Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine.

Paneth cells are the primary source of C-type lysozyme, a ß-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.

Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Dependency-aware deep generative models for multitasking analysis of spatial omics data.

Spatially resolved transcriptomics (SRT) technologies have significantly advanced biomedical research, but their data analysis remains challenging due to the discrete nature of the data and the high levels of noise, compounded by complex spatial dependencies. Here, we propose spaVAE, a dependency-aware, deep generative spatial variational autoencoder model that probabilistically characterizes count data while capturing spatial correlations. spaVAE introduces a hybrid embedding combining a Gaussian process prior with a Gaussian prior to explicitly capture spatial correlations among spots. It then optimizes the parameters of deep neural networks to approximate the distributions underlying the SRT data. With the approximated distributions, spaVAE can contribute to several analytical tasks that are essential for SRT data analysis, including dimensionality reduction, visualization, clustering, batch integration, denoising, differential expression, spatial interpolation, resolution enhancement and identification of spatially variable genes. Moreover, we have extended spaVAE to spaPeakVAE and spaMultiVAE to characterize spatial ATAC-seq (assay for transposase-accessible chromatin using sequencing) data and spatial multi-omics data, respectively.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Complex hierarchical structures in single-cell genomics data unveiled by deep hyperbolic manifold learning.

With the advances in single-cell sequencing techniques, numerous analytical methods have been developed for delineating cell development. However, most are based on Euclidean space, which would distort the complex hierarchical structure of cell differentiation. Recently, methods acting on hyperbolic space have been proposed to visualize hierarchical structures in single-cell RNA-seq (scRNA-seq) data and have been proven to be superior to methods acting on Euclidean space. However, these methods have fundamental limitations and are not optimized for the highly sparse single-cell count data. To address these limitations, we propose scDHMap, a model-based deep learning approach to visualize the complex hierarchical structures of scRNA-seq data in low-dimensional hyperbolic space. The evaluations on extensive simulation and real experiments show that scDHMap outperforms existing dimensionality-reduction methods in various common analytical tasks as needed for scRNA-seq data, including revealing trajectory branches, batch correction, and denoising the count matrix with high dropout rates. In addition, we extend scDHMap to visualize single-cell ATAC-seq data.

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity.

Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells.

A model-based constrained deep learning clustering approach for spatially resolved single-cell data.

Spatially resolved scRNA-seq (sp-scRNA-seq) technologies provide the potential to comprehensively profile gene expression patterns in tissue context. However, the development of computational methods lags behind the advances in these technologies, which limits the fulfillment of their potential. In this study, we develop a deep learning approach for clustering sp-scRNA-seq data, named Deep Spatially constrained Single-cell Clustering (DSSC). In this model, we integrate the spatial information of cells into the clustering process in two steps: (1) the spatial information is encoded by using a graphical neural network model, and (2) cell-to-cell constraints are built based on the spatial expression pattern of the marker genes and added in the model to guide the clustering process. Then, a deep embedding clustering is performed on the bottleneck layer of autoencoder by Kullback-Leibler (KL) divergence along with the learning of feature representation. DSSC is the first model that can use information from both spatial coordinates and marker genes to guide cell/spot clustering. Extensive experiments on both simulated and real data sets show that DSSC boosts clustering performance significantly compared with the state-of-the-art methods. It has robust performance across different data sets with various cell type/tissue organization and/or cell type/tissue spatial dependency. We conclude that DSSC is a promising tool for clustering sp-scRNA-seq data.

Colonic healing requires Wnt produced by epithelium as well as Tagln+ and Acta2+ stromal cells.

Although Wnt signaling is clearly important for the intestinal epithelial homeostasis, the relevance of various sources of Wnt ligands themselves remains incompletely understood. Blocking the release of Wnt in distinct stromal cell types suggests obligatory functions of several stromal cell sources and yields different observations. The physiological contribution of epithelial Wnt to tissue homeostasis remains unclear. We show here that blocking epithelial Wnts affects colonic Reg4+ epithelial cell differentiation and impairs colonic epithelial regeneration after injury in mice. Single-cell RNA analysis of intestinal stroma showed that the majority of Wnt-producing cells were contained in transgelin (Tagln+) and smooth muscle actin α2 (Acta2+) expressing populations. We genetically attenuated Wnt production from these stromal cells using Tagln-Cre and Acta2-CreER drivers, and found that blockage of Wnt release from either epithelium or Tagln+ and Acta2+ stromal cells impaired colonic epithelial healing after chemical-induced injury. Aggregated blockage of Wnt release from both epithelium and Tagln+ or Acta2+ stromal cells drastically diminished epithelial repair, increasing morbidity and mortality. These results from two uncharacterized stromal populations suggested that colonic recovery from colitis-like injury depends on multiple Wnt-producing sources.

Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells.

RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Preparation and Application of Hemostatic Hydrogels.

Hemorrhage remains a critical challenge in various medical settings, necessitating the development of advanced hemostatic materials. Hemostatic hydrogels have emerged as promising solutions to address uncontrolled bleeding due to their unique properties, including biocompatibility, tunable physical characteristics, and exceptional hemostatic capabilities. In this review, a comprehensive overview of the preparation and biomedical applications of hemostatic hydrogels is provided. Particularly, hemostatic hydrogels with various materials and forms are introduced. Additionally, the applications of hemostatic hydrogels in trauma management, surgical procedures, wound care, etc. are summarized. Finally, the limitations and future prospects of hemostatic hydrogels are discussed and evaluated. This review aims to highlight the biomedical applications of hydrogels in hemorrhage management and offer insights into the development of clinically relevant hemostatic materials.

Nature-Inspired Molecular-Crowding Enabling Wide-Humidity Range Applicable, Anti-Freezing, and Robust Zwitterionic Hydrogels for On-Skin Electronics.

Hydrogels are currently in the limelight for applications in soft electronics but they suffer from the tendency to lose water or freeze when exposed to dry environments or low temperatures. Molecular crowding is a prevalent occurrence in living cells, in which molecular crowding agents modify the hydrogen bonding structure, causing a significant reduction in water activity. Here, a wide-humidity range applicable, anti-freezing, and robust hydrogel is developed through the incorporation of natural amino acid proline (Pro) and conductive MXene into polyvinyl alcohol (PVA) hydrogel networks. Theoretical calculations reveal that Pro can transform "free water" into "locked water" via the molecular-crowding effect, thereby suppressing water evaporation and ice forming. Accordingly, the prepared hydrogel exhibits high water retention capability, with 77% and 55% being preserved after exposure to 20 °C, 28% relative humidity (RH) and 35 °C, 90% RH for 12 h. Meanwhile, Pro lowers the freezing temperature of the hydrogel to 34 °C and enhances its stretchability and strength. Finally, the PVA/Pro/MXene hydrogels are assembled as multifunctional on-skin strain sensors and conductive electrodes to monitor human motions and detect tiny electrophysiological signals. Collectively, this work provides a molecular crowding strategy that will motivate researchers to develop more advanced hydrogels for versatile applications.

CD8+ tissue-resident memory T cells are expanded in primary Sjögren's disease and can be therapeutically targeted by CD103 blockade.

OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.

Identifying high-order plasmon modes in silver nanoparticle-over-mirror configuration.

Metallic nanoparticle-over-mirror (NPOM) represents as a versatile plasmonic configuration for surface enhanced spectroscopy, sensing and light-emitting metasurfaces. However, experimentally identifying the high-order localized surface plasmon modes in NPOM, especially for the best plasmonic material silver, is often hindered by the small scattering cross-section of high-order plasmon modes and the poor reproducibility of the spectra across different NPOMs, resulted from the polyhedral morphology of the colloidal nanoparticles or the rough surface of deposited polycrystalline metals. In this study, we identify the high-order localized surface plasmon modes in silver NPOM by using differential reflection spectroscopy. We achieved reproducible single-particle absorption spectra by constructing uniform NPOM consisting of silver nanospheres, single-crystallized silver microplates, and a self-assembled monolayer of 1,10-decanedithiol. For comparison, silver NPOM created from typical polycrystalline films exhibits significant spectral fluctuations, even when employing template stripping methods to minimize the film roughness. Identifying high-order plasmon modes in the NPOM configuration offers a pathway to construct high-quality plasmonic substrates for applications such as colloidal metasurface, surface-enhanced Raman spectroscopy, fluorescence, or infrared absorption.

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurologic disorders characterized by progressive lower-extremity spasticity. Despite the identification of several HSP-related genes, many patients lack a genetic diagnosis. OBJECTIVES: The aims were to confirm the pathogenic role of biallelic COQ4 mutations in HSP and elucidate the clinical, genetic, and functional molecular features of COQ4-associated HSP. METHODS: Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single-cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell-derived pyramidal neurons, and zebrafish. RESULTS: Compound heterozygous variants in COQ4, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient-derived fibroblasts and COQ4 knockout complementation lines, stable expression of these missense variants exerted loss-of-function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high COQ4 levels, coq4 knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation. CONCLUSIONS: Our study confirms that loss-of-function, compound heterozygous, pathogenic COQ4 variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. © 2023 International Parkinson and Movement Disorder Society.

Substrate-Independent Superhydrophobic Coating Capable of Photothermal-Induced Repairability for Multiple Damages Fabricated via Simple Blade Coating.

Repairable superhydrophobic surfaces have promising application potential in many fields. However, so far, it is still a challenge to develop a superhydrophobic surface with repairability for multiple types of damage through a simple method. In this paper, a repairable superhydrophobic coating was obtained on various substrates by blade-coating mixtures of polydimethylsiloxane (PDMS), polyvinylidene fluoride (PVDF), and multiwalled carbon nanotubes (MWCNTs) modified with dopamine (PDA) and octadecylamine (ODA). The obtained coating has a good liquid-repellent property with a water contact angle above 150° and a water sliding angle of ∼6° and possesses an excellent absorbance (∼97%) in the wavelength range of 250-2500 nm. Due to its high absorbance, the coating displays an outstanding photothermal effect with a temperature rise of ∼65 °C under irradiation by 1.0 kW/m2 of simulated sunlight. Furthermore, after being degraded by multiple stimuli, including plasma treatment, acid/alkali/oil immersion, sand impact, and the icing-thawing cycle, the coating can recover superhydrophobicity via sunlight irradiation, demonstrating the good photothermal-induced repairability of the coating. It can be expected that the good water-repellent property, photothermal effect, and repairability give this coating a promising prospect in practical applications.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

Integrative analysis of transcriptomic and metabolomic profiles reveals abnormal phosphatidylinositol metabolism in follicles from endometriosis-associated infertility patients.

Endometriosis is a common gynecological disorder that causes female infertility. Our recent research found that excessive oxidative stress in ovaries of endometriosis patients induced senescence of cumulus granulosa cells. Here, we analyzed the transcriptomic and metabolomics profiles of follicles in a mouse model of endometriosis and in patients with endometriosis and investigated the potential function of changed metabolites in granulosa cells. RNA-sequencing indicated that both endometriosis lesions and oxidative stress in mice induced abnormalities of reactive oxidative stress, steroid hormone biosynthesis, and lipid metabolism. The mouse model and women with endometriosis showed altered lipid metabolism. Nontargeted metabolite profiling of follicular fluid from endometriosis and male-factor infertility patients by liquid chromatography mass spectrometry identified 55 upregulated and 67 downregulated metabolites. These differential metabolites were mainly involved in steroid hormone biosynthesis and glycerophospholipid metabolism. Phosphatidylinositol (PI 16:0/18:2) was significantly elevated in follicular fluid from endometriosis patients compared with controls (p < 0.05), while lysophosphatidylinositol (LPI 18:2, 20:2, 18:1, 20:3 and 18:3) was reduced (p < 0.05). Upregulated PI and downregulated LPI correlated with oocyte retrieval number and mature oocyte number. LPI inhibited cellular reactive oxidative stress induced by hemin in granulosa cells. Cell proliferation inhibition, senescence, and apoptosis induced by hemin were partially reversed by LPI. Moreover, LPI administration rescued hemin blocking of cumulus-oocyte complex expansion and stimulated expression of ovulation-related genes. Transcriptomic Switching mechanism at 5' end of the RNA transcript sequencing and western blot revealed that LPI effects on granulosa cells were associated with its regulation of MAPK-ERK1/2 signaling, which was suppressed in the presence of hemin. In conclusion, our results revealed the dysregulation of lipid metabolism in endometriotic follicles. LPI may represent a novel agent for in vitro follicular culture that reverses the excessive oxidative stress from endometriotic lesions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Antifungal mechanism of rose, mustard, and their blended essential oils against Cladosporium allicinum isolated from Xinjiang naan and its storage application.

AIMS: To reveal the inhibition mechanism of rose, mustard, and blended essential oils against Cladosporium allicinum isolated from Xinjiang naan, and investigate the effect of the three essential oils on oxidative damage and energy metabolism. METHODS AND RESULTS: Rose and mustard essential oils significantly inhibited mycelial growth and spore viability in a dose-dependent relationship. After essential oil treatment, the cell membrane permeability was altered, and significant leakage of intracellular proteins and nucleic acids occurred. SEM observations further confirmed the disruption of cell structure. ROS, MDA, and SOD measurements indicated that essential oil treatment induced a redox imbalance in C. allicinum, leading to cell death. As for energy metabolism, essential oil treatment significantly reduced Na+K+-ATPase, Ca2+Mg2+-ATPase, MDH activity, and CA content, impairing metabolic functions. Finally, storage experiments showed that all three essential oils ensured better preservation of naan, with mustard essential oil having the best antifungal effect. CONCLUSIONS: Rose and mustard essential oils and their blends can inhibit C. allicinum at multiple targets and pathways, destroying cell morphological structure and disrupting metabolic processes.