A genomic compendium of cultivated human gut fungi characterizes the gut mycobiome and its relevance to common diseases.

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.

Altered gut mycobiome in patients with end-stage renal disease and its correlations with serum and fecal metabolomes.

BACKGROUND: The relationship between the gut mycobiome and end-stage renal disease (ESRD) remains largely unexplored. METHODS: In this study, we compared the gut fungal populations of 223 ESRD patients and 69 healthy controls (HCs) based on shotgun metagenomic sequencing data, and analyzed their associations with host serum and fecal metabolites. RESULTS: Our findings revealed that ESRD patients had a higher diversity in the gut mycobiome compared to HCs. Dysbiosis of the gut mycobiome in ESRD patients was characterized by a decrease of Saccharomyces cerevisiae and an increase in various opportunistic pathogens, such as Aspergillus fumigatus, Cladophialophora immunda, Exophiala spinifera, Hortaea werneckii, Trichophyton rubrum, and others. Through multi-omics analysis, we observed a substantial contribution of the gut mycobiome to host serum and fecal metabolomes. The opportunistic pathogens enriched in ESRD patients were frequently and positively correlated with the levels of creatinine, homocysteine, and phenylacetylglycine in the serum. The populations of Saccharomyces, including the HC-enriched Saccharomyces cerevisiae, were frequently and negatively correlated with the levels of various toxic metabolites in the feces. CONCLUSIONS: Our results provided a comprehensive understanding of the associations between the gut mycobiome and the development of ESRD, which had important implications for guiding future therapeutic studies in this field.

Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

Augmented reality system based on the integration of polarization-independent metalens and micro-LEDs.

Augmented reality (AR), a technology that superimposes virtual information onto a user's direct view of real-world scenes, is considered one of the next-generation display technologies and has been attracting considerable attention. Here, we propose a flat optic AR system that synergistically integrates a polarization-independent metalens with micro light-emitting diodes (LEDs). A key component is a meticulously designed metalens with a numerical aperture of 0.25, providing a simulated focusing efficiency of approximately 76.5% at a wavelength of 532 nm. Furthermore, the laser measurement system substantiates that the fabricated metalens achieves a focusing efficiency of 70.8%. By exploiting the reversibility of light characteristics, the metalens transforms the divergent light from green micro-LEDs into a collimated beam that passes through the pupil and images on the retina. Monochromatic pixels with a size of 5×5 µm2 and a pitch of 10 µm can be distinctly resolved with a power efficiency of 50%. This work illustrates the feasibility of integrating the metalens with microdisplays, realizing a high-efficiency AR device without the need for additional optical components and showcasing great potential for the development of near-eye display applications.

Characterizations of gut bacteriome, mycobiome, and virome of healthy individuals living in sea-level and high-altitude areas.

BACKGROUND: The contribution of gut microbiota to human high-altitude adaptation remains inadequately understood. METHODS: Here a comparative analysis of gut microbiota was conducted between healthy individuals living at sea level and high altitude using deep whole-metagenome shotgun sequencing, to investigate the adaptive mechanisms of gut microbiota in plateau inhabitants. RESULTS: The results showed the gut bacteriomes in high-altitude individuals exhibited greater within-sample diversity and significant alterations in both bacterial compositional and functional profiles when compared to those of sea-level individuals, indicating the potential selection of unique bacteria associated with high-altitude environments. The strain-level investigation revealed enrichment of Collinsella aerofaciens and Akkermansia muciniphila in high-altitude populations. The characteristics of gut virome and gut mycobiome were also investigated. Compared to sea-level subjects, high-altitude subjects exhibited a greater diversity in their gut virome, with an increased number of viral operational taxonomic units (vOTUs) and unique annotated genes. Finally, correlation analyses revealed 819 significant correlations between 42 bacterial species and 375 vOTUs, while no significant correlations were observed between bacteria and fungi or between fungi and viruses. CONCLUSION: The findings have significantly contributed to an enhanced comprehension of the mechanisms underlying the high-altitude geographic adaptation of the human gut microbiota.

The association of preconceptional folic acid supplementation with gestational age and preterm birth risk in twin pregnancies: a prospective cohort study in China.

PURPOSE: This study aims to explore the association of maternal preconceptional folic acid (FA) supplementation with gestational age and preterm birth in twin pregnancies, and whether the association varies by chorionicity or conception mode. METHODS: From November 2018 to December 2021, the information of FA supplementation and pregnancy outcomes were collected in twin pregnant women. The linear regression models and the logistic regression were used to test the association of preconceptional FA supplementation with gestational age at delivery and preterm birth and premature rupture of membranes (PROM). RESULTS: A total of 416 twin pregnancies were included. Compared with no use in twins, maternal preconceptional FA use was associated with a 0.385-week longer gestational age (95% CI 0.019-0.751) and lower risk of preterm birth < 36 weeks (adjusted OR 0.519; 95% CI 0.301-0.895) and PROM (adjusted OR 0.426; 95% CI 0.215-0.845). The protective effect on preterm birth < 36 weeks and PROM is similar whether taking FA supplements alone or multivitamins. However, the associations varied by chorionicity and conception mode of twins or compliance with supplementation. The positive associations between preconceptional FA use and gestational age only remained significant among twins via assisted reproductive technology or dichorionic diamniotic twins. Significant protective effects on preterm birth < 36 weeks and PROM were only found among women who took FA at least 4 times a week before conception. CONCLUSION: Maternal preconceptional FA supplementation was associated with longer gestation duration and lower risk of preterm birth < 36 weeks and PROM in twin pregnancies. To improve the success of their pregnancies, reproductive women should start taking FA supplements well before conception and with good compliance.

Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury.

BACKGROUND: Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. METHODS: Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2'3'-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. RESULTS: Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2'3'-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. CONCLUSION: Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI.

Characterizations of the multi-kingdom gut microbiota in Chinese patients with gouty arthritis.

OBJECTIVE: The gut microbial composition has been linked to metabolic and autoimmune diseases, including arthritis. However, there is a dearth of knowledge on the gut bacteriome, mycobiome, and virome in patients with gouty arthritis (GA). METHODS: We conducted a comprehensive analysis of the multi-kingdom gut microbiome of 26 GA patients and 28 healthy controls, using whole-metagenome shotgun sequencing of their stool samples. RESULTS: Profound alterations were observed in the gut bacteriome, mycobiome, and virome of GA patients. We identified 1,117 differentially abundant bacterial species, 23 fungal species, and 4,115 viral operational taxonomic units (vOTUs). GA-enriched bacteria included Escherichia coli_D GENOME144544, Bifidobacterium infantis GENOME095938, Blautia_A wexlerae GENOME096067, and Klebsiella pneumoniae GENOME147598, while control-enriched bacteria comprised Faecalibacterium prausnitzii_G GENOME147678, Agathobacter rectalis GENOME143712, and Bacteroides_A plebeius_A GENOME239725. GA-enriched fungi included opportunistic pathogens like Cryptococcus neoformans GCA_011057565, Candida parapsilosis GCA_000182765, and Malassezia spp., while control-enriched fungi featured several Hortaea werneckii subclades and Aspergillus fumigatus GCA_000002655. GA-enriched vOTUs mainly attributed to Siphoviridae, Myoviridae, Podoviridae, and Microviridae, whereas control-enriched vOTUs spanned 13 families, including Siphoviridae, Myoviridae, Podoviridae, Quimbyviridae, Phycodnaviridae, and crAss-like. A co-abundance network revealed intricate interactions among these multi-kingdom signatures, signifying their collective influence on the disease. Furthermore, these microbial signatures demonstrated the potential to effectively discriminate between patients and controls, highlighting their diagnostic utility. CONCLUSIONS: This study yields crucial insights into the characteristics of the GA microbiota that may inform future mechanistic and therapeutic investigations.

Variants in genes related to development of the urinary system are associated with Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also known as Müllerian agenesis, is characterized by uterovaginal aplasia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Previous studies have associated sequence variants of PAX8, TBX6, GEN1, WNT4, WNT9B, BMP4, BMP7, HOXA10, EMX2, LHX1, GREB1L, LAMC1, and other genes with MRKH syndrome. The purpose of this study was to identify the novel genetic causes of MRKH syndrome. Ten patients with MRKH syndrome were recruited at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Whole-exome sequencing was performed for each patient. Sanger sequencing confirmed the potential causative genetic variants in each patient. In silico analysis and American College of Medical Genetics and Genomics (ACMG) guidelines helped to classify the pathogenicity of each variant. The Robetta online protein structure prediction tool determined whether the variants affected protein structures. Eleven variants were identified in 90% (9/10) of the patients and were considered a molecular genetic diagnosis of MRKH syndrome. These 11 variants were related to nine genes: TBC1D1, KMT2D, HOXD3, DLG5, GLI3, HIRA, GATA3, LIFR, and CLIP1. Sequence variants of TBC1D1 were found in two unrelated patients. All variants were heterozygous. These changes included one frameshift variant, one stop-codon variant, and nine missense variants. All identified variants were absent or rare in gnomAD East Asian populations. Two of the 11 variants (18.2%) were classified as pathogenic according to the ACMG guidelines, and the remaining nine (81.8%) were classified as variants of uncertain significance. Robetta online protein structure prediction analysis suggested that missense variants in TBC1D1 (p.E357Q), HOXD3 (p.P192R), and GLI3 (p.L299V) proteins caused significant structural changes compared to those in wild-type proteins, which in turn may lead to changes in protein function. This study identified many novel genes, especially TBC1D1, related to the pathogenesis of MRKH syndrome. The identification of these variants provides new insights into the etiology of MRKH syndrome and a new molecular genetic reference for the development of the reproductive tract.

Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression.

The intricate processes of microbiota-gut-brain communication in modulating human cognition and emotion, especially in the context of mood disorders, have remained elusive. Here we performed faecal metagenomic, serum metabolomics and neuroimaging studies on a cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterise the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids. These metabolites could be linked to the abundance of gut microbiota presented with corresponding biosynthetic potentials, including Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundii and Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederiksenii and Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacae and Enterobacter kobei) and Flavobacterium spp. Based on functional neuroimaging, BD-related neuroactive microbes and metabolites were discovered as potential markers associated with BD-typical features of functional connectivity of brain networks, hinting at aberrant cognitive function, emotion regulation, and interoception. Our study combines gut microbiota and neuroactive metabolites with brain functional connectivity, thereby revealing potential signalling pathways from the microbiota to the gut and the brain, which may have a role in the pathophysiology of BD.

Dietary cultured supernatant mixture of Cetobacterium somerae and Lactococcus lactis improved liver and gut health, and gut microbiota homeostasis of zebrafish fed with high-fat diet.

Postbiotics have the ability to improve host metabolic disorders and immunity. In order to explore whether the postbiotics SWFC (cultured supernatant mixture of Cetobacterium somerae and Lactococcus lactis) repaired the adverse effects caused by feeding of high-fat diet (HFD), zebrafish were selected as the experimental animal and fed for 6 weeks, with dietary HFD as the control group, and HFD containing 0.3 g/kg and 0.4 g/kg SWFC as the treatment groups. The results indicated that addition of SWFC in the diet at a level of 0.3 and 0.4 g/kg didn't affect the growth performance of zebrafish (P > 0.05). Supplementation of dietary SWFC0.3 relieved lipid metabolism disorders through significant increasing in the expression of pparα and cpt1, and decreasing the expression of cebpα, pparγ, acc1 and dgat-2 genes (P < 0.05). Moreover, the content of triacylglycerol was markedly lower in the liver of zebrafish grouped under SWFC0.3 (P < 0.05). Dietary SWFC0.3 also improved the antioxidant capacity via increasing the expression level of ho-1, sod and gstr genes, and significant inducing malondialdehyde content in the liver of zebrafish (P < 0.05). Besides, dietary SWFC0.3 also notably improved the expression level of lysozyme, c3a, defbl1 and defbl2 (P < 0.05). The expression level of pro-inflammatory factors (nf-κb, tnf-α, and il-1ß) were significantly decreased and the expression level of anti-inflammatory factor (il-10) was markedly increased in the postbiotics 0.3 g/kg group (P < 0.05). Feeding with SWFC0.3 supplemented diet for 6 weeks improved the homeostasis of gut microbiota and increased the survival rate of zebrafish after challenged with Aeromonus veronii Hm091 (P < 0.01). It was worth noting that the positive effect of dietary SWFC at a level of 0.3 g/kg was considerably better than that of 0.4 g/kg. This may imply that the effectiveness and use of postbiotics is limited by dosage.

The positive effects of postbiotic (SWF concentration®) supplemented diet on skin mucus, liver, gut health, the structure and function of gut microbiota of common carp (Cyprinus carpio) fed with high-fat diet.

Postbiotics are an emerging research interest in recent years, which shows that metabolites, lysate extracts, cell wall components and even culture supernatants of probiotics can also exhibit significant prebiotic effects. In this study postbiotic stress worry free concentration® (SWFC) were prepared from the composition of culture supernatant of Cetobacterium somerae and Lactococcus lactis. The positive effects of SWFC supplemented diets on the growth performance, skin mucus, liver and gut health, and intestinal microbiota profile of Cyprinus carpio fed with high fat diets were investigated. 180 C. carpio with an average body weight of (3.01 ± 0.01) g were selected and randomly divided into three groups. They were fed with one of the three experimental diets supplemented with SWFC of 0 (control), 0.2 and 0.3 g/kg for 98 days, afterwards indexes were detected. The results revealed that, addition of SWFC had no significant effect on growth performance of C. carpio, while it can improve the health of the fish remarkably. In addition, SWFC improved mucosal C3, T-AOC, SOD activities, and decreased lipid peroxidation product MDA level, which were notably better than those in the control group (P < 0.05). In terms of the liver health systems, C. carpio fed on the diet supplemented with 0.2 g/kg of SWFC, showed significant improvement of the liver injured by HFD and reduce the contents of serum ALT and AST, and liver TAG (P < 0.05; P < 0.01). The expression of inflammation-related and lipid synthesis genes revealed that SWFC0.2 group could noteworthy enhance antioxidant capacity, reduced the expression of pro-inflammatory factors (TNF-α, IL-1ß) and lipid synthesis genes (ACC, FAS, PPAR-ß, PPAR-γ), and up-regulated the expression of anti-inflammatory factors (TGF-ß). Additionally, intestinal morphology arose inflammatory cell infiltration, while intestinal integrity was better in SWFC groups compared with the control. Furthermore, the contents of serum LPS and LBP were remarkably lower in the SWFC0.2 group compared with the control (P < 0.01). The mRNA expression of genes related to gut health indicated that SWFC supplementation noteworthy up-regulated the expression of antioxidant (Nrf2, CAT, GPX), immune (Hepcidin, IL-10) and tight junction protein-related (ZO-1, Occludin). Simultaneously, the results of GF-zebrafish showed that the relative expression of anti-inflammatory genes (IL-1ß, TGF-ß) and antioxidant related genes (Nrf2, HO-1) were significantly up-regulated in SWFC groups. Data on intestinal microbiota profile verified that, at the phylum level, the abundance of Fusobacteria was remarkably elevated in the SWFC groups (P < 0.05), whereas the abundance of Firmicutes was declined noteworthy in SWFC0.2 and SWFC0.3 compared to the control group (P < 0.05; P < 0.01) respectively. At the genus level, the abundance of Cetobacterium in the SWFC groups were notably higher than those in the control group (P < 0.05), while the Vibrio content in the SWFC groups was significantly decreased (P < 0.05). PCoA result indicated that the intestinal microflora of SWFC0.2 group was abundant and diverse. Our results elucidate that dietary supplementation of SWFC protects C. carpio from HFD induced inflammatory response and oxidative stress, ameliorate skin mucus, liver and gut health, and improve the gut microbiota balance. Therefore, SWFC could be considered as an improving-fish-health additive, when supplemented to aquatic animal feed. With regards to how SWFC regulates the immunity and inflammatory responses and which signal transductions are involved remains unclear and more scientific evidences are needed to address these issues.

Higher greenspace exposure is associated with a decreased risk of childhood asthma in Shanghai - A megacity in China.

Inconsistent evidence exists about whether exposure to greenspace benefits childhood asthma. Previous studies have only focused on residential or school greenspace, and no research has combined greenspace exposures at both homes and schools to determine their link with childhood asthma. A population-based cross-sectional study was conducted among 16,605 children during 2019 in Shanghai, China. Self-reported questionnaires were used to collect information on childhood asthma and demographic, socioeconomic and behavioural factors. Environmental data including ambient temperature, particulate matter with aerodynamic diameter less than 1 µm (PM1), enhanced vegetation index (EVI), and normalized difference vegetation index (NDVI) were collected from satellite data. Binomial generalized linear models with a logit link were carried out to evaluate the association between greenspace exposure and children's asthma, as well as the effect modifiers. An interquartile range increment of whole greenspace (NDVI500, NDVI250, EVI500, and EVI250) exposure was associated with a reduced odds ratio of children's asthma (0.88, 95% CI: 0.78, 0.99; 0.89, 95% CI: 0.79, 1.01; 0.87, 95% CI: 0.77, 0.99; and 0.88, 95% CI: 0.78, 0.99, respectively) after controlling potential confounders. Low temperature, low PM1, males, vaginal delivery, suburban/rural area, and without family history of allergy appeared to enhance the greenspace-asthma association. Increased greenspace exposure was associated with a lower risk of childhood asthma, and the association was modified by a range of socio-environmental factors. These findings add to the body of evidence on the benefits of biodiversity and supporting the promotion of urban greenspace to protect children's health.

Independent and combined associations of multiple-heavy-metal exposure with lung function: a population-based study in US children.

Previous research has found relationships between some single metals and lung function parameters. However, the role of simultaneous multi-metal exposure is poorly understood. The crucial period throughout childhood, when people are most susceptible to environmental dangers, has also been largely ignored. The study aimed to evaluate the joint and individual associations of 12 selected urinary metals with pediatric lung function measures using multi-pollutant approaches. A total of 1227 children aged 6-17 years from the National Health and Nutrition Examination Survey database of the 2007-2012 cycles were used. The metal exposure indicators were 12 urine metals adjusted for urine creatinine, including arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), cobalt (Co), mercury (Hg), molybdenum (Mo), lead (Pb), antimony (Sb), thallium (Tl), tungsten (Tu), and uranium (Ur). The outcomes of interest were lung function indices, including the 1st second of a forceful exhalation (FEV1), forced vital capacity (FVC), forced expiratory flow between 25 and 7% of vital capacity (FEF25-75%), and peak expiratory flow (PEF). Multivariate linear regression, quantile g-computation (QG-C), and Bayesian kernel machine regression models (BKMR) were adopted. A significantly negative overall effect of metal mixtures on FEV1 (ß = - 161.70, 95% CI - 218.12, - 105.27; p < 0.001), FVC (ß = - 182.69, 95% CI - 246.33, - 119.06; p < 0.001), FEF25-75% (ß = - 178.86 (95% CI - 274.47, - 83.26; p < 0.001), and PEF (ß = - 424.17, 95% CI - 556.55, - 291.80; p < 0.001) was observed. Pb had the largest negative contribution to the negative associations, with posterior inclusion probabilities (PIPs) of 1 for FEV1, FVC, and FEF25-75%, and 0.9966 for PEF. And Pb's relationship with lung function metrics showed to be nonlinear, with an approximate "L" shape. Potential interactions between Pb and Cd in lung function decline were observed. Ba was positively associated with lung function metrics. Metal mixtures were negatively associated with pediatric lung function. Pb might be a crucial element. Our findings highlight the need for prioritizing children's environmental health to protect them from later respiratory disorders and to guide future research into the toxic mechanisms of metal-mediated lung function injury in the pediatric population.

Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists.

OBJECTIVE: Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN: Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS: The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION: This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

Exploring genetic association of insomnia with allergic disease and asthma: a bidirectional Mendelian randomization study.

BACKGROUND: Insomnia is highly prevalent among patients with allergic disease and asthma; however, few studies have investigated their causal relationship. We aim to explore the causal association between insomnia and allergic disease/asthma by performing bidirectional Mendelian randomization (MR) study. METHODS: Instrumental variables were constructed using single nucleotide polymorphisms (SNPs). Summary statistics for insomnia, allergic disease, and asthma were obtained from four large-scale genome-wide association studies (GWAS) of European ancestry. The pleiotropy analysis was applied by using the MR-Egger intercept test and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. MR analyses were conducted by using inverse variance weighted (IVW), weighted median, and MR-Egger method. RESULTS: Based on the multiplicative random effects IVW method, the MR analysis showed that genetically predicted insomnia was causally associated with an increased risk of allergic disease [odds ratio (OR) = 1.054, 95% confidence interval (CI) = 1.031-1.078, P = 3.817 × 10-06], asthma (OR = 1.043, 95% CI = 1.010-1.077, P = 9.811 × 10-03), moderate-severe asthma (OR = 1.168, 95% CI = 1.069-1.277, P = 6.234 × 10-04), and adult-onset asthma (OR = 1.086, 95% CI = 1.037-1.138, P = 4.922 × 10-04). In bidirectional analyses, we did not find evidence supporting the reverse causality relations. CONCLUSIONS: Our MR study suggested that genetically predicted insomnia was the risk factor for allergic disease and asthma. Improving sleep quality could be one of the cornerstones in the prevention of allergic disease and asthma.

Inhibition of exosome release augments neuroinflammation following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a severe stroke subtype without effective pharmacological treatment. Following ICH, peripheral leukocytes infiltrate into the brain and contribute to neuroinflammation and brain edema. However, the intercellular machinery controlling the initiation and propagation of leukocyte infiltration remains elusive. Exosomes are small extracellular vesicles released from donor cells and bridge intercellular communication. In this study, we investigated the effects of inhibition of exosome release on neuroinflammation and ICH injury. Using a mouse model of ICH induced by collagenase injection, we found that ICH induced an increase of exosome level in the brain. Inhibition of exosome release using GW4869 augmented neurological deficits and brain edema after ICH. The exacerbation of ICH injury was accompanied by increased barrier disruption and brain infiltration of leukocytes. The detrimental effects of GW4869 were ablated in ICH mice receiving antibody depletion of Gr-1+ myeloid cells. Extracted exosomes from the ICH brains suppressed the production of inflammatory factors by splenocytes. Additionally, exosomes extracted from brain tissues of donor ICH mice reduced ICH injury in recipient mice. These results demonstrate that inhibition of exosome release augments neuroinflammation and ICH injury. The impact of exosomes released from the ICH brain on the immune system deserves further investigation.

Association of childhood asthma with intra-day and inter-day temperature variability in Shanghai, China.

OBJECTIVES: Short-term temperature variability (TV) is associated with the exacerbation of asthma, but little is known about the relative effects of intra- and inter-day TV. We aimed to assess the relative impacts of intra- and inter-day TV on childhood asthma and to explore the modification effects by season. METHODS: A quasi-Poisson generalized linear regression model combined with a distributed lag nonlinear model was adopted to evaluate the nonlinear and lagged effects of TV on childhood asthma in Shanghai from 2009 to 2017. Intra- and inter-day TV was measured with diurnal temperature range (DTR) and temperature changes between neighboring days (TCN), respectively. RESULTS: Increased DTR was associated with the elevated relative risk (RR) of daily outpatient visits for childhood asthma (DOVCA) in both the whole year (RRlag0-14 for the 99th percentile: 1.264, 95% confidence interval (CI): 1.052, 1.518) and cold season (RRlag0-12 for the 99th percentile: 1.411, 95% CI: 1.053, 1.889). Higher TCN in the warm season was associated with the increased RR of DOVCA (RRlag0-14 for the 99th percentile: 2.964, 95% CI: 1.636, 5.373). The number and fraction of DOVCA attributed to an interquartile range (IQR) increase of TCN were higher than those attributed to DTR in both the whole year period and warm season. However, the number and fraction of DOVCA attributed to an IQR increase of DTR were greater than those attributed to TCN in the cold season. CONCLUSIONS: Our results provide novel evidence that both intra- and inter-day TV might be a trigger of childhood asthma. Higher DTR appeared to have greater impacts on childhood asthma in the cold season while an increase in TCN seemed to have bigger effects in the warm season.

Environmental Exposure and Childhood Atopic Dermatitis in Shanghai: A Season-Stratified Time-Series Analysis.

BACKGROUND: Childhood atopic dermatitis (AD) is an inflammatory skin disease which sometimes predisposes to allergies. Environmental factors (low humidity, irritants, etc.) are prominent causative triggers of AD. OBJECTIVES: This study aims to explore the effects of both meteorological factors and air pollutants on childhood AD, and the modification effects by season in Shanghai, China. METHODS: Quasi-Poisson generalized linear regression model, combined with a distributed lag nonlinear model was used to examine the nonlinear and lagged effects of environmental factors on childhood AD from 2009 to 2017 in Shanghai. We also performed a season-stratified analysis to determine the modification effects of environmental exposure by season on childhood AD. RESULTS: There were 1,043,240 outpatient visits for childhood AD in total, at 3 major pediatric hospitals. Low temperature and relative humidity (RH), and high daily temperature difference (DTD) and air pollutants (i.e., NO2) increased the relative risks (RRs) of outpatient visits for childhood AD in the whole year. In the cold season, an increased risk of outpatient visits for childhood AD was associated with low RH (RR 2.26, 95% CI 1.69-3.02) and high NO2 (1.11, 95% CI 1.06-1.17). In the warm season, outpatient visits for childhood AD were associated with low temperature (3.49, 95% CI 3.22-3.77), low RH (1.89, 95% CI 1.74-2.06), high DTD (1.41, 95% CI 1.31-1.53), and high NO2 (1.05, 95% CI 1.03-1.06). CONCLUSIONS: This study suggests that environmental exposure may be a key trigger for outpatient visits for childhood AD with apparent seasonal effects. Tailored preventive strategies to avoid environmental triggers of childhood AD should be developed.

Integrated bioinformatic analysis of dysregulated microRNA-mRNA co-expression network in ovarian endometriosis.

INTRODUCTION: Ovarian endometriosis is a frequently occurring gynecological disease with large socioeconomic impact. Accumulating evidence has suggested that aberrant miRNA-mRNA interactions are involved in the pathogenesis and progression of ovarian endometriosis. This study aims to identify key miRNAs in ovarian endometriosis by using integrated bioinformatic analysis of a dysregulated miRNA-mRNA co-expression network. MATERIAL AND METHODS: Expression profiling of miRNA and mRNA in three normal endometria and five pairs of ectopic/eutopic endometria from patients with ovarian endometriosis was determined by high-throughput sequencing techniques. The data were then integrated with the public sequencing datasets (GSE105764 and GSE105765) using a non-biased approach and a miRNA-mRNA co-expression regulatory network was constructed by in-depth bioinformatic analysis. RESULTS: The constructed miRNA-mRNA network included 87 functionally DEMs, 482 target mRNAs and 1850 paired miRNA-mRNA regulatory interactions. Specifically, five miRNAs (miR-141-3p, miR-363-3p, miR-577, miR-767-5p, miR-96-5p) were gradually decreased and two miRNAs (miR-493-5p, miR-592) were gradually increased from normal endometria to eutopic endometria, and then ectopic endometria tissues. Importantly, miR-141-3p, miR-363-3p and miR-96-5p belonged to the miR-200 family, miR-106a-363 cluster and miR-183/96/182 cluster, respectively. Their target mRNAs were mainly associated with cell adhesion, locomotion and binding, which are suggested to play vital regulatory roles in the pathogenesis of ovarian endometriosis. CONCLUSIONS: Integrated bioinformatic analysis of the miRNA-mRNA co-expression network defines the crucial roles of the miR-200 family, miR-106a-363 cluster and miR-183/96/182 cluster in the pathogenesis of ovarian endometriosis. Further in-depth functional studies are needed to unveil the molecular mechanisms of these miRNAs, and may provide clues for the optimization of therapeutic strategies for ovarian endometriosis.