CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway.

Adhesion molecules play critical roles in maintaining the structural integrity of the airway epithelium in airways under stress. Previously, we reported that catenin alpha-like 1 (CTNNAL1) is downregulated in an asthma animal model and upregulated at the edge of human bronchial epithelial cells (HBECs) after ozone stress. In this work, we explore the potential role of CTNNAL1 in the structural adhesion of HBECs and its possible mechanism. We construct a CTNNAL1 ‒/‒ mouse model with CTNNAL1-RNAi recombinant adeno-associated virus (AAV) in the lung and a CTNNAL1-silencing cell line stably transfected with CTNNAL1-siRNA recombinant plasmids. Hematoxylin and eosin (HE) staining reveals that CTNNAL1 ‒/‒ mice have denuded epithelial cells and structural damage to the airway. Silencing of CTNNAL1 in HBECs inhibits cell proliferation and weakens extracellular matrix adhesion and intercellular adhesion, possibly through the action of the cytoskeleton. We also find that the expressions of the structural adhesion-related molecules E-cadherin, integrin ß1, and integrin ß4 are significantly decreased in ozone-treated cells than in vector control cells. In addition, our results show that the expression levels of RhoA/ROCK1 are decreased after CTNNAL1 silencing. Treatment with Y27632, a ROCK inhibitor, abolished the expressions of adhesion molecules induced by ozone in CTNNAL1-overexpressing HBECs. Overall, the findings of the present study suggest that CTNNAL1 plays a critical role in maintaining the structural integrity of the airway epithelium under ozone challenge, and is associated with epithelial cytoskeleton dynamics and the expressions of adhesion-related molecules via the RhoA/ROCK1 pathway.

Short daylight photoperiod alleviated alarm substance-stimulated fear response of zebrafish.

Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis.

Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice.

Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Anion-(π)n -π Catalytic Micelles.

Anion-π catalysis operates by stabilizing anionic transition states on π-acidic aromatic surfaces. In anion-(π)n -π catalysis, π stacks add polarizability to strengthen interactions. In search of synthetic methods to extend π stacks beyond the limits of foldamers, the self-assembly of micelles from amphiphilic naphthalenediimides (NDIs) is introduced. To interface substrates and catalysts, charge-transfer complexes with dialkoxynaphthalenes (DANs), a classic in supramolecular chemistry, are installed. In π-stacked micelles, the rates of bioinspired ether cyclizations exceed rates on monomers in organic solvents by far. This is particularly impressive considering that anion-π catalysis in water has been elusive so far. Increasing rates with increasing π acidity of the micelles evince operational anion-(π)n -π catalysis. At maximal π acidity, autocatalytic behavior emerges. Dependence on position and order in confined micellar space promises access to emergent properties. Anion-(π)n -π catalytic micelles in water thus expand supramolecular systems catalysis accessible with anion-π interactions with an inspiring topic of general interest and great perspectives.

Anion-π catalysis on carbon allotropes.

Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion-π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels-Alder reactions and autocatalytic ether cyclizations. Currently, anion-π catalysis on carbon allotropes gains momentum because the combination with electric-field-assisted catalysis promises transformative impact on organic synthesis.

In vitro antibiofilm activity of resveratrol against avian pathogenic Escherichia coli.

BACKGROUND: Avian pathogenic Escherichia coli (APEC) strains cause infectious diseases in poultry. Resveratrol is extracted from Polygonum cuspidatum, Cassia tora Linn and Vitis vinifera, and displays good antimicrobial activity. The present study aimed to investigate the antibiofilm effect of resveratrol on APEC in vitro. The minimum inhibitory concentration (MIC) of resveratrol and the antibiotic florfenicol toward APEC were detected using the broth microdilution method. Then, the effect of resveratrol on swimming and swarming motility was investigated using a semisolid medium culture method. Subsequently, the minimum biofilm inhibitory concentration (MBIC) and the biofilm eradication rate were evaluated using crystal violet staining. Finally, the antibiofilm activity of resveratrol was observed using scanning electron microscopy (SEM). Meanwhile, the effects of florfenicol combined with resveratrol against biofilm formation by APEC were evaluated using optical microscopy (OM) and a confocal laser scanning microscopy (CLSM). RESULTS: The MICs of resveratrol and florfenicol toward APEC were 128 µg/mL and 64 µg/mL, respectively. The swimming and swarming motility abilities of APEC were inhibited in a resveratrol dose-dependent manner. Furthermore, resveratrol showed a significant inhibitory activity against APEC biofilm formation at concentrations above 1 µg/mL (p < 0.01). Meanwhile, the inhibitory effect of resveratrol at 32 µg/mL on biofilm formation was observed using SEM. The APEC biofilm was eradicated at 32 µg/mL of resveratrol combined with 64 µg/mL of florfenicol, which was observed using CLSM and OM. Florfenicol had a slight eradication effect of biofilm formation, whereas resveratrol had a strong biofilm eradication effect toward APEC. CONCLUSION: Resveratrol displayed good antibiofilm activity against APEC in vitro, including inhibition of swimming and swarming motility, biofilm formation, and could eradicate the biofilm.

Temporal Multiplexed in Vivo Upconversion Imaging.

Upconversion nanoparticles (UCNPs), typically converting near-infrared (NIR) light into visible luminescence, are promising for bioimaging applications. However, optical multiplexed in vivo upconversion experiments have long been hampered by the exceptional rarity of available luminescence bands in UCNPs that can penetrate deep in tissues. Herein, we describe an approach to accomplish multiplexed upconversion in vivo imaging through time-domain discrimination of tissue-penetrating NIR luminescence at 808 nm (from thulium ions) with a multitude of distinct lifetimes. A tetradomain nanostructure design enables one to regulate energy migration and upconverting processes within confined nanoscopic domains in defined ways, thus yielding high quantum yield upconversion luminescence (maximum ≈ 6.1%, 0.11 W/cm2) with precisely controlled lifetimes that span 2 orders of magnitude (from 78 to 2157 µs). Importantly, intravenous and subcutaneous administration of aqueous form UCNPs into a Kunming mouse demonstrates high-contrast lifetime-colored imaging of them in liver and two abdomen subcutis. Moreover, optical patterns of these UCNPs allow multicolour presentation of a series of deciphered images that are hued with precisely defined lifetimes. The described temporal multiplexed upconversion approach, demonstrated in in vivo imaging and multilevel anticounterfeiting, has implications for high-throughput biosensing, volumetric displays, and diagnosis and therapy.

Accurate In Vivo Nanothermometry through NIR-II Lanthanide Luminescence Lifetime.

Luminescence nanothermometry is promising for noninvasive probing of temperature in biological microenvironment at nanometric spatial resolution. Yet, wavelength- and temperature-dependent absorption and scattering of tissues distort measured spectral profile, rendering conventional luminescence nanothermometers (ratiometric, intensity, band shape, or spectral shift) problematic for in vivo temperature determination. Here, a class of lanthanide-based nanothermometers, which are able to provide precise and reliable temperature readouts at varied tissue depths through NIR-II luminescence lifetime, are described. To achieve this, an inert core/active shell/inert shell structure of tiny nanoparticles (size, 13.5 nm) is devised, in which thermosensitive lanthanide pairs (ytterbium and neodymium) are spatially confined in the thin middle shell (sodium yttrium fluoride, 1 nm), ensuring being homogenously close to the surrounding environment while protected by the outmost calcium fluoride shell (CaF2 , ≈2.5 nm) that shields out bioactive milieu interferences. This ternary structure enables the nanothermometers to consistently resolve temperature changes at depths of up to 4 mm in biological tissues, having a high relative temperature sensitivity of 1.4-1.1% °C-1 in the physiological temperature range of 10-64 °C. These lifetime-based thermosensitive nanoprobes allow for in vivo diagnosis of murine inflammation, mapping out the precise temperature distribution profile of nanoprobes-interrogated area.

[Progress of epithelial-mesenchymal transition in respiratory system and the modulatory mechanism of cell adhesion].

Epithelial-mesenchymal transition (EMT) plays an important role in the development and pathogenesis of respiratory system. Epithelial cells are characterized by well-developed, intercellular contacts, whereas EMT triggers the sequential destabilization of cell-cell adhesive junctions. The dynamic remodeling of the epithelial cell adhesion molecules is important for maintaining the integrity and normal function of epithelium. This paper reviews the research progress of EMT in lung development, lung injury repair and chronic lung diseases, and summarizes the effect of cell junctions and cell adhesion molecules on EMT molecular events.

Oxygen- and Nitrogen-Embedded Zigzag Hydrocarbon Belts.

Despite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom-embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N-doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular SN Ar and palladium-catalyzed intermolecular C-N bond formation reactions. Preorganized conformations of mono-macrocyclic, half-belt and quasi-belt compounds were revealed to facilitate cyclization reactions to construct heteroatom-linked octahydrobelt[8]arenes. The acquired products had strained square-prism-shaped belt structures in which all six-membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom-bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.

CTNNAL1 inhibits ozone-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

NEW FINDINGS: What is the central question of this study? What is the effect of catenin alpha-like 1 (CTNNAL1), an asthma-related epithelial adhesion molecule that plays a vital role in airway epithelial wound repair, on airway epithelial-mesenchymal transition? What is the main finding and its importance? CTNNAL1 inhibits ozone-induced airway epithelial-mesenchymal transition features, mediated by repressing the expression of Twist1 mRNA and reducing TGF-ß1 levels. These findings contribute to our understanding of the pathology of airway EMT and may indicate a possible therapeutic target for airway remodelling in bronchial asthma. ABSTRACT: Epithelial-mesenchymal transition (EMT), a crucial event occurring during epithelial and mesenchymal repair, was reported to be a possible mechanism for airway remodelling. Our previous work showed that the expression of catenin alpha-like 1 (CTNNAL1) was down-regulated in the bronchial epithelial cells of asthmatic models and played a vital role in airway epithelial wound repair. The aim of this study was to investigate the effect of CTNNAL1 on airway EMT. Overexpression or silencing of CTNNAL1 in human bronchial epithelial cells was induced by stable transfection. CTNNAL1 was silenced in primary mouse airway epithelial cells with an effective siRNA vector. Cells were stressed by ozone for 4 days at 30 min day-1 to induce EMT. EMT features, changes in the function of co-cultured lung fibroblasts, changes in the expression of the transcriptional repressors Snail/Slug and Twist1/Twist2 and changes in the secretion of transforming growth factor ß1 (TGF-ß1) were assayed in different cell lines with or without ozone exposure. Both ozone exposure and silencing of CTNNAL1 induced EMT features in airway epithelial cells. Functional changes in lung fibroblasts increased after co-culture with (ozone-stressed) CTNNAL1-silenced cells. Snail and Twist1 expression increased, and the level of TGF-ß1 was enhanced. Conversely, CTNNAL1 overexpression reversed EMT features, repressed mRNA levels of Twist1 and reduced the secretion of TGF-ß1, both alone and in combination with ozone exposure. Our results indicate that ozone exposure induces airway EMT and that CTNNAL1 inhibits ozone-induced airway EMT. CTNNAL1 may play a role in airway EMT by repressing the expression of Twist1 mRNA and reducing the level of TGF-ß1.

Synthesis of Phenalenyl-Fused Pyrylium Cations: Divergent C-H Activation/Annulation Reaction Sequence of Naphthalene Aldehydes with Alkynes.

Described herein is the synthesis of stable oxonium-doped polycyclic aromatic hydrocarbons (PAHs) by the rhodium-catalyzed C-H activation/annulations of naphthalene-type aldehydes with internal alkynes. This protocol provides four divergent reaction types, including two unexpected annulations with an oxygen transposition process, which lead to diverse types of phenalenyl-fused pyrylium cations comprising a four-, five-, or six-ring-fused π-conjugated core. The annulations exhibit an exquisite regioselectivity and a high tolerance of sensitive functional groups. These PAHs feature intriguing photophysical properties such as full-color tunable fluorescence emission, high quantum yield, and positively charged core, and can be reduced easily to the phenalenyl radicals.

[Allergens-induced sensitization alters airway epithelial adhesion molecules expression in mice].

To explore the relationship between the epithelial adhesion molecules and immune responses of airway epithelium, we observed the expression of integrin ß4 and intercellular adhesion molecule-1 (ICAM-1) in the mice airway epithelium after sensitization with allergens. BALB/c mice were sensitized with intraperitoneal injection of ovalbumin (OVA) or house dust mite (HDM) and then developed airway hyper-responsiveness as determined by barometric whole-body plethysmography. Both OVA and HDM sensitization led to increases of the number of peripheral leukocytes as well as inflammatory cells infiltration in lungs. OVA sensitized mice showed more severe inflammatory cells infiltration than HDM sensitized mice. Immunohistochemistry analysis of mice lung tissues revealed that sensitization with both allergens also led to a decrease of integrin ß4 expression and an increase of ICAM-1 expression in airway epithelia. OVA sensitized mice showed a more significant increase of ICAM-1 expression compared with HDM sensitized mice. siRNA mediated silencing of integrin ß4 gene in 16HBE cells resulted in an up-regulation of ICAM-1 expression. Our results indicate a possible role of airway epithelial adhesion molecules in allergen-induced airway immune responses.

Dorsal and ventral fronto-amygdala networks underlie risky decision-making in age-related cognitive decline.

Older adults often have difficulty in making decisions under uncertainty, increasing the risk of financial exploitation. However, it is still under investigation about the extent to which cognitive decline influences risky decision-making and the underlying neural correlates. We hypothesized that the individual differences of risk-taking behavior depend on cognitive integrity, in which the dorsal and ventral fronto-amygdala connectivity would play dissociable roles. In the current study, thirty-six young and 51 older adults were tested with the Iowa gambling task combing resting-state and task-related functional magnetic resonance imaging. The results showed significant changes in behaviors and the fronto-amygdala network in older adults relative to young adults. More importantly, age-effect on risk-taking behaviors was remarkably different in cognitively normal and impaired older adults. In resting-state analysis, task performance was positively correlated with the ventral fronto-amygdala connectivity and negatively correlated with the dorsal fronto-amygdala connectivity in cognitively impaired older adults, compared with cognitively normal individuals. Furthermore, task-related analysis confirmed the relationships between dorsal/ventral fronto-amygdala network and risk-taking behaviors depending on cognitive integrity. These findings indicate that the fronto-amygdala network is crucial for understanding altered risky decision-making in aging, suggesting dissociable contributions of the dorsal and ventral pathways in the context of cognitive decline.

Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis.

While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1ß (IL-1ß) production in bone-marrow-derived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1ß secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.

Environmentally relevant estrogens impaired spermatogenesis and sexual behaviors in male and female zebrafish.

Environmental estrogens (EEs) are found extensively in natural waters and negatively affect fish reproduction. Research on the reproductive toxicity of EEs mixtures in fish at environmentally relevant concentrations is scarce. In this study, adult male zebrafish were exposed for 60 days to EES (a mixture of EEs), EE2-low (5.55 ng/L, with an estrogenic potency equal to EES), and EE2-high (11.1 ng/L). After exposure, the expression levels of vtg1, vtg3, and esr1 in the livers in EES-treated fish remained unaltered, whereas they were significantly increased in EE2-treated fish. Both EE2-high and EES exposures notably reduced the gonad somatic index and sperm count. A disrupted spermatogenesis was also observed in the testes of EE2-high- and EES-exposed fish, along with an alteration in the expression of genes associated with spermatogonial proliferation (pcna, nanog), cell cycle transition (cyclinb1, cyclind1), and meiosis (aldh1a2, cyp26a1, sycp3). Both EE2 and EES significantly lowered plasma 11-ketotestosterone levels in males, likely by inhibiting the expression level of genes for its synthesis (scc, cyp17a1 and cyp11b2), and increased 17ß-estradiol (E2) levels, possibly through upregulating the expression of cyp19a1a. A significant increase in tnfrsf1a expression and the tnfrsf1a/tnfrsf1b ratio in EE2-high and EES-treated males also suggests increased apoptosis via the extrinsic pathway. Further investigation showed that both EE2-high and EES diminished the sexual behavior of male fish, accompanied with reduced E2 levels in the brain and the expression of genes in the kisspeptin/gonadotropin-releasing hormone system. Interestingly, the sexual behavior of unexposed females paired with treated males was also reduced, indicating a synergistic effect. This study suggests that EES have a more severe impact on reproduction than EE2-low, and EEs could interfere not only with spermatogenesis in fish, but also with the sexual behaviors of both exposed males and their female partners, thereby leading to a more significant disruption in fish reproduction.

Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome.

The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5'-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5'-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5'-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.

The Origin of Anion-π Autocatalysis.

The autocatalysis of epoxide-opening ether cyclizations on the aromatic surface of anion-π catalysts stands out as a leading example of emergent properties expected from the integration of unorthodox interactions into catalysis. A working hypothesis was proposed early on, but the mechanism of anion-π autocatalysis has never been elucidated. Here, we show that anion-π autocatalysis is almost independent of peripheral crowding in substrate and product. Inaccessible asymmetric anion-π autocatalysis and sometimes erratic reproducibility further support that the origin of anion-π autocatalysis is more complex than originally assumed. The apparent long-distance communication without physical contact calls for the inclusion of water between substrate and product on the catalytic aromatic surface. Efficient anion-π autocatalysis around equimolar amounts but poor activity in dry solvents and with excess water indicate that this inclusion of water requires high precision. Computational models suggest that two water molecules transmit dual substrate activation by the product and serve as proton shuttles along antiparallel but decoupled hydrogen-bonded chains to delocalize and stabilize evolving charge density in the transition state by "anion-π double bonds". This new transition-state model of anion-π autocatalysis provides a plausible mechanism that explains experimental results and brings anion-π catalysis to an unprecedented level of sophistication.

Aging-related changes in reward-based decision-making depend on punishment frequency: An fMRI study.

Introduction: Aging is often accompanied by significant cognitive decline and altered decision making. Previous studies have found that older adults have difficulty in processing reward/risk information, leading to suboptimal decision strategy. However, it is still under investigated about the neural substrates of risky decision-making under ambiguity in aging. Methods: Using the Iowa Gambling Task, the current study investigated inter-individual differences of risk-taking behaviors in healthy older adults with task-related functional magnetic resonance imaging. Results: It was found that participants were able to improve their decisions in advantageous decks, but failed to avoid disadvantageous decks during task performance. The task-related activations within multiple brain regions were observed significantly different across the four decks, and showed negative correlations with age in disadvantageous decks but not in advantageous decks. Consistently, age-related whole brain analyses confirmed the negative age-effect on brain activations in disadvantageous decks, especially in high punishment frequency. In addition, the relationship between age and task performance in high punishment frequency was mediated by activation in the frontal subregions such as the middle frontal cortex and superior medial frontal cortex. Discussion: Our findings shed light on the neural substrates of altered risk-taking behaviors in aging, suggesting a greater sensitivity to high punishment frequency in older adults.

Bile acids ameliorates lipopolysaccharide-induced endometritis in mice by inhibiting NLRP3 inflammasome activation.

AIMS: Endometritis is a common inflammatory disorder affecting the reproductive health in both humans and livestock. The NLR family pyrin domain containing 3 (NLRP3) inflammasome has recently been identified as a possible therapeutic target for several inflammatory disorders. Bile acids (BAs) have been shown to possess anti-inflammatory properties by inhibiting the activation of the NLRP3 inflammasome. However, whether BAs ameliorate endometritis by targeting NLRP3 inflammasome remain poorly understood. MAIN METHODS: Female NLRP3+/+ and NLRP3-/- mice were subjected to uterine perfusion with lipopolysaccharide (LPS) to establish the endometritis model. For BAs pre-treatment, wild-type mice were administered oral gavage of BAs for seven days followed by uterine perfusion with LPS. All mice were euthanized and the uterine tissues were collected for analysis. KEY FINDINGS: The abundances of NLRP3 and interleukin-1 beta (IL-1ß) were significantly upregulated in the uterine tissues of endometritis mice. NLRP3 deficiency led to a reduction in the inflammatory response, neutrophil infiltration, and myeloperoxidase (MPO) activity in the uterus, as well as an inhibition of IL-1ß secretion. Moreover, BAs pre-treatment successfully decreased LPS-induced upregulation of NLRP3, ASC, and Caspase1, lessened histopathological alteration in the uterus, and notably reduced MPO activity and secretion of IL-1ß. SIGNIFICANCE: NLRP3 inflammasome is a promising target for endometritis treatment and BAs exhibit anti-inflammatory properties by repressing NLRP3 inflammasome activation, making them a possible novel therapeutic strategy for endometritis.