory effects of β-alanine were further investigated in vitro using organoids obtained from the jejunum of piglets. In vivo, the addition of β-alanine to the diet had no significant effect on the growth performance of weaned piglets (P > 0.05), but significantly reduced serum levels of immunoglobulin G (IgG) (P

Objective: To explore the clinicopathological features of solitary fibrous tumors (SFTs) of the lung. Methods: We collected the clinical data of 52 patients with SFTs of the lung confirmed by pathology, and summarized the clinical, radiological, and morphological features, the immunophenotypes, and the prognosis of SFTs. Results: Fifty-two cases of SFTs of the lung were enrolled in this study, including 51 cases of borderline and 1 case of malignancy, 22 males and 30 females. The average onset age was 52.7 years. The lower lobe of the left lung was the preferred site of SFTs, accounting for 30.77% (16/52). Chest CT showed regular and well-demarcated soft tissue density mass, and the tumor size of most cases (46/52, 88.46%) was 1–10 cm. Morphological features: The distribution of tumor cells showed sparse and dense areas. Tumor cells were spindle-shaped, in whorls or hemangiopericytoma-like conformation. Atypia, mitotic figures, and necrosis were found. Immunohistochemistry showed positive expression of CD34, STAT6, Vimentin, BCL2, and CD99. Ki-67 was ≤ 5% in borderline SFTs and >20% in a malignant SFT. Conclusions: Solitary fibrous tumors of the lung occur more frequently in middle-aged and elderly people, and there is no significant difference in gender. The lower lobe of the left lung is the preferred site of SFTs. The size of most SFTs is 1–10 cm. Chest CT shows morphologically regular and well-demarcated soft tissue density mass. Pathologically, SFTs of the lung are mostly borderline and occasionally malignant. Immunohistochemistry shows the positive expression of CD34, STAT6, Vimentin, BCL2, and CD99.

More and more attention has been paid to research on variable geometry turbine engines with the increasing improvement of performance requirements for military turbines. Due to the fixed working angle of the inlet guide vane, the performance of a conventional fixed geometry turbine is optimal only for turbines near the design point. To match the aircraft’s starting, climbing, cruising, deceleration, landing and other working states, it is necessary to change the turbine speed. This will not only reduce the performance of the turbine but also increase the fuel loss. The variable geometry turbine is a perfect solution to this problem. It is not necessary to change the speed of the turbine, but only the working angle of the inlet rotating guide vane of the turbine. The variable geometry turbine can be matched to each state of the aircraft’s entire voyage. The turbine guide vane can be adjusted by 7° to bring about a 10% change in the flow rate of the entire machine. With constant turbine inlet temperature, the fuel loss can be effectively reduced. The rotating guide vane is impacted by the high-temperature and high-pressure gas and cold air in the inner culvert. Hot and cold air produce two types of aerodynamic torque on the rotating guide vane. There is also a friction torque on the rotating shaft of the guide vane. Therefore, the rotating guide vanes of variable geometry turbines are subjected to three types of torques. The main objective of this paper is to study three factors influencing the guide vane torque in the main flow path. The three influencing factors are the turbulence intensity of the gas, the flow ratio of cold gas to hot gas and the location distribution of the gas film holes on the guide vane. In this paper, CFD temperature-fluid-solid coupling algorithm combined with UDF program is applied to solve the torque of guide vane shaft at three influencing factors. The results show that the three factors, turbulence intensity, flow ratio and air film hole distribution, can have a significant effect on the guide vane torque. This is of great significance for the research and design of variable geometry turbines.

Thirty-six healthy 21-day-old weaned ternary piglets (Duroc × Landrace × Yorkshire) were randomly divided into two treatments with 18 replicates per treatment and one pig per replicate. The control group was fed with a basal diet and the test group was fed with diets supplemented with 1 kg/t tea residue. The test period was 28 days. The results are as follows: The addition of tea residue in the diet had no significant effect on the growth performance of weaned piglets (p > 0.05), but it could significantly reduce the diarrhea rate of piglets from 1 to 7 days and 1 to 28 days (p < 0.05). Compared with the control group, the dietary supplementation of tea residue had no significant effect on nutrient apparent digestibility, plasma biochemical indexes and plasma immune indexes (p > 0.05) but increased the content of glutathione in plasma (p < 0.05). Tea residue had no significant effect on the morphology of the jejunum and ileum of piglets (p > 0.05), but it could significantly reduce the content of chloride ions in feces (p < 0.05). Compared with the basal diet group, there was no significant difference in the relative expression of TMEM16A and CFTR mRNA in the colon of weaned piglets (p > 0.05). The whole-cell patch clamp recording showed that the TMEM16A and CFTR ion channels could be activated by ionomycin and forskolin, respectively. However, when HT-29 cells transfected with TMEM16A and CFTR channels were treated with tea residue extract, it could significantly inhibit the chloride current of the TMEM16A and CFTR ion channels (p < 0.05).

Background: 3M syndrome is a rare autosomal recessive disease, characterized by intrauterine and postnatal growth retardation, facial dysmorphism, large head circumference, and skeletal changes, has rarely been reported in the Chinese population.Methods: We describe the clinical manifestations and gene variants in four sporadic cases of 3M syndrome in Chinese individuals from different families.Results: All cases had significant growth retardation, relative macrocephaly, and typical facial features. Exome sequencing revealed that two patients with 3M syndrome had homozygous variants of the CUL7 gene: one novel pathogenic variant and one previously reported pathogenic variant; the other two patients were heterozygous for variants in OBSL1, one of which had not been reported previously. Clinical evaluation indicated that these Chinese patients with 3M syndrome shared similar recognizable features with those reported in patients of other ethnic backgrounds, but not all patients with 3M syndrome in this study had normal development milestones. Two patients underwent recombinant human growth hormone (rhGH) therapy and showed accelerated growth in the first 2 years; however, the growth rate slowed in the third year in one case. There were no obvious adverse reactions during rhGH treatment.Conclusion: We report one novel CUL7 and one novel OBSL1 mutation in patients with 3M syndrome. Children with short stature, specific facial features, and physical symptoms should be referred for genetic testing to obtain precise diagnosis and appropriate treatment. The effects of rhGH treatment on adult height requires long-term observation and study in a large sample.

Objective To explore the role and value of applied muscle tension (AMT) in preventing vasovagal nerve reaction (VVR) in blood donors. Methods A total of 2 992 people, susceptible to suffer VVR from May 2020 to may 2022, were randomly divided into control group (1406 cases) and observation group (1 586 cases). The control group was not given AMT intervention, while the observation group received AMT intervention at different periods during blood donation. The changes of systolic blood pressure, diastolic blood pressure, heart rate and psychological state of anxiety (self-rating anxiety scale, SAS) of blood donors were monitored in the two groups at each period to compare the occurrence of VVR. Results There were no statistically significant differences in blood pressure and heart rate between the two groups before blood donation (P>0.05). The parameters were relatively stable in observation group during and after donation, but significantly different from that of the controls(P>0.05). SAS score was similar in two groups before blood donation(P>0.05), while decreased in observation group during and after donation in comparison with the controls(P

Abstract Background To evaluate the effectiveness of individualized-dose polyethylene glycol recombinant human growth hormone (PEG-rhGH) for short stature. Methods This real-world study enrolled children with short stature in 19 hospitals throughout China. They were treated with PEG-rhGH for 6 months. The starting dosage ranged from 0.10 to 0.20 mg/kg/week. The primary outcome was the change in height standard deviation score (ΔHt SDS). Results Five hundred and ten patients were included and grouped based on dosage as A (0.10–0.14 mg/kg/week), B (0.15–0.16 mg/kg/week), C (0.17–0.19 mg/kg/week), and D (0.20 mg/kg/week). The mean 6-month ΔHt SDS for the total cohort was 0.49 ± 0.27, and the means differed among the four dose groups (P = 0.002). The ΔHt SDS was lower in group A than in groups B (LSM difference [95%CI], -0.09 [-0.17, -0.01]), C (LSM difference [95%CI], -0.10 [-0.18, -0.02]), and D (LSM difference [95%CI], -0.13 [-0.21, -0.05]) after adjusting baseline covariates. There were no significant differences among groups B, C, and D. When the baseline IGF-1 was 0 SDS, the △Ht SDS was not different among the four groups (P = 0.931 and P = 0.400). In children with baseline IGF-1 SDS of -2 ~ 0 SDS, a higher dosage was associated with a better treatment effect (P = 0.003), and the △Ht SDS was lower in older children than in younger ones (P

Abstract Background Few studies have investigated the differences in clinical features of patients with mastitis following Corynebacterium kroppenstedtii infection, and most focused on the bacterial antimicrobial susceptibility, detection methods and therapy. Methodology There were 133 patients with mastitis infected by C. kroppenstedtii between August 2016 and September 2019. C. kroppenstedtii was identified using mass spectrometry. The demographics, clinical diagnosis, laboratory test results of different types of mastitis combined with bacillus infection, and the effects of different treatments in reducing recurrence were compared. Results The incidence of pus following C. kroppenstedtii infection was higher in patients with non-granulomatous lobular mastitis (NGLM; 56.6%) than in those with granulomatous lobular mastitis (GLM; 33.3%; χ2 = 7.072, p = 0.008). While C-reactive protein (CRP) was higher in the GLM group (12.50 mg/L) than in the NGLM group (6.05 mg/L; Z = − 2.187, p = 0.029). Treatment with local lavage (triamcinolone acetonide) and antibiotics (cefuroxime) showed a recurrent rate of 25.9% in C. kroppenstedtii infection. Conclusion Increased pus, large masses, and an elevated CRP level may occur in patients with mastitis infected by C.kroppenstedtii. These clinical features may guide the determination of the bacterial infection in patients with mastitis. Combining an antibiotic with a triamcinolone acetonide lavage, preferably cefuroxime, may reduce the recurrence.

ABSTRACT Recent evidence emphasized the role of the microbiota in the etiopathogenesis of rheumatoid arthritis (RA). Indeed, it has been demonstrated that urinary tract infections are implicated in RA pathogenesis. However, a definitive association between the urinary tract microbiota and RA remains to be investigated. Urine samples from 39 patients affected by RA, including treatment-naive patients, and 37 age- and sex-matched healthy individuals were collected. In RA patients, the urinary microbiota showed an increase in microbial richness and a decrease in microbial dissimilarity, especially in treatment-naive patients. A total of 48 altered genera with different absolute quantities were detected in patients with RA. The 37 enriched genera included Proteus, Faecalibacterium, and Bacteroides, while the 11 deficient genera included Gardnerella, Ruminococcus, Megasphaera, and Ureaplasma. Notably, the more abundant genera in RA patients were correlated with the disease activity score of 28 joints-erythrocyte sedimentation rates (DAS28-ESR) and an increase in plasma B cells. Furthermore, the altered urinary metabolites, such as proline, citric acid, and oxalic acid, were positively associated with RA patients, and they were closely correlated with urinary microbiota. These findings suggested a strong association between the altered urinary microbiota and metabolites with disease severity and dysregulated immune responses in RA patients. IMPORTANCE We revealed that the profile of the urinary tract microbiota in RA featured with increased microbial richness and shifted taxa, associated with immunological and metabolic changes of the disease, underlining the interplay between urinary microbiota and host autoimmunity.

Abstract Background Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate‐frequency and low‐intensity electric field and can lead to the development of novel therapeutic options. Recent Findings A series of biological processes induced by TTFields to exert anti‐cancer effects have been identified. Recent studies have shown that TTFields can alter the bioelectrical state of macromolecules and organelles involved in cancer biology. Massive alterations in cancer cell proteomics and transcriptomics caused by TTFields were related to cell biological processes as well as multiple organelle structures and activities. This review addresses the mechanisms of TTFields and recent advances in the application of TTFields therapy in malignant brain tumors, especially in glioblastoma (GBM). Conclusions As a novel therapeutic strategy, TTFields have shown promising results in many clinical trials, especially in GBM, and continue to evolve. A growing number of patients with malignant brain tumors are being enrolled in ongoing clinical studies demonstrating that TTFields‐based combination therapies can improve treatment outcomes.

Tumor-associated macrophages (TAMs) are closely related to tumorigenesis and metastasis of multiple cancer types. The infiltration of TAMs is used for predicting the prognosis of cancers, including colorectal cancer (CRC). However, the density and prognostic significance of M1 and M2 TAM phenotypes in the intratumor versus the invasive front (IF) are largely unknown in CRC. In this study, CD68 was selected as a general marker of TAMs, CD11c, NOS2 and CXCL10 as markers for M1 phenotype and CD163, CD206, CD115 as markers for M2 phenotype. Firstly, immunohistochemistry staining and double-labeling immunofluorescence staining showed that M1 molecular markers (NOS2, CXCL10, CD11c) were lowly expressed at both IF and intratumor, while M2 molecular markers (CD163, CD206, CD115) were highly expressed mainly at IF. Moreover, we also demonstrated that three M1 molecular markers including NOS2, CXCL10 and CD11c were correlated to each other. Meanwhile, three M2 molecular markers including CD163, CD206, and CD115 were also correlated to each other. Patients with low expression of three M1 molecular markers (NOS2/CXCL10/CD11c) exhibited low overall survival (OS) rate, whereas patients with high expression of three M2 molecular markers (CD163/CD206/CD115) exhibited low OS rate. We also observed that the prognostic value of treble markers combination (NOS2/CXCL10/CD11c or CD163/CD206/CD115) was superior to that of single marker. Together, our results reveal the combination of treble TAMs markers (NOS2/CXCL10/CD11c or CD163/CD206/CD115) could better evaluate the prognosis of CRC patients, which might be used as a more comprehensive method for predicting the prognosis of CRC patients.

Melastoma, consisting of ~100 species diversified in tropical Asia and Oceania in the past 1-2 million years, represents an excellent example of rapid speciation in flowering plants. Trichomes on hypanthia, twigs and leaves vary markedly among species of this genus and are the most important diagnostic traits for species identification. These traits also play critical roles in contributing to differential adaptation of these species to their own habitats. Here we sequenced the genome of M. candidum, a common, erect-growing species from southern China, with the aim to provide genomic insights into trichome evolution in this genus. We generated a high-quality, chromosome-level genome assembly of M. candidum, with the genome size of 256.2 Mb and protein-coding gene number of 40,938. The gene families specific to, and significantly expanded in Melastoma are enriched for GO terms related to trichome initiation and differentiation. We provide evidence that Melastoma and its sister genus Osbeckia have undergone two whole genome duplications (WGDs) after the triplication event (γ) shared by all core eudicots. Preferential retention of trichome development-related transcription factor genes such as C2H2, bHLH, HD-ZIP, WRKY, and MYB after both WGDs might provide raw materials for trichome evolution and thus contribute to rapid species diversification in Melastoma. Our study provides candidate transcription factor genes related to trichome evolution in Melastoma, which can be used to evolutionary and functional studies of trichome diversification among species of this genus.

Abstract Background Tumor budding is included in the routine diagnosis of colorectal cancer (CRC) and is considered a tumor prognostic factor independent of TNM staging. This study aimed to identify the fibroblast-mediated effect of tumor bud-derived C–C chemokine ligand 5 (CCL5) on the tumor microenvironment (TME). Methods Recruitment assays and a human cytokine array were used to detect the main cytokines that CRC tumor buds secrete to recruit fibroblasts. siRNA transfection and inhibitor treatment were used to investigate the role of fibroblast CCL5 receptors in fibroblast recruitment. Subsequently, transcriptome sequencing was performed to explore the molecular changes occurring in fibroblasts upon stimulation with CCL5. Finally, clinical specimens and orthotopic xenograft mouse models were studied to explore the contribution of CCL5 to angiogenesis and collagen synthesis. Results Hematoxylin–eosin staining and immunochemistry revealed a higher number of fibroblasts at the invasive front of CRC tissue showing tumor budding than at sites without tumor budding. In vitro experiments demonstrated that CCL5 derived from tumor buds could recruit fibroblasts by acting on the CCR5 receptors on fibroblasts. Tumor bud-derived CCL5 could also positively regulate solute carrier family 25 member 24 (SLC25A24) expression in fibroblasts, potentially activating pAkt-pmTOR signaling. Moreover, CCL5 could increase the number of α-SMAhigh CD90high FAPlow fibroblasts and thus promote tumor angiogenesis by enhancing VEGFA expression and making fibroblasts transdifferentiate into vascular endothelial cells. Finally, the results also showed that CCL5 could promote collagen synthesis through fibroblasts, thus contributing to tumor progression. Conclusions At the invasive front of CRC, tumor bud-derived CCL5 can recruit fibroblasts via CCR5-SLC25A24 signaling, further promoting angiogenesis and collagen synthesis via recruited fibroblasts, and eventually create a tumor-promoting microenvironment. Therefore, CCL5 may serve as a potential diagnostic marker and therapeutic target for tumor budding in CRC.

Cdc42-interacting protein 4 (CIP4), a member of the F-BAR family, which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and be closely associated with tumor invadopodia formation. In this study, we found that CIP4 expression was significantly higher in human CRC tissues and correlated with the CRC infiltrating depth and metastasis, as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability in vitro and tumor metastasis in vivo, while the overexpression of CIP4 promoted invadopodia formation and matrix degradation ability. We then identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression of CRC cells contributing to invadopodia formation, while the inhibition of either CIP4 or Cdc42 led to the suppression of the NF-κB pathway and resulted in a decreased quantity of invadopodia. Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis.

Abstract Background Basic life support and advanced life support are essential emergency management skills for medical workers, and pediatricians' first aid skills can be improved through emergency knowledge training. Methods A controlled pre–post-intervention quasi-experimental study design was used. The study setting was a tertiary children's hospital in China. In November 2019, a KSS model of emergency knowledge learning was developed and tested, and pediatric medical workers (N = 1448) were trained with it. The outcome measures were based on an emergency knowledge questionnaire devised by the authors that measured the effectiveness of training by comparing the pre-and post-training scores of the particpants. Results Pediatric medical workers scored significantly higher in total emergency knowledge after the training course than before [75.00 (62.50, 85.00) versus 100.00 (95.00, 100.00); P = 0.00]. Basic life support and advanced life support knowledge score significantly improved after training. Teamwork scores were significantly higher after the training than before [5.00 (5.00, 10.00) versus 10.00 (10.00, 10.00); P = 0.00]. Scores were significantly higher after the training (P

Leaf epidermal characteristics are important for phylogenetic and taxonomic studies of many plants, but there is currently insufficient such data for this application in Zingiber species. Therefore, the leaf epidermal micromorphology of 22 species in three sections of Zingiber was investigated by light microscopy and scanning electron microscopy. Differences between various taxonomic groups of Zingiberaceae were also compared to assess their phylogenetic and taxonomic significance. As in other genera of Zingiberaceae, the epidermal cells in both the adaxial and abaxial epidermis of Zingiber species were found to be hexagonal or polygonal, with non-sinuous anticlinal walls that are arranged parallel to leaf veins. Tetracytic stomata are mostly randomly distributed in the intercostal regions of both surfaces and are more common on the abaxial surface. The stomatal density of the species in sect. Pleuranthesis is significantly lower than that in sects. Zingiber and Cryptanthium. There are two types of trichome in Zingiber: so-called “delicate” trichomes are present in most species, while “stout” trichomes with a swollen base are only found in Z. corallinum and Z. montanum. Oil cells occur in both epidermal layers of some species in sects. Zingiber and Cryptanthium, but only in the abaxial epidermis of Z. ellipticum in sect. Pleuranthesis. Crystals are found in the abaxial epidermis only in all species, but are present in both epidermal layers of Z. corallinum and Z. montanum. Although the epidermal morphology is similar in most Zingiber species, stomatal density, type of trichome and distribution of oil cells and crystals offer valuable information for the systematic and taxonomic studies in this genus.

The walnut (Juglans regia L.) is an important economic tree worldwide, often cultivated in arid and semiarid regions. Improving the drought tolerance is of significance for walnut growth, production, and economic effectiveness. 5-Aminolevulinic acid (ALA) is a novel plant growth regulator which raises plant tolerance to various stressful conditions. Here, foliage application of ALA was carried out to uncover its effect on walnuts under polyethylene glycol (PEG) 6000-stimulated osmotic stress. Our results displayed that exogenous ALA greatly promoted the chlorophyll content, photochemical activities, and gas exchange in walnuts under osmotic stress. ALA led to a considerable accumulation of compatible osmotic solutes, enabling walnuts to maintain osmotic equilibrium against drought stress. Furthermore, ALA alleviated the reactive oxygen species (ROS) damages on osmotically stressed walnuts through enhancing the antioxidant enzyme activities, as well as decreasing the ROS and malondialdehyde (MDA) content. The relative water content (RWC) in the ALA-treated leaves was higher than that of PEG-stressed, while the RWC in the substrate of ALA treatment was significantly lower than that of the PEG-stressed, further suggesting that ALA promotes plant water uptake from the substrate under osmotic stress. These demonstrate that ALA improves the photosynthesis, osmotic adjustment, antioxidant systems and, consequently, the walnuts’ drought tolerance.

The review briefly introduces the natural occurrence, physicochemical properties, and biosynthesis of 5-aminolevuinic acid (ALA) and highlights a variety of applications in the planting industry and its possible mechanisms. It has been known that ALA can be used as biological pesticides, fungicides, and herbicides when the concentrations are higher than 838 mg L−1 (about 5 mmol L−1). When ALA concentrations are 100–300 mg L−1, it can be used to thin surplus flowers in the spring of orchards and promote fruit coloration before maturation. When the concentrations are lower than 100 mg L−1, especially not higher than 10 mg L−1, ALA can be used as a new plant growth regulator to promote seed germination, plant (including root and shoot) growth, enhance stress tolerance, increase crop yield, and improve product quality. In photosynthesis, ALA is involved in the regulation of the whole process. In stress tolerance, ALA induces plant preventive and protective systems through the NO/H2O2 signaling network. In secondary metabolism, ALA regulates many gene expressions encoding transcription factors or function proteins to promote anthocyanin and flavonol biosynthesis and accumulation. In general, ALA promotes plant health and robustness, reduces the use of chemical fertilizers and pesticides—which is conducive to improving the ecological environment, human production, and living conditions—and has a broad application prospect in agroforestry production. As a new plant growth regulator with multiple and powerful functions, the underlying regulatory mechanisms need more study.

Sugars and organic acids significantly impact fruit sensory quality, but their accumulation patterns and regulatory mechanisms during the development of Rosa roxburghii fruit are still unclear. We utilized transcriptomics and metabolomics to investigate genes related to sugar and organic acid metabolism in Rosa roxburghii. Metabolomics data revealed that sucrose, glucose and fructose were the primary sugars, whereas citric acid and malic acid were the primary organic acids in Rosa roxburghii fruit. We constructed the metabolic pathways of major sugars and organic acids in Rosa roxburghii and identified five key genes involved in sugar and organic acid synthesis. In addition, we identified a module containing 132 transcription factors that was significantly associated with sucrose, citric acid and malic acid. Based on quantitative polymerase chain reaction (qPCR), we identified 13 transcription factors involved in sugar and organic acid metabolism, including the transcription factor RrANL2 and the sucrose synthase gene RrSUS3. Further yeast one-hybrid and dual luciferase assays showed that RrANL2 could bind to the promoter of RrSUS3 to increase its expression. These results provide new insights into the metabolism of sugars and organic acids in Rosa roxburghii fruit.

ObjectivesThe aim of the current study is to explore the association between extended adjuvant endocrine treatment and prognosis of women with hormone receptor-positive (HR+) early breast cancer.MethodsDatabases including PubMed, Web of Science, Embase and the Cochrane Library databases were electronically searched to identify randomized controlled trials (RCTs) that reported extended endocrine therapy for women with HR+ early breast cancer. The retrieval time was limited from inception to September 2022. Two reviewers independently screened literature, extracted data, and assessed risk bias of included studies. Meta-analysis was performed by using R software Version 4.1.2 and STATA Version 12.0.ResultsA total of 15 RCTs involving 29497 cases were included. The overall analysis showed that compared with the control, extended adjuvant endocrine therapy increased disease-free survival (DFS) (HR=0.814, 95% CI: 0.720-0.922, 95% PI: 0.556-1.194), overall survival (OS) (HR=0.885, 95% CI: 0.822-0.953, 95% PI: 0.771-1.035), relapse-free survival (RFS) (HR=0.833, 95% CI: 0.747-0.927, 95% PI: 0.575-1.159), distant metastatic-free survival (DMFS) (HR=0.824, 95% CI: 0.694-0.979, 95% PI: 0.300-2.089) and reduced new breast cancer cumulative incidence (NBCCI) (HR=0.484, 95% CI: 0.403-0.583, 95% PI: 0.359-0.654). For adverse events, extended adjuvant endocrine treatment was associated with a significantly higher risk of bone fracture (RR=1.446, 95% CI: 1.208-1.730, 95% PI: 1.154-1.854) and osteoporosis (RR=1.377, 95% CI: 1.018-1.862, 95% PI: 0.347-5.456).ConclusionOur study showed that extended adjuvant endocrine therapy increased DFS, OS, RFS, DMFS, the incidence of bone fracture and osteoporosis, and reduced NBCCI.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier (CRD42022351295)

Abstract Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin‐21 (IL‐21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL‐6 and IL‐21 receptors, thereby inhibiting the bindings of IL‐6 and IL‐21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides‐mediated immunomodulation.

Vascular calcification (VC) is an important hallmark of cardiovascular disease, the osteo-/chondrocyte phenotype differentiation of vascular smooth muscle cells (VSMCs) is the main cause of vascular calcification. Accumulating evidence shows that mitochondrial dysfunction may ultimately be more detrimental in the VSMCs calcification. Mitochondrial participate in essential cellular functions, including energy production, metabolism, redox homeostasis regulation, intracellular calcium homeostasis, apoptosis, and signal transduction. Mitochondrial dysfunction under pathological conditions results in mitochondrial reactive oxygen species (ROS) generation and metabolic disorders, which further lead to abnormal phenotypic differentiation of VSMCs. In this review, we summarize existing studies targeting mitochondria as a treatment for VC, and focus on VSMCs, highlighting recent progress in determining the roles of mitochondrial processes in regulating the phenotype transition of VSMCs, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial energy metabolism, and mitochondria/ER interactions. Along these lines, the impact of mitochondrial homeostasis on VC is discussed.

Abstract Background Rivers and streams facilitate movement of individuals and their genes across the landscape and are generally recognized as dispersal corridors for riparian plants. Nevertheless, some authors have reported directly contrasting results, which may be attributed to a complex mixture of factors, such as the mating system and dispersal mechanisms of propagules (seed and pollen), that make it difficult to predict the genetic diversity and population structure of riparian species. Here, we investigated a riparian self-fertilizing herb Caulokaempferia coenobialis, which does not use anemochory or zoochory for seed dispersal; such studies could contribute to an improved understanding of the effect of rivers or streams on population genetic diversity and structure in riparian plants. Using polymorphic ISSR and cpDNA loci, we studied the effect at a microgeographic scale of different stream systems (a linear stream, a dendritic stream, and complex transverse hydrological system) in subtropical monsoon forest on the genetic structure and connectivity of C. coenobialis populations across Dinghu Mountain (DH) and Nankun Mountain (NK). Results The results indicate that the most recent haplotypes (DH: H7, H8; NK: h6, h7, h11, h12) are not shared among local populations of C. coenobialis within each stream system. Furthermore, downstream local populations do not accumulate genetic diversity, whether in the linear streamside local populations across DH (H: 0.091 vs 0.136) or the dendritic streamside local populations across NK (H: 0.079 vs 0.112, 0.110). Our results show that the connectivity of local C. coenobialis populations across DH and NK can be attributed to historical gene flows, resulting in a lack of spatial genetic structure, despite self-fertilization. Selfing C. coenobialis can maintain high genetic diversity (H = 0.251; I = 0.382) through genetic differentiation (G ST = 0.5915; F ST = 0.663), which is intensified by local adaptation and neutral mutation and/or genetic drift in local populations at a microgeographic scale. Conclusion We suggest that streams are not acting as corridors for dispersal of C. coenobialis, and conservation strategies for maintaining genetic diversity of selfing species should be focused on the protection of all habitat types, especially isolated fragments in ecosystem processes.

Mitogenomes of most flowering plants evolve slowly in sequence, but rapidly in structure. The rearrangements in structure are mainly caused by repeat-mediated recombination. However, patterns of repeat-mediated recombination vary substantially among plants, and to provide a comprehensive picture, characterization of repeat-mediated recombination should extend to more plant species, including parasitic plants with a distinct heterotrophic lifestyle. Here we assembled the mitogenome of the holoparasitic plant Aeginetia indica (Orobanchaceae) using Illumina sequencing reads. The mitogenome was assembled into a circular chromosome of 420,362 bp, 18,734 bp longer than that of another individual of A. indica which was assembled before as a linear molecule. Synteny analysis between the two mitogenomes revealed numerous rearrangements, unique regions of each individual and 0.2% sequence divergence in their syntenic regions. The A. indica mitogenome contains a gene content typical of flowering plants (33 protein-coding, 3 rRNA, and 17 tRNA genes). Repetitive sequences >30 bp in size totals 57,060 bp, representing 13.6% of the mitogenome. We examined recombination mediated by repeats >100 bp in size and found highly active recombination for all the repeats, including a very large repeat of ~16 kb. Recombination between these repeats can form much smaller subgenomic circular chromosomes, which may lead to rapid replication of mitochondrial DNA and thus be advantageous for A. indica with a parasitic lifestyle. In addition, unlike some other parasitic plants, A. indica shows no evidence for horizontal gene transfer of protein-coding genes in its mitogenome.

Chromoblastomycosis (CBM) is a chronic fungal infection of the cutaneous and subcutaneous tissues caused by brown pigmented fungi. Fonsecaea monophora is one of the most common pathogens of CBM in China. Most formal cases have been reported from Southern China, however, the infection is not uncommon in Eastern China where very few case series are available. To describe the clinical aspects of CBM, we report a series of 11 cases between 2018 and 2021 at a single medical center in Eastern China. The patients were predominately male (n = 9) and the disease duration ranged from 3 months to 20 years. Plaque type lesions were the most common clinical manifestations. There were 7 cases of mild forms and 3 cases of severe forms. Among the 3 severe cases, one case gave up treatment due to economic poverty; one case did not respond to a 1-year systemic treatmen; one case was cured by combination therapy of 10 months. Other cases were cured by treatment with antifungal agents. All cases of direct mycological examination were positive. All isolates were identified by morphology and sequencing of the the ITS regions of ribosomal DNA, Ten were F. monophora and 1 was Cladophialophora carrionii. All cases had been evaluated at other clinics, where 8 cases were misdiagnosed as other diseases. As a neglected tropical disease (NTD), CBM is still a major challenge in the field of dermatology, especially in its severe clinical forms. As an effective and simple diagnostic method of CBM, direct microscopic examination should be further promoted in rural hospitals.

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1β, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.

ObjectiveTo investigate whether radiomics can help radiologists and thoracic surgeons accurately predict invasive adenocarcinoma (IAC) manifesting as part-solid nodules (PSNs) with solid components