A nomogram for predicting the risk of cancer-related cognitive impairment in breast cancer patients based on a scientific symptom model.

Cancer-related cognitive impairment is a significant clinical challenge observed in patients with breast cancer, manifesting during or after treatment. This impairment leads to deteriorations in memory, processing speed, attention, and executive functioning, which profoundly impact patients' occupational performance, daily living activities, and overall quality of life. Grounded in the Symptom Science Model 2.0, this study investigates the contributing factors to Cancer-related cognitive impairment in breast cancer patients and develops a predictive nomogram for this demographic. Employing both univariate and multivariate logistic regression analyses, this investigation delineates the predictive factors influencing outcomes in breast cancer patients. A nomogram was constructed leveraging these identified predictive factors, accompanied by internal validation through bootstrap resampling methodology (1000 bootstrap samples). The efficacy of the predictive model was assessed by employing the Hosmer-Lemeshow goodness-of-fit test and calibration curves. The prevalence of cognitive impairment in breast cancer patients was identified to be 45.83%.Multivariate logistic regression analysis identified the independent predictors of Cancer-related cognitive impairment in breast cancer patients as place of residence, educational level, chemotherapy, benefit finding, post-traumatic growth, anxiety, fear of cancer progression, and fasting blood glucose levels. these factors were integrated into the nomogram. The Hosmer-Lemeshow goodness-of-fit test demonstrated that the prediction model was appropriately calibrated (χ2 = 11.520, P = 0.174). Furthermore, the model exhibited an area under the curve of 0.955 (95% CI 0.939 to 0.971) and a sensitivity of 0.906, evidencing its robust discriminative capacity and accuracy. Utilizing the Symptom Science Model 2.0 as a framework, this study comprehensively examines the multifaceted factors influencing Cancer-related cognitive impairment in breast cancer patients, spanning five critical domains: complex symptoms, phenotypic characterization, biobehavioral factors, social determinants of health, and patient-centered experiences. A predictive nomogram model was established, demonstrating satisfactory predictive accuracy and capability. This model is capable of identifying breast cancer patients with cognitive impairments with high precision. The findings furnish empirical evidence in support of the early detection, diagnosis, and intervention strategies for high-risk breast cancer patients afflicted with Cancer-related cognitive impairment.

PRRC2B modulates oligodendrocyte progenitor cell development and myelination by stabilizing Sox2 mRNA.

Oligodendrocyte progenitor cells (OPCs) differentiate into myelin-producing cells and modulate neuronal activity. Defects in OPC development are associated with neurological diseases. N6-methyladenosine (m6A) contributes to neural development; however, the mechanism by which m6A regulates OPC development remains unclear. Here, we demonstrate that PRRC2B is an m6A reader that regulates OPC development and myelination. Nestin-Cre-mediated Prrc2b deletion affects neural stem cell self-renewal and glial differentiation. Moreover, the oligodendroglia lineage-specific deletion of Prrc2b reduces the numbers of OPCs and oligodendrocytes, causing hypomyelination and impaired motor coordination. Integrative methylated RNA immunoprecipitation sequencing, RNA sequencing, and RNA immunoprecipitation sequencing analyses identify Sox2 as the target of PRRC2B. Notably, PRRC2B, displaying separate and cooperative functions with PRRC2A, stabilizes mRNA by binding to m6A motifs in the coding sequence and 3' UTR of Sox2. In summary, we identify the posttranscriptional regulation of PRRC2B in OPC development, extending the understanding of PRRC2 family proteins and providing a therapeutic target for myelin-related disorders.

The Role of PRRC2B in Cerebral Vascular Remodeling Under Acute Hypoxia in Mice.

High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.

PVT1 alleviates hypoxia-induced endothelial apoptosis by enhancing autophagy via the miR-15b-5p/ATG14 and miR-424-5p/ATG14 axis.

Endothelial dysfunction plays a crucial role in the pathogenesis of vascular disease. Long noncoding RNA (lncRNA) and microRNA (miRNA) play important roles in various cellular processes and are involved in several vascular endothelial cells (VECs) biological processes, including cell growth, migration, autophagy, and apoptosis. The functions of plasmacytoma variant translocation 1 (PVT1) in VECs have been progressively investigated in recent years, mainly with regard to proliferation and migration of endothelial cells (ECs). However, the mechanism underlying the regulation of autophagy and apoptosis in human umbilical vein endothelial cells (HUVEC) by PVT1 remains unclear. The present study showed that PVT1 knockdown accelerated apoptosis induced by oxygen and glucose deprivation (OGD) through suppression of cellular autophagy. Bioinformatic prediction of PVT1 target miRNAs revealed that PVT1 interacts with miR-15b-5p and miR-424-5p. The study further showed that miR-15b-5p and miR-424-5p inhibit the functions of autophagy related 14 (ATG14) and suppress cellular autophagy. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy by competitive binding, which down-regulates apoptosis. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy through competitive binding, which down-regulates apoptosis. The study provides insight into a novel therapeutic target that may be explored in the future for the treatment of cardiovascular disease.

Deletion of Calhm2 alleviates MPTP-induced Parkinson's disease pathology by inhibiting EFHD2-STAT3 signaling in microglia.

Background: Neuroinflammation is involved in the development of Parkinson's disease (PD). Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear. Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model. Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms. Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice. Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia. Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion: We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.

Nao Tan Qing ameliorates Alzheimer's disease-like pathology by regulating glycolipid metabolism and neuroinflammation: A network pharmacology analysis and biological validation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aß and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aß burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD.

Spore Powder of Paecilomyces hepiali Shapes Gut Microbiota to Relieve Exercise-Induced Fatigue in Mice.

Paecilomyces hepiali, a fungal strain isolated from natural Ophiocordyceps sinensis, contains similar pharmacologically active components, has been used widely as a substitute of O. sinensis in functional food and medicine. However, the components and anti-fatigue effects of P.hepiali spores and their mechanisms of action are largely unknown. Here, we compared the chemical composition in P.hepiali spore (HPS) and mycelium (HPM) by liquid chromatography with tandem mass spectrometry analysis. We found 85 metabolites with significant differences, and HPS contains more L-Malic acid, Oxalacetic acid, Fructose-1,6-bisphosphate, and L-Arginine than HPM. Then we evaluated their anti-fatigue effects and regulatory effects on the gut microbiota in mice. The forced swimming time (SW) was only significantly increased in HPS groups: the high and low dose of the HPS group was 101% and 72% longer than the control group, respectively. Both HPS and HPM treatment decreased lactic acid, blood urea nitrogen, creatine kinase while increased lactate dehydrogenase (LDH) levels in the blood. Moreover, mice treated with HPS and HPM showed less skeletal muscle fiber spacing and breakage. The relative abundance of Alistips, Eubacterium, Bacterium, Parasutterella, and Olsenella in the gut microbiota of the HPS group was higher than that in the HPM group through 16S rRNA gene sequencing analysis. These changes may be related to the regulation of nucleotide, amino acid, and carbohydrate metabolism. Correlation analysis between the gut microbiota and fatigue-related indicators suggested that Alistips, Clostridium, Akkermansia, Olsenella, and Lactobacillus were positively correlated with the SW and LDH content. Our findings demonstrated that HPS has beneficial anti-fatigue effects by regulating gut microbiota.

Individual and Combined Application of Nematophagous Fungi as Biological Control Agents against Gastrointestinal Nematodes in Domestic Animals.

Gastrointestinal nematodes (GINs) are a group of parasites that threaten livestock yields, and the consequent economic losses have led to major concern in the agricultural industry worldwide. The high frequency of anthelmintic resistance amongst GINs has prompted the search for sustainable alternatives. Recently, a substantial number of both in vitro and in vivo experiments have shown that biological controls based on predatory fungi and ovicidal fungi are the most promising alternatives to chemical controls. In this respect, the morphological characteristics of the most representative species of these two large groups of fungi, their nematicidal activity and mechanisms of action against GINs, have been increasingly studied. Given the limitation of the independent use of a single nematophagous fungus (NF), combined applications which combine multiple fungi, or fungi and chemical controls, have become increasingly popular, although these new strategies still have antagonistic effects on the candidates. In this review, we summarize both the advantages and disadvantages of the individual fungi and the combined applications identified to date to minimize recurring infections or to disrupt the life cycle of GINs. The need to discover novel and high-efficiency nematicidal isolates and the application of our understanding to the appropriate selection of associated applications are discussed.

Sodium rutin extends lifespan and health span in mice including positive impacts on liver health.

BACKGROUND AND PURPOSE: Ageing is associated with progressive metabolic dysregulation. Rutin is a metabolic regulator with a poor solubility. Using soluble sodium rutin we investigating the effect and mechanisms of rutin in ageing process. EXPERIMENTAL APPROACH: Wild type male mice were treated with or without sodium rutin ( 0.2 mg·ml-1 in drinking water from 8-month-old until end of life. Kaplan-Meier survival curve was used for lifespan assay, ageing-related histopathology analysis and metabolic analysis were performed to determine the effects of chronic sodium rutin on the longevity. Serological test, liver tissue metabolomics and transcriptomics were used for liver function assay. SiRNA knockdown Angptl8 and autophagy flux assay in HepG2 cell lines explored the mechanism through which sodium rutin might impact the function of hepatocyte. KEY RESULTS: Sodium rutin treatment extends the lifespan of mice by 10%. Sodium rutin supplementation alleviates ageing-related pathological changes and promotes behaviour performance in ageing mice. Sodium rutin supplementation altered the whole-body metabolism in mice, which exhibited increased energy expenditure and lower respiratory quotient. Transcriptomics analysis showed that Sodium rutin affected the expression of metabolic genes. Metabolomics analysis showed that Sodium rutin reduced liver steatosis through increased lipid ß-oxidation. Sodium rutin treatment increased the autophagy level both in vivo and in vitro. The inhibition of autophagy partially abolished the sodium rutin-mediated effect on lipolysis in HepG2 cells. CONCLUSION AND IMPLICATIONS: Sodium rutin treatment extends the lifespan and health span of mice with beneficial effects on metabolism, which were achieved by enhancing the autophagy activity in hepatocytes. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

A shrinkage-based criterion for evaluating resistance spot weldability of alloyed steels.

For many decades, several classical formulas on carbon equivalent (CE) have been widely used for evaluating the weldability of steels. Unfortunately, a single CE is impossible for various types of steels. In this study, the resistance spot weldability of medium-Mn steels was investigated. In particular, the influences of paint baking processes at different temperatures on the mechanical properties, fracture mode, and microstructure of weldment were studied. It was found that the paint baking above 170°C can change the tensile-shear failure of weldment from the undesired interfacial failure to the desired pull-out one, because the shrinkage of weldment during welding was compensated by the thermal expansion during the baking, leading to the "cold welding" realized for solid joining. Furthermore, a shrinkage-based criterion (∆l) was established for evaluating the weldability of greater range of alloyed steels more accurately and robustly than CE. The proposed criterion on measuring the weldability of high alloyed steels opens a promising path forward for designing a new generation of advanced high strength steels requiring good weldability.

Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Neuronal calcium dysfunction and microglial-mediated neuroinflammation are closely associated with the development of AD. However, it remains unknown whether calcium dysfunction contributes to microglial activation and, in turn, AD pathology in vivo. In this study, we demonstrated that the expression of calcium homeostasis modulator family protein 2 (Calhm2) is increased in an AD mouse model. In 5×FAD mice carrying five familial AD gene mutations, both conventional knockout of Calhm2 and conditional microglial knockout of Calhm2 significantly reduced amyloid ß deposition, neuroinflammation, and cognitive impairments. Mechanistically, knockout of Calhm2 inhibited microglial proinflammatory activity but increased phagocytic activity, leading to restoration of the balance between inflammation and phagocytosis. In addition, knockout of Calhm2 reduced acute LPS-induced neuroinflammation. These results highlight an important role for Calhm2 in microglial activation and provide a potential therapeutic target for diseases related to microglia-mediated neuroinflammation.

Extensive Genetic Diversity and Widespread Azole Resistance in Greenhouse Populations of Aspergillus fumigatus in Yunnan, China.

Aspergillus fumigatus is the main cause of invasive aspergillosis (IA) with a high annual global incidence and mortality rate. Recent studies have indicated an increasing prevalence of azole-resistant A. fumigatus (ARAF) strains, with agricultural use of azole fungicides as a potential contributor. China has an extensive agricultural production system and uses a wide array of fungicides for crop production, including in modern growth facilities such as greenhouses. Soils in greenhouses are among the most intensively cultivated. However, little is known about the occurrence and distribution of ARAF in greenhouse soils. Here, we investigated genetic variation and triazole drug susceptibility in A. fumigatus from greenhouses around metropolitan Kunming in Yunnan, southwest China. Abundant allelic and genotypic variations were found among 233 A. fumigatus strains isolated from nine greenhouses in this region. Significantly, ∼80% of the strains were resistant to at least one medical triazole drug, with >30% showing cross-resistance to both itraconazole and voriconazole. Several previously reported mutations associated with triazole resistance in the triazole target gene cyp51A were also found in our strains, with a strong positive correlation between the frequency of mutations at the cyp51A promoter and that of voriconazole resistance. Phylogenetic analyses of cyp51A gene sequences showed evidence for multiple independent origins of azole-resistant genotypes of A. fumigatus in these greenhouses. Evidence for multiple origins of azole resistance and the widespread distributions of genetically very diverse triazole-resistant strains of A. fumigatus in greenhouses calls for significant attention from public health agencies.IMPORTANCE The origin and prevalence of azole-resistant Aspergillus fumigatus have been attracting increasing attention from biologists, clinicians, and public health agencies. Current evidence suggests agricultural fungicide use as a major cause. In southwest China, greenhouses are used to produce large amounts of fruits, flowers, and vegetables for consumers throughout China as well as those in other countries, primarily in southeast Asia. Here, we found a very high frequency (∼80%) of triazole-resistant A. fumigatus in our sample, the highest reported so far, with a significant proportion of these strains resistant to both tested agricultural fungicides and medical triazole drugs. In addition, we found novel allelic and genotypic diversities and evidence for multiple independent origins of azole-resistant genotypes of A. fumigatus in greenhouse populations in this region. Our study calls for a systematic evaluation of the effects of azole fungicide usage in greenhouses on human health.

Microglial deletion and inhibition alleviate behavior of post-traumatic stress disorder in mice.

BACKGROUND: Alteration of immune status in the central nervous system (CNS) has been implicated in the development of post-traumatic stress disorder (PTSD). However, the nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear. METHODS: We constructed a mouse PTSD model by electric foot-shocks followed by contextual reminders and verified the PTSD-related symptoms by behavior test (including contextual freezing test, open-field test, and elevated plus maze test). We examined the immunocyte panorama in the brains of the naïve or PTSD mice by using single-cell mass cytometry. Microglia number and morphological changes in the hippocampus, prefrontal cortex, and amygdala were analyzed by histopathological methods. The gene expression changes of those microglia were detected by quantitative real-time PCR. Genetic/pharmacological depletion of microglia or minocycline treatment before foot-shocks exposure was performed to study the role of microglia in PTSD development and progress. RESULTS: We found microglia are the major brain immune cells that respond to PTSD. The number of microglia and ratio of microglia to immunocytes was significantly increased on the fifth day of foot-shock exposure. Furthermore, morphological analysis and gene expression profiling revealed temporal patterns of microglial activation in the hippocampus of the PTSD brains. Importantly, we found that genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure alleviated PTSD-associated anxiety and contextual fear. CONCLUSION: Our results demonstrated a critical role for microglial activation in PTSD development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition.

Fungi-Nematode Interactions: Diversity, Ecology, and Biocontrol Prospects in Agriculture.

Fungi and nematodes are among the most abundant organisms in soil habitats. They provide essential ecosystem services and play crucial roles for maintaining the stability of food-webs and for facilitating nutrient cycling. As two of the very abundant groups of organisms, fungi and nematodes interact with each other in multiple ways. Here in this review, we provide a broad framework of interactions between fungi and nematodes with an emphasis on those that impact crops and agriculture ecosystems. We describe the diversity and evolution of fungi that closely interact with nematodes, including food fungi for nematodes as well as fungi that feed on nematodes. Among the nematophagous fungi, those that produce specialized nematode-trapping devices are especially interesting, and a great deal is known about their diversity, evolution, and molecular mechanisms of interactions with nematodes. Some of the fungi and nematodes are significant pathogens and pests to crops. We summarize the ecological and molecular mechanisms identified so far that impact, either directly or indirectly, the interactions among phytopathogenic fungi, phytopathogenic nematodes, and crop plants. The potential applications of our understanding to controlling phytophagous nematodes and soilborne fungal pathogens in agricultural fields are discussed.

HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway.

Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke.

Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice.

BACKGROUND: Persistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear. METHOD: Wild-type and Nlrp3-/- mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1ß (IL-1ß) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test. RESULTS: We demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1ß administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior. CONCLUSION: Taken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.

Mib2 Deficiency Inhibits Microglial Activation and Alleviates Ischemia-Induced Brain Injury.

Neuroinflammation plays a critical role in ischemia-induced brain injury. Mib2, an E3 ubiquitin ligase, has been reported to regulate Notch signaling and participate in the peripheral immune system. However, the roles of Mib2 in the nervous system are not well characterized. In this study, we show that Mib2 is involved in lipopolysaccharide (LPS)- and oxygen-glucose deprivation (OGD)-induced microglial activation. Mechanistically, Mib2 interacts with the IKK complex and regulates the activation of NF-κB signaling, thus modulating Notch1 transcription in the microglia. Furthermore, we generated a microglia-specific Mib2 knockout mice and found that microglia-specific deletion of Mib2 significantly alleviates ischemia-induced neuroinflammation and brain injury. Taken together, our results reveal a critical role of Mib2 in microglial activation and ischemia-induced brain injury, thus providing a potential target for the treatment of stroke.

Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice.

Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)-cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1ß in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.

Promotion of Metabolite Synthesis in Isaria cicadae, a Dominant Species in the Cicada Flower Microbiota, by Cicada Pupae.

Cicada flowers, which are edible and medicinal mushrooms, are the fruiting bodies of Isaria cicadae, a fungus that is parasitic on the larvae of cicada pupae. We hypothesize that host factors might possess stimulatory activity on metabolite synthesis in Isaria cicadae. Here, we first compared the microbial community structures of different wild cicada flowers across geographical regions, compartments, and growth stages via high-throughput sequencing. Isaria cicadae TZC-3, an isolate of the most abundant operational taxonomic unit (OTU6782) in all the fungal communities, was isolated from wild cicada flowers. Furthermore, the effects of cicada pupae on metabolite synthesis in Isaria cicadae TZC-3 were studied in submerged culture. The contents of intercellular polysaccharides, adenosine, N6-(2-hydroxyethyl)-adenosine, free amino acids, and hydrolyzed monosaccharides in the mycelia cultured with cicada pupa powder (4%) were significantly increased as compared with the contents in the control group. This indicates that a cicada pupa can act as an elicitor for metabolite synthesis in Isaria cicadae.