Notable Enrichment Research Articles

Effect of potato glycoside alkaloids on mitochondria energy metabolism of Fusarium solani, the root rot pathogen of Lycium barbarum

Fusarium solani is a widely distributed pathogenic fungus that can cause soil borne diseases in various plants and is also one of the main pathogenic bacteria of Lycium barbarum root rot. This study employed tandem mass labeling (TMT) quantitative proteomics technology to investigate the antifungal mechanism of potato glycoside alkaloids (PGA) against Fusarium solani. We elucidated the antifungal mechanism of PGA from the perspective of mitochondrial proteome molecular biology. Furthermore, we identified and annotated the differentially expressed proteins (DEP) of F. solani under PGA stress. A total of 2,412 DEPs were identified, among which 1,083 were significantly up-regulated and 1,329 significantly down-regulated. Subsequent analysis focused on five DEPs related to energy metabolism for verification at both protein and gene levels. Gene Ontology (GO) function analysis revealed that the DEPs were primarily involved in the integral component of the membrane, intrinsic component of the membrane, pyridine-containing compound metabolic processes, carbon-oxygen lyase activity, and the endoplasmic reticulum, with a notable enrichment in membrane components. Furthermore, a total of 195 pathways were identified through KEGG analysis, with significant enrichment in critical pathways including pentose and glucuronate interconversions, propanoate metabolism, various types of N-glycan biosynthesis, the pentose phosphate pathway, and carbon fixation in photosynthetic organisms. The results from both parallel reaction monitoring (PRM) and real-time RT-qPCR were consistent with the overall trends observed in TMT proteomics, thereby confirming the validity of the TMT proteomics analysis. These findings indicate that PGA inhibits the growth of F. solani by impacting mitochondrial energy metabolism. This study reveals the antifungal mechanism of PGA from the perspective of energy metabolism, providing a theoretical basis for the development and application of PGA as a biopesticide.

P0137 Primary bile acids promote epithelial necroptosis via Stat1 signaling

Abstract Background Gut barrier dysfunction and microbial dysbiosis play a crucial role in the pathogenesis of Inflammatory Bowel Disease (IBD), including Ulcerative colitis (UC) and Crohn´s disease (CD)1. Although IBD is marked by dynamic changes in the intestinal microbiome, little is known about the corresponding changes in the gut metabolism, the molecular interface between the host and its microbiota. In CD, changes in bile acid (BA) metabolism and composition have been observed, with a notable the enrichment of the primary BA chenodeoxycholic acid (CDCA) specifically in CD2, suggesting a potential involvement in disease pathogenesis. However, it is still poorly understood how BAs influence epithelial homeostasis. Methods Serum bile acid (BA) profiles of CD patients and healthy controls were analyzed using BA-targeted metabolomics. Data normalization and statistical analyses were performed to identify significant differences in BA composition between groups. Human ileal organoids were established from biopsy samples obtained from CD patients, while murine small intestinal organoids were derived from wildtype, Stat1-/-, and farnesoid X receptor (FXR) deficient mice. Bulk RNA sequencing was performed on organoids treated with CDCA to investigate transcriptional changes and identify molecular mechanisms underlying CDCA-induced toxicity. A cell death inhibitor screen was applied to delineate the pathways contributing to CDCA-induced IEC toxicity. Results Our findings reveal a significant difference in BA profiles between CD patients and healthy controls, with a notable enrichment of the primary BA, CDCA, in CD patients. CDCA exerts a pronounced toxic effect on both human and murine small intestinal organoids (SIO) in a dose-dependent manner, whereas the secondary BA, deoxycholic acid (DCA), does not. Importantly, the cytotoxicity of CDCA was markedly reduced when it was conjugated with glycine or taurine, suggesting that conjugation mitigates CDCA's impact on IEC viability. Mechanistically, CDCA disrupts BA signaling pathways, enhances the interferon (IFN) response, and activates cell death pathways within SIO models. CDCA specifically promotes epithelial necroptosis via STAT1 signaling, highlighting a pathway through which CDCA may exacerbate epithelial damage in CD. Therapeutically, both tofacitinib (Tofa) and glucocorticoids (GCs) demonstrate a protective effect, significantly suppressing the CDCA-induced IFN response. These findings suggest that modulation of BA signaling and inhibition of the IFN response may be promising strategies to protect intestinal epithelial integrity in CD patients. Conclusion These findings suggest that modulation of BA signaling may be promising strategies to protect intestinal epithelial integrity in CD patients.

Estrogenic and anti-estrogenic assessment of the flame retardant, 2-ethylhexyl diphenyl phosphate (EHDPP), and its metabolites: Evidence from in vitro, in silico, and transcriptome studies.

2-Ethylhexyl diphenyl phosphate (EHDPP) is a replacement flame-retardant commonly found in several environmental matrices and human biospecimens. Although some adverse effects of EHDPP have been identified, the endocrine-disrupting effects of EHDPP and its key metabolites on the human estrogen receptor (ER) are largely unknown. Herein, we report for the first time that EHDPP, at concentrations found in the environment and humans, significantly promoted estrogenic activity and synergized with 17β-estradiol-induced ER transactivation. However, two major EHDPP metabolites 2-ethyl-3-hydroxyhexyl diphenyl phosphate (3-OH-EHDPP) and 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), inhibited the ER through a non-competitive binding mechanism. Molecular docking showed that Pi-Pi stacking, hydrogen, and hydrophobic bonds primarily stabilize intermolecular interactions between EHDPP and the binding pockets of human ERα and ERβ. Moreover, transcriptome analysis confirmed the estrogenic effects of EHDPP, revealing notable enrichments in ER-mediated signaling and breast cancer pathways, consistent with the validated estrogenic gene expression profile. Intriguingly, EHDPP markedly promoted the clonogenic growth of two ER+ breast cancer cell lines, corroborating the expression levels of ERα protein. Our findings indicate that the common flame-retardant EHDPP activates the ER and downstream signaling, providing far-reaching implications for environmental and health risks associated with estrogen-related adversities such as the development of ER+ breast cancer.

Carbendazim led to neurological abnormalities by interfering metabolic profiles in zebrafish brain after short-term exposure

Carbendazim is an agricultural fungicide and a widely present ecotoxic pollutant, but its damaging effects on the nervous system are not fully understood. Here, we assessed effects of short-term exposure to carbendazim on zebrafish brains. It has been revealed firstly that carbendazim can accumulate in the brain after a 7-day exposure, with the maximum concentration of 68.22 ± 9.84 μg/kg, which caused tissue vacuolization and neuronal damage, then led to a decline in motor behavioral abilities, especially a significant reduction in the distance moved. These changes may be attributed to metabolism abnormalities. Based on metabolomics and lipidomics, substantial alterations were observed in 264 lipids and 135 metabolites, with notable enrichment in 5 metabolic pathways, including glycerophospholipid metabolism, glycerolipid metabolism, and sphingolipid metabolism. To investigate system-level variations, weighted correlation network analysis was utilized to screen for 4 biomarkers strongly associated with carbendazim exposure: citric acid, guanosine-5′-monophosphate, sphingosine, and monoacylglycerol. The alterations of these markers confirmed damages of carbendazim to zebrafish nervous system, further elucidating that metabolic disorders caused by carbendazim in brains led to tissue damage and subsequent changes in motor behavior. This study provides scientific evidence for neurotoxicities of carbendazim and offers new insights into ecological risks.

TFAP2A Activates ADAM8 to Promote Lung Adenocarcinoma Angiogenesis Through the JAK/STAT Signaling Pathway.

As the most prevalent subtype of lung cancer, lung adenocarcinoma (LUAD) is closely associated with angiogenesis, which is fundamental to its progression. ADAM8 (A disintegrin and metalloproteinase 8) is an enzyme associated with tumor invasion, while its implications in LUAD angiogenesis are a field that awaits exploration. A thorough investigation into the impacts of ADAM8 on LUAD angiogenesis could contribute to the development of therapeutic drugs for LUAD. Bioinformatics delineated the expression profiles of TFAP2A and ADAM8 in LUAD tissues, focusing on ADAM8-enriched pathways. qRT-PCR confirmed their expression in LUAD cells. The CCK-8 assay was applied to gauge cell viability, and Western blot detected the presence of JAK2/STAT3 pathway proteins and VEGFR-2 and VEGF. Angiogenesis assays quantified the length of angiogenesis, and dual-luciferase and Chromatin immunoprecipitation assays verified the TFAP2A-ADAM8 binding. ADAM8 exhibited high expression in LUAD tissues and cells, with notable enrichment in the VEGF and JAK/STAT pathways. Cellular assays revealed that elevated ADAM8 expression enhanced cell viability, promoted the phosphorylation of JAK2 and STAT3, and boosted angiogenic capacity. The JAK inhibitor Peficitinib reversed the proangiogenic effects induced by ADAM8 overexpression. We also discovered overexpression of TFAP2A, an upstream transcription factor of ADAM8, in LUAD. Rescue experiments indicated that ADAM8 overexpression could counteract the inhibitory effects of TFAP2A knockdown on LUAD angiogenesis. This study reveals for the first time the critical role of ADAM8 in LUAD angiogenesis, demonstrating that TFAP2A promotes JAK/STAT pathway conduction by activating ADAM8. This finding not only provides a new perspective for understanding the pathogenesis of LUAD but also lays the foundation for the development of new therapies targeting ADAM8.

Explore Alteration of Lung and Gut Microbiota in a Murine Model of OVA-Induced Asthma Treated by CpG Oligodeoxynucleotides.

We sought to investigate the impact of CpG oligodeoxynucleotides (CpG-ODN) administration on the lung and gut microbiota in asthmatic mice, specifically focusing on changes in composition, diversity, and abundance, and to elucidate the microbial mechanisms underlying the therapeutic effects of CpG-ODN and identify potential beneficial bacteria indicative of its efficacy. HE staining were used to analyze inflammation in lung, colon and small intestine tissues. High-throughput sequencing technology targeting 16S rRNA was employed to analyze the composition, diversity, and correlation of microbiome in the lung, colon and small intestine of control, model and CpG-ODN administration groups. (1) Histopathologically, both lung and intestinal tissue in asthmatic mice exhibited significant structural damage and inflammatory response, whereas the structure of both lung and intestinal tissue approached normal levels, accompanied by a notable improvement in the inflammatory response after CpG-ODN treatment. (2) In the specific microbiota composition analysis, bacterial dysbiosis observed in the asthmatic mice, accompanied by enrichment of Proteobacteria found to cause lung and intestinal epithelial damage and inflammatory reaction. After CpG-ODN administration, bacterial dysbiosis was improved, and a notable enrichment of beneficial bacteria, indicating a novel microecology. Meanwhile Oscillospira and Clostridium were identified as two biomarkers of the CpG-ODN treatment. (3) Heatmap analysis revealed significant correlations among lung, small intestine, and colon microbiota. CpG-ODN treatment can ameliorate OVA-induced asthma in mice. One side, preserving the structural integrity of the lung and intestine, safeguarding the mucosal physical barrier, the other side, improving the dysbiosis of lung and gut microbiota in asthmatic mice. Beneficial bacteria and metabolites take up microecological advantages, regulate immune cells and participate in the mucosal immune response to protect the immune barrier. Meanwhile, Oscillospira and Clostridium as biomarkers for CpG-ODN treatment, has reference significance for exploring precise Fecal microbiota transplantation treatment for asthma.

Disentangling the genetic overlap between ischemic stroke and obesity

ObjectiveObesity has been recognized as a risk factor for cerebrovascular diseases, with observational studies suggesting a heightened incidence of stroke. However, the genetic epidemiology field has yet to reach a consensus on the causal relationship and genetic overlap between ischemic stroke (IS) and obesity.MethodsWe utilized linkage disequilibrium score regression, high-definition likelihood, and local analysis of variant associations to assess the genetic correlation between body mass index (BMI) and IS. Bidirectional Mendelian randomization was employed to infer causality. We identified shared risk single nucleotide polymorphisms (SNPs) through cross-trait meta-analyses and estimated heritability using summary statistics. Summary-data-based Mendelian randomization (SMR) was applied to explore potential functional genes.ResultsOur analysis revealed a significant positive genetic correlation between BMI and IS, supporting a causal link from BMI to IS. Cross-trait analysis yielded 9 and 16 shared risk SNPs for IS and small vessel stroke (SVS), respectively. We observed a notable enrichment of SNP heritability for IS and BMI in brain tissues, suggesting tissue-specific influences. The genes shared between the traits were predominantly involved in brain development, synaptic electrical activity, and immunoregulation. Notably, our SMR analysis identified the risk genes CHAF1A, CEP192, ULK4, CYP2D6, AS3MT, and WARS2 across the majority of the 14 enriched tissues shared by both traits.ConclusionOur study uncovered a significant genetic correlation and identified shared risk SNPs between BMI and IS. The identification of CHAF1A, CEP192, ULK4, CYP2D6, AS3MT, and WARS2 as potential functional genes common to both obesity and IS enriched our understanding of their genetic interplay, potentially advanced our grasp of their pathogenesis and therapeutic targets.

Single-cell RNA sequencing reveals the critical role of alternative splicing in cattle testicular spermatagonia

Spermatogonial stem cells (SSCs) form haploid gametes through the precisely regulated process of spermatogenesis. Within the testis, SSCs undergo self-renewal through mitosis, differentiation, and then enter meiosis to generate mature spermatids. This study utilized single-cell RNA sequencing on 26,888 testicular cells obtained from five Holstein bull testes, revealing the presence of five distinct germ cell types and eight somatic cell types in cattle testes. Gene expression profiling and enrichment analysis were utilized to uncover the varied functional roles of different cell types involved in cattle spermatogenesis. Additionally, unique gene markers specific to each testicular cell type were identified. Moreover, differentially expressed genes in spermatogonia exhibited notable enrichment in GO terms and KEGG pathway linked to alternative splicing. Notably, our study has shown that the activity of the YY1 regulation displays distinct expression patterns in spermatogonia, specifically targeting spliceosome proteins including RBM39, HNRNPA2B1, HNRNPH3, CPSF1, PCBP1, SRRM1, and SRRM2, which play essential roles in mRNA splicing. These results emphasize the importance of mRNA processing in spermatogonia within cattle testes, providing a basis for further investigation into their involvement in spermatogonial development.

EHMT2 as a Candidate Gene for an Autosomal Recessive Neurodevelopmental Syndrome.

Neurodevelopmental disorders (NDD) comprise clinical conditions with high genetic heterogeneity and a notable enrichment of genes involved in regulating chromatin structure and function. The EHMT1/2 epigenetic complex plays a crucial role in repression of gene transcription in a highly tissue- and temporal-specific manner. Mutations resulting in heterozygous loss-of-function (LoF) of EHMT1 are implicated in Kleefstra syndrome 1 (KS1). EHMT2 is a gene acting inepigenetic regulation; however, the involvement of mutations in this gene in the etiology of NDDs has not been established thus far. A homozygous EHMT2 LoF variant [(NM_006709.5):c.328 + 2T > G] was identified by exome sequencing in an adult female patient with a phenotype resembling KS1, presenting with intellectual disability, aggressive behavior, facial dysmorphisms, fused C2-C3 vertebrae, ventricular septal defect, supernumerary nipple, umbilical hernia, and fingers and toes abnormalities. The absence of homozygous LoF EHMT2 variants in population databases underscores the significant negative selection pressure exerted on these variants. In silico evaluation of the effect of the EHMT2(NM_006709.5):c.328 + 2T > G variant predicted the abolishment of intron 3 splice donor site. However, manual inspection revealed potential cryptic donor splice sites at this EHMT2 region. To directly access the impact of this splice site variant, RNAseq analysis was employed and disclosed the usage of two cryptic donor sites within exon 3 in the patient's blood, which are predicted to result in either an out-of-frame or in-frame effect on the protein. Methylation analysis was conducted on DNA from blood samples using the clinically validated EpiSign assay, which revealed that the patient with the homozygous EHMT2(NM_006709.5):c.328 + 2T > G splice site variant is conclusively positive for the KS1 episignature. Taken together, clinical, genetic, and epigenetic data pointed to a LoF mechanism for the EHMT2 splice variant and support this gene as a novel candidate for an autosomal recessive Kleefstra-like syndrome. The identification of additional cases with deleterious EHMT2 variants, alongside further functional validation studies, is required to substantiate EHMT2 as a novel NDD gene.

M6A methylation profiling as a prognostic marker in nasopharyngeal carcinoma: insights from MeRIP-Seq and RNA-Seq.

Nasopharyngeal carcinoma (NPC) is a type of malignant tumors commonly found in Southeast Asia and China, with insidious onset and clinical symptoms. N6-methyladenosine (m6A) modification significantly contributes to tumorigenesis and progression by altering RNA secondary structure and influencing RNA-protein binding at the transcriptome level. However, the mechanism and role of abnormal m6A modification in nasopharyngeal carcinoma remain unclear. Nasopharyngeal Carcinoma tissues from 3 patients and non-cancerous nasopharyngeal tissues from 3 individuals, all from Fujian Cancer Hospital, were sequenced for m6A methylation. These were combined with transcriptome sequencing data from 192 nasopharyngeal cancer tissues. Genes linked to prognosis were discovered using differential analysis and univariate Cox regression. Subsequently, a prognostic model associated with m6A was developed through the application of LASSO regression analysis. The model's accuracy was verified using both internal transcriptome databases and external databases. An extensive evaluation of the tumor's immune microenvironment and signaling pathways was performed, analyzing both transcriptomic and single-cell data. The m6A methylation sequencing analysis revealed 194 genes with varying expression levels, many of which are predominantly associated with immune pathways. By integrating transcriptome sequencing data, 19 m6A-modified genes were found to be upregulated in tumor tissues, leading to the development of a three-gene (EME1, WNT4, SHISA2) risk prognosis model. The group with lower risk exhibited notable enrichment in pathways related to immunity, displaying traits like enhanced survival rates, stronger immune profiles, and increased responsiveness to immunotherapy when compared to the higher-risk group. Single-cell analysis revealed that malignant cells exhibited the highest risk score levels compared to immune cells, with a high-risk score indicating worse biological behavior. The three hub genes demonstrated significant correlation with m6A modification regulators, and MeRIP-RT-PCR confirmed the occurrence of m6A methylation in these genes within nasopharyngeal carcinoma cells. A prognostic model for nasopharyngeal carcinoma risk based on m6A modification genes was developed, and its prognostic value was confirmed through self-assessment data. The study highlighted the crucial impact of m6A modification on the immune landscape of nasopharyngeal cancer.

Application of core-shell magnetic metal-organic framework in developing dispersive micro solid phase extraction combined with dispersive liquid-liquid microextraction for the extraction and enrichment of some pesticides in orange blossom, Aloysia Citrodora, and fennel herbal infusions.

This paper introduces an innovative technique for extracting pesticides from herbal infusions using a core-shell magnetic adsorbent (i.e., Cu-BTC@Fe3O4) where achieving a notable enrichment factor for the target pesticides by coupling with a dispersive liquid-liquid microextraction method. To validate the successful synthesis of the adsorbent, a range of analytical techniques were utilized including vibrating sample magnetometer, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, energy dispersive X-ray, and Brunauer-Emmett-Teller analyses. A vortex agitation and an external magnetic field were used during the extraction process to aid the analytes' desorption and adsorbent separation, respectively. Also, a mixture of iso-propanol and deionized water was used to desorb the analytes from the adsorbent surface. The resulting supernatant containing the desorbed pesticides was mixed with 1,2-dibromoethane as the extraction solvent and then injected into an aqueous medium. After centrifugation, 1 μL of the sedimented phase was introduced into the gas chromatograph system equipped with a flame ionization detector. The reliability of the proposed methodology was confirmed by obtaining low relative standard deviations (1.0-8.5 %), acceptable extraction recoveries (39-93 %), substantial enrichment factors (195-475), calibration curve linearity (r2=0.993-0.998), and significantly low limits of quantification (0.34-3.0 μg L-1) and detection (1.1-9.9 μg L-1). Absence of matrix effects with relative recovery values of 80-120 % for real samples, minimal use of the adsorbent and extraction solvent, a reduction in extraction time due to the elimination of two centrifugation steps (facilitated by an external magnetic field), and the use of environmentally friendly solvents collectively highlight the advantages and significant values of this approach.

Tailored recovery of antioxidant fractions enriched in caffeine and phenolic compounds from coffee pulp using ethanol-modified supercritical carbon dioxide

Coffee pulp (CP) is the by-product of coffee processing that urgently needs to be revalorized using sustainable technologies. This work applied a design of experiment (DoE) for modeling the extraction of bioactive compounds from CP using supercritical carbon dioxide (sc-CO2) with ethanol as a co-solvent under variable conditions (temperature, pressure, and ethanol percentage). Considering extraction efficiency (per unit of CP) and extraction selectivity (per unit of extract), results showed that ethanol percentage significantly enhanced the efficiency of total phenolic content, as well as the selectivity of chlorogenic acid and protocatechuic acid (p < 0.05). The effects of temperature and pressure in EtOH-modified sc-CO2 extraction exhibited non-linear patterns, highlighting the interaction between temperature and ethanol. Total phenolic content was responsible for the antioxidant activity of the EtOH-modified sc-CO2 extracts, which was also affected by caffeine in the extracts. The extraction condition that balances both efficiency and selectivity was found at 65 °C, 23 MPa, and 9 % ethanol as co-solvent. The extraction yield (5.8 mg/g CP) was 3.8 times and 6.7 times lower than that of aqueous and ethanolic extraction, respectively, indicating a relatively lower efficiency of sc-CO2. However, the selectivity of caffeine (106.3 mg/g extract) and sum of identified phenolic compounds (16.3 mg/g extract) such as chlorogenic, protocatechuic, and caffeic acids, especially for protocatechuic acid (14.9 mg/g extract), was superior to conventional extraction, resulting in the better ABTS chemical (182.3 mg TE/g extract) and cellular antioxidant (384.9 U/mg extract) activities. The notable enrichment of caffeine and protocatechuic acid, together with the antioxidant potential observed in the EtOH-modified sc-CO2 extracts of CP could be promising for functional food, cosmetic, and pharmaceutical industries.

Genome-Wide Identification of Cell Type-Specific Susceptibility Genes for SLE Through the Analysis of RNA Modification-Associated SNPs

ABSTRACT Introduction This study aimed to elucidate the functional genes associated with systemic lupus erythematosus (SLE) in various cell types through the utilization of RNAm-SNPs. Methods Utilizing large-scale genetic data, we identified associations between RNAm-SNPs and SLE. The association between RNAm-SNPs and bulk and single-cell mRNA expression (eQTL) and protein levels (pQTL) were examined. Mendelian randomization and differential expression analyses were conducted to explore the links between gene expression, protein levels, and SLE. Results We identified 41 RNAm-SNPs that were significantly associated with SLE. The GWAS signals exhibited notable enrichment in m6A-SNPs and m7G-SNPs. These RNAm-SNPs showed both eQTL and pQTL effects. In our single-cell analysis, 16 RNAm-SNPs exhibited associations with gene expression levels across 13 distinct cell types, including HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1 and IRF7. We identified 58 noteworthy associations between the expression levels of 20 genes and SLE across 12 distinct immune cell types. Notably, HLA-DQB1, HLA-DRB1 and IRF7 exhibited abnormalities in CD8+ T cells, IRF7 displayed abnormal expression in CD4+ T cells, while HLA-DRB1 and IRF7 were also distinctly perturbed in natural killer cells. Discussion This study advances our understanding of the genetic basis of SLE by highlighting the significance of RNAm-SNPs and immune cell gene expression in SLE.

Ecological and Health Risks from Trace Elements Contamination in Soils at the Rutile Bearing Area of Akonolinga, Cameroon

This study evaluates the concentrations of trace elements (TEs) in soils from the rutile deposit area of Akonolinga, Cameroon, and analyzes the associated health risks. A total of 25 samples were analyzed using flame atomic absorption spectrometry (FAAS). The results show that TE concentrations follow the decreasing order Fe, Ti, Zr, Mn, Cr, V, Ba, Zn, Nb, Ni, Pb, Ga, Cu, Co, Y, Br, and Sn. Pollution indices and the Pearson correlation matrix reveal moderate correlations between Fe and several other TEs, indicating a common origin. Enrichment Factors show significant enrichment in Zr, Nb, and Ti, with notable enrichment in Cr and Co at certain sites. Although the Geo-Accumulation Index indicates no direct contamination and the overall ecological risk is low, the Contamination Factor reveals high levels for Cr, Nb, Ti, and Zr. The carcinogenic risk is moderate, while non-carcinogenic risks are high for children and considerable for adults. These research highlight the potential public health impacts in this mining region and provide essential baseline data for future environmental risk management.

Microstructural and mechanical analysis of (Y0.2Yb0.2Lu0.2Eu0.2Er0.2)3Al5O12 high-entropy oxide ceramic fabricated in-situ via laser powder bed fusion

High-entropy ceramics (HECs) have gained attention for their exceptional properties, yet their manufacturing techniques face challenges of long cycles and complex processes. Laser powder bed fusion (LPBF) technology has the potential to address these challenges. In this study, the phase composition, microstructure, crystallography, density, and hardness were investigated at various scanning speeds. The findings reveal that (Y0.2Yb0.2Lu0.2Eu0.2Er0.2)3Al5O12 (RE3Al5O12) were in-situ synthesized via LPBF. Samples deposited at varying scanning speeds exhibited RE3Al5O12 phase with dendritic morphologies, showing notable enrichment of Al, O, and Eu elements at inter-dendritic and grain boundary. The interior of dendrites has been confirmed to be a garnet-structured high-entropy phase, and it is inferred that the segregation may consist of incompletely reacted Al2O3 and an intermediate phase of (Y0.2Yb0.2Lu0.2Eu0.2Er0.2)3AlO3 (REAlO3). Density, pore morphology, and grain size changed with scanning speed, achieving a density of 97.83 % ± 0.55 % at 60 mm/s. Hardness peaked at 15.09 ± 0.68 GPa at 120 mm/s.

Quantitative characterization and mapping relationship between microstructure, composition, orientation, and mechanical properties of nickel-based superalloy Inconel 718

Abstract This study explores the relationship between the microstructure, composition, orientation, and mechanical properties of the nickel-based superalloy Inconel 718. Employing scanning electron microscopy (SEM), electron microprobe (EMP), nano-indentation, and other techniques, the study observes the structure, confirms the composition, determines orientation, and tests mechanical properties in specific micro-zones. Findings reveal a uniform grain distribution in Inconel 718, with a minor δ-phase presence at grain boundaries. There is a notable enrichment of Nb at the grain boundaries, whereas Fe and Cr levels are lower at these boundaries compared to the grain interiors. The indentation hardness and modulus at the grain boundaries are markedly higher than those within the grains. Moreover, grains with different orientations exhibit diverse microscale mechanical properties, such as hardness and elastic modulus. This research establishes a quantitative mapping relationship between the microstructure, composition, orientation, and mechanical properties of Inconel 718, providing a foundation for future multiscale (micro to macro) mechanical property investigations.&amp;#xD;

Identification and validation of autophagy-related genes in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a congenital disorder characterized by aganglionosis in the intermuscular and submucosal nerve plexuses of the gut, leading to impaired gastrointestinal function. Although the precise cause and pathophysiology of HSCR remain elusive, increasing evidence points to a significant role of autophagy in its development, warranting further investigation into its underlying mechanisms. This study utilized publicly available microarray expression profiling datasets, GSE96854 and GSE98502, from the Gene Expression Omnibus (GEO). The R software (version 4.2.0) was employed to identify autophagy-related genes potentially showing differential expression in HSCR. Subsequent analyses included correlation analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analysis using the STRING database (version 11.0) and Cytoscape software (version 3.8.2). Ultimately, HSCR samples were used to verify the mRNA levels of important genes by quantitative real-time polymerase chain reaction (qRT-PCR) in a laboratory setting. We have discovered 20 genes that are involved in autophagy and show variable expression. Among these genes, 15 are up-regulated and five are down-regulated. The enrichment analysis using the GO and KEGG pathways revealed a notable enrichment in pathways related to the control of autophagy. Nine hub genes were found via the investigation of the PPI network constructed from STRING database and module analysis using Cytoscape. Moreover, the concordance between SIRT1 expression in the HSCR model and the bioinformatics analysis of mRNA chip findings was validated using qRT-PCR. Utilizing bioinformatics analysis, we identified 20 potential genes associated with Hirschsprung's disease that play a role in autophagy. Notably, the upregulation of SIRT1 may profoundly influence the progression of HSCR by regulating autophagy-related pathways, offering a novel perspective on the disease's pathogenesis.

Revealing Yukon’s hidden treasure: an atomic-scale investigation of Carlin-type gold mineralization in the Nadaleen Trend, Canada

AbstractThe invisible-gold deposits known as Carlin-type are becoming more important as easier to find deposits are progressively depleted. The combination of the invisible nature of the Au in these deposits, as well as the limited surface indicators of these deposits, makes exploration to find new Carlin-type deposits extremely difficult. Comprehensive mineralization models are essential to find new Carlin-type deposits in similar geologic settings. The Nadaleen Trend of Yukon, Canada, is one such district where an improved understanding of this deposit type has led to new discoveries. Previous studies compared and contrasted the tectonic setting, host rock depositional setting, structural preparation, and mineralization style of the Nadaleen Trend with those in Carlin-type localities, Nevada. However, the comparisons at an atomic scale, between Carlin-type Au deposits in the Nadaleen Trend and those in Nevada, has yet to be investigated. This study fills this knowledge gap by combining high resolution microanalytical techniques with atom probe tomography to examine the distribution of Au and other trace elements in the Nadaleen Trend, compare them to a representative Carlin-type deposit in Nevada (Turquoise Ridge), and determine how widespread the mineralization model is. Our findings show that in the Nadaleen Trend, as in Nevada, Au is generally directly linked with As at the macro to atomic scale, and is incorporated into As/Au rich overgrowths on sedimentary/diagenetic pyrite. Gold-rich pyrite rims in the Nadaleen Trend are generally smaller than those found in Nevada (0.5–2 µm vs &gt; 10 µm), although the ore grades appear comparable. We find that the Au in the pyrite of the Nadaleen Trend is homogenously distributed (i.e. lattice bound) at the atomic scale, but that there is a notable enrichment of As surrounding individual Au atoms. These findings are in agreement with those from previous work on a representative deposit in Nevada, and support the assertation that As is the key ingredient in facilitating the incorporation of Au into the pyrite lattice. Arsenic as an essential component in the trapping mechanisms of Au in CTG deposits, is something that has been as to yet underappreciated in the current models of CTG deposit formation.

Changes in Gut Microbial Composition and DNA Methylation in Obese Patients with NAFLD After Bariatric Surgery.

This study investigates the effects of bariatric surgery on non-alcoholic fatty liver disease (NAFLD) by examining the interplay between gut microbiota, epigenetics, and metabolic health. A cohort of 22 patients undergoing sleeve gastrectomy (SG) was analyzed for changes in gut microbial composition and DNA methylation profiles before and six months after surgery. Correlations between gut microbial abundance and clinical markers at baseline revealed that certain genera were associated with worse metabolic health and liver markers. Following SG, significant improvements were observed in the clinical, anthropometric, and biochemical parameters of the NAFLD patients. Although alpha-diversity indices (i.e., Chao1, Simpson, Shannon) did not show significant changes, beta-diversity analysis revealed a slight shift in microbial composition (PERMANOVA, p = 0.036). Differential abundance analysis identified significant changes in specific bacterial taxa, including an increase in beneficial Lactobacillus species such as Lactobacillus crispatus and Lactobacillus iners and a decrease in harmful taxa like Erysipelotrichia. Additionally, DNA methylation analysis revealed 609 significant differentially methylated CpG sites between the baseline values and six months post-surgery, with notable enrichment in genes related to the autophagy pathway, such as IRS4 and ATG4B. The results highlight the individualized responses to bariatric surgery and underscore the potential for personalized treatment strategies. In conclusion, integrating gut microbiota and epigenetic factors into NAFLD management could enhance treatment outcomes, suggesting that future research should explore microbiome-targeted therapies and long-term follow-ups on liver health post-surgery.

Non-tuberculous mycobacteria enhance the tryptophan-kynurenine pathway to induce immunosuppression and facilitate pulmonary colonization.

The increasing prevalence of non-tuberculous mycobacterium (NTM) infections alongside tuberculosis (TB) underscores a pressing public health challenge. Yet, the mechanisms governing their infection within the lung remain poorly understood. Here, we integrate metagenomic sequencing, metabolomic sequencing, machine learning classifiers, SparCC, and MetOrigin methods to profile bronchoalveolar lavage fluid (BALF) samples from NTM/TB patients. Our aim is to unravel the intricate interplay between lung microbial communities and NTM/Mycobacterium tuberculosis infections. Our investigation reveals a discernible reduction in the compositional diversity of the lung microbiota and a diminished degree of mutual interaction concomitant with NTM/TB infections. Notably, NTM patients exhibit a distinct microbial community characterized by marked specialization and notable enrichment of Pseudomonas aeruginosa and Staphylococcus aureus, driving pronounced niche specialization for NTM infection. Simultaneously, these microbial shifts significantly disrupt tryptophan metabolism in NTM infection, leading to an elevation of kynurenine. Mycobacterium intracellulare, Mycobacterium paraintracellulare, Mycobacterium abscessus, and Pseudomonas aeruginosa have been implicated in the metabolic pathways associated with the conversion of indole to tryptophan via tryptophan synthase within NTM patients. Additionally, indoleamine-2,3-dioxygenase converts tryptophan into kynurenine, fostering an immunosuppressive milieu during NTM infection. This strategic modulation supports microbial persistence, enabling evasion from immune surveillance and perpetuating a protracted state of NTM infection. The elucidation of these nuanced microbial and metabolic dynamics provides a profound understanding of the intricate processes underlying NTM and TB infections, offering potential avenues for therapeutic intervention and management.