Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

On-chip integrated metasystem for spin-dependent multi-channel color holography.

On-chip integrated metasurface driven by in-plane guided waves is of great interests in various light-field manipulation applications such as colorful augmented reality and holographic display. However, it remains a challenge to design colorful multichannel holography by a single on-chip metasurface. Here we present metasurfaces integrated on top of a guided-wave photonic slab that achieves multi-channel colorful holographic light display. An end-to-end scheme is used to inverse design the metasurface for projecting off-chip preset multiple patterns. Particular examples are presented for customized patterns that were encoded into the metasurface with a single-cell meta-atom, working simultaneously at RGB color channels and for several different diffractive distances, with polarization dependence. Holographic images are generated at 18 independent channels with such a single-cell metasurface. The proposed design scheme is easy to implement, and the resulting device is viable for fabrication, promising plenty of applications in nanophotonics.

The use of longitudinal CT-based radiomics and clinicopathological features predicts the pathological complete response of metastasized axillary lymph nodes in breast cancer.

BACKGROUND: Accurate assessment of axillary status after neoadjuvant therapy for breast cancer patients with axillary lymph node metastasis is important for the selection of appropriate subsequent axillary treatment decisions. Our objectives were to accurately predict whether the breast cancer patients with axillary lymph node metastases could achieve axillary pathological complete response (pCR). METHODS: We collected imaging data to extract longitudinal CT image features before and after neoadjuvant chemotherapy (NAC), analyzed the correlation between radiomics and clinicopathological features, and developed models to predict whether patients with axillary lymph node metastasis can achieve axillary pCR after NAC. The clinical utility of the models was determined via decision curve analysis (DCA). Subgroup analyses were also performed. Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots. RESULTS: A total of 549 breast cancer patients with metastasized axillary lymph nodes were enrolled in this study. 42 independent radiomics features were selected from LASSO regression to construct a logistic regression model with clinicopathological features (LR radiomics-clinical combined model). The AUC of the LR radiomics-clinical combined model prediction performance was 0.861 in the training set and 0.891 in the testing set. For the HR + /HER2 - , HER2 + , and Triple negative subtype, the LR radiomics-clinical combined model yields the best prediction AUCs of 0.756, 0.812, and 0.928 in training sets, and AUCs of 0.757, 0.777 and 0.838 in testing sets, respectively. CONCLUSIONS: The combination of radiomics features and clinicopathological characteristics can effectively predict axillary pCR status in NAC breast cancer patients.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

Identification and biological characteristics of Enterococcus casseliflavus TN-47 isolated from Monochamus alternatus.

With the widespread use of antibiotics, the incidence of antibiotic resistance in microorganisms has increased. Monochamus alternatus is a trunk borer of pine trees. This study aimed to investigate the in vitro antimicrobial and biological characteristics of Enterococcus casseliflavus TN-47 (PP411196), isolated from the gastrointestinal tract of M. alternatus in Jilin Province, PR China. Among 13 isolates obtained from the insects, five were preliminarily screened for antimicrobial activity. E. casseliflavus TN-47, which exhibited the strongest antimicrobial activity, was identified. E. casseliflavus TN-47 possessed antimicrobial activity against Staphylococcus aureus USA300 and Salmonella enterica serovar Pullorum ATCC 19945. Furthermore, E. casseliflavus TN-47 was sensitive to tetracyclines, penicillins (ampicillin, carbenicillin, and piperacillin), quinolones and nitrofuran antibiotics, and resistant to certain beta-lactam antibiotics (oxacillin, cefradine and cephalexin), macrolide antibiotics, sulfonamides and aminoglycosides. E. casseliflavus TN-47 could tolerate low pH and pepsin-rich conditions in the stomach and grow in the presence of bile acids. E. casseliflavus TN-47 retained its strong auto-aggregating ability and hydrophobicity. This strain did not exhibit any haemolytic activity. These results indicate that E. casseliflavus TN-47 has potential as a probiotic. This study provides a theoretical foundation for the future applications of E. casseliflavus TN-47 and its secondary metabolites in animal nutrition and feed.

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

IFI204 protects host defense against Staphylococcus aureus-induced pneumonia by promoting extracellular traps formation.

Interferon-inducible protein 204 (IFI204) is an intracellular DNA receptor that can recognize DNA viruses and intracellular bacteria. Extracellular traps (ETs) have been recognized as an indispensable antimicrobial barrier that play an indispensable role in bacterial, fungal, parasitic, and viral infections. However, how ETs form and the mechanisms by which IFI204 function in Staphylococcus aureus pneumonia are still unclear. Moreover, by in vitro experiments, we proved that IFI204 deficiency decreases the formation of ETs induced by Staphylococcus aureus in a NOX-independent manner. More importantly, Deoxyribonuclease I (DNase I) treatment significantly inhibited the formation of ETs. IFI204 contributed to ETs formation by promoting citrullination of histone H3 and the expression of PAD4 (peptidylarginine deiminase 4). Altogether, these findings highlight the potential importance of IFI204 for host defense against S. aureus USA300-TCH1516 infection.

Starting a Romantic Relationship, Breakups, and Sleep: A Longitudinal Study of Chinese Adolescents.

BACKGROUND: Epidemiological data on the association between romantic experiences and sleep in adolescents are limited. This study examined the associations of starting a romantic relationship (SRR) and romantic breakups with insomnia symptoms and sleep duration in adolescents. METHODS: A total of 7,072 Chinese adolescents were surveyed in November-December 2015 and 1 year later. A self-administered questionnaire was used to assess SRR, romantic breakups, sleep duration, insomnia symptoms, depressive symptoms, substance use, and demographics. RESULTS: The mean age of the sample was 14.58 (SD = 1.46) years and half were female. SRR only, breakups only, and both (SRR + breakups) in the past year were reported by 7.0%, 8.4%, and 15.4% of the sample, respectively. At the baseline and 1-year follow-up, 15.2% and 14.7% of the sample had insomnia symptoms and 47.7% and 42.1% reported short sleep duration (<7 h/night), respectively. After adjusting for depressive symptoms, substance use, and demographics, SRR and breakups were significantly associated with 35-45% increased odds of insomnia symptoms at baseline. SRR + breakups were significantly associated with short sleep duration (OR = 1.28, 95%CI = 1.05-1.56). SRR (OR = 1.61, 95%CI = 1.16-2.23) and breakups (OR = 1.43, 95%CI = 1.04-1.96) were significantly associated with increased odds of incident insomnia symptoms at 1-year follow-up. These associations were stronger in younger adolescents (<15 years) than in older adolescents (≥15 years), especially in girls. CONCLUSIONS: The findings suggest that SRR and breakups are associated with insomnia symptoms and short sleep duration, underscoring the importance of romantic relationships education and management of romantic stress for healthy sleep especially in early adolescent girls.

Culturing the Chicken Intestinal Microbiota and Potential Application as Probiotics Development.

Pure cultures of chicken intestinal microbial species may still be crucial and imperative to expound on the function of gut microbiota, and also contribute to the development of potential probiotics and novel bioactive metabolites from gut microbiota. In this study, we isolated and identified 507 chicken intestinal bacterial isolates, including 89 previously uncultured isolates. Among these, a total of 63 Lactobacillus strains, belonging to L. vaginalis, L. crispatus, L. gallinarum, L. reuteri, L. salivarius, and L. saerimneri, exhibited antibacterial activity against S. Pullorum. Acid tolerance tests showed Limosilactobacillus reuteri strain YPG14 (L. reuteri strain YPG14) has a particularly strong tolerance to acid. We further characterized other probiotic properties of L. reuteri strain YPG14. In simulated intestinal fluid, the growth of L. reuteri strain YPG14 remained stable after incubation for 4 h. The auto-aggregation test showed the auto-aggregation percentage of L. reuteri strain YPG14 was recorded as 15.0 ± 0.38%, 48.3 ± 2.51%, and 75.1 ± 4.44% at 3, 12, and 24 h, respectively. In addition, the mucin binding assay showed L. reuteri strain YPG14 exhibited 12.07 ± 0.02% adhesion to mucin. Antibiotic sensitivity testing showed that L. reuteri strain YPG14 was sensitive to the majority of the tested antibiotics. The anti-Salmonella Pullorum (S. Pullorum) infection effect in vivo revealed that the consumption of L. reuteri strain YPG14 could significantly improve body weight loss and survival rate of chicks infected by S. Pullorum; reduce the loads of S. Pullorum in the jejunum, liver, spleen, and feces; and alleviate the jejunum villi morphological structure damage, crypt loss, and inflammatory cell infiltration caused by S. Pullorum. Overall, this study may help us to understand the diversity of chicken intestinal microflora and provide some insights for potential probiotic development from gut microbiota and may find application in the poultry industry.

Prevalence and Associated Factors of Premenstrual Syndrome in Chinese Adolescent Girls.

Epidemiological data on premenstrual syndrome (PMS) in Chinese adolescents are limited. This study reported the prevalence and associated factors of PMS in a large sample of Chinese adolescents. A total of 5099 adolescent girls who had menarche participated in the baseline survey of Shandong Adolescent Behavior and Health Cohort study in Shandong, China. A self-administered questionnaire was used to ask about PMS, age at menarche, menstrual cycle interval, menstrual flow length, menstrual regularity, period pain, body weight and height, trait anger, stressful life events, and demographics. The mean age of the sample was 15.19 years (SD = 1.32). The overall prevalence of PMS was 24.6%. The prevalence rates of PMS-anxiety, PMS-water retention, PMS-craving, and PMS-depression were 18.9%, 4.0%, 7.9%, and 11.5%, respectively. The most common symptoms were premenstrual irritability (54%) and fatigue (52.5%). Stepwise logistic regression showed that high levels of life stress (OR 2.26), high levels of trait anger (OR 4.65), alcohol consumption (OR 1.28), menstrual cycle interval ≤ 24 days (OR 1.45), and mild (OR 1.50), moderate (OR 2.57) or severe period pain (OR 4.84) were all significantly associated with increased likelihood of PMS. In conclusion, approximately 1 in 4 Chinese adolescent girls suffered from PMS. Multiple psychosocial and menstrual factors were associated with PMS. Further research is needed to understand developmental changes of PMS and its long-term impacts on psychosocial wellbeing in Chinese adolescent girls.

Chemical Constituents of Thesium chinense Turcz and Their In Vitro Antioxidant, Anti-Inflammatory and Cytotoxic Activities.

Three novel compounds (1-3) along with twenty-six known compounds, two known steroids (4-5) and twenty-four known phenylpropanoids (6-29) were isolated from the whole plant of Thesium chinense Turcz. The structures of the three new compounds were elucidated on the basis of ESI-MS, HR-ESIMS, 1D and 2D NMR, IR, UV spectroscopic data. The absolute stereochemistry of compound 1 was determined by the Gauge-Including Atomic Orbitals (GIAO) method. The in vitro antioxidant, anti-inflammatory and cytotoxic activities of the isolated compounds were evaluated by DPPH radical-scavenging assay, LPS-activated RAW 264.7 cells model and CCK-8 kit, respectively. Compound 11 showed high antioxidant activity with an SC50 value of 16.2 ± 1.6 µM. Compound 21 showed considerable anti-inflammatory activity with an IC50 value of 28.6 ± 3.0 µM. Compounds 4 and 5 displayed potent cytotoxic activity against human NCI-H292, SiHa, A549, and MKN45 cell lines, with the compound 4 having IC50 values of 17.4 ± 2.4, 22.2 ± 1.1, 9.7 ± 0.9, 9.5 ±0.7 µM, and the compound 5 having all IC50 values less than 0.1 µM in vitro.

[Clinical Analysis of Voriconazole Concentrations in Cerebrospinal Fluid and Blood in Patients with Ryptococcal Meningitis].

Objective: To investigate the concentrations of voriconazole (VCZ) in the central nervous system (CNS) of patients with cryptococcal meningitis and the relationship thereof. Methods: We retrospectively analyzed the trough concentration of VCZ in the cerebrospinal fluid (CSF) and the blood of 25 adult patients who had cryptococcal meningitis, and who were not infected with HIV. We also examined patient-level characteristics that could contribute to the differences in CSF/plasma VCZ concentration ratio. Results: The trough concentration of VCZ in plasma ranged from 0.38 to 8.56 mg/L, and the median (P 25, P 75) was 1.81 (1.40, 3.84) mg/L. The trough concentration of VCZ in CSF ranged from 0.17 to 3.92 mg/L, and the median (P 25, P 75) was 1.02 (0.54, 1.84) mg/L. The CSF VCZ trough concentration showed a slight negative correlation with the nucleated cell counts in CSF, but the correlation was not statistically significant ( r=-0.377, P=0.063). There was a positive correlation between VCZ concentrations in CSF and that in the plasma ( r=0.736, P<0.001), and the median (P 25, P 75) CSF/plasma ratio was 0.43 (0.34, 0.68). The CSF/plasma ratio did not statistically correlate with age, body surface area (BSA), radiology changes (hydrocephalus), or intracranial pressure. Conclusion: There is a positive correlation between VCZ concentration in CSF and VCZ concentration in the plasma, and no influencing factors of CSF/plasma ratio were found.

Genome mining reveals polysaccharide-degrading potential and new antimicrobial gene clusters of novel intestinal bacterium Paenibacillus jilinensis sp. nov.

BACKGROUND: Drug-resistant bacteria have posed a great threat to animal breeding and human health. It is obviously urgent to develop new antibiotics that can effectively combat drug-resistant bacteria. The commensal flora inhabited in the intestines become potential candidates owing to the production of a wide range of antimicrobial substances. In addition, host genomes do not encode most of the enzymes needed to degrade dietary structural polysaccharides. The decomposition of these polysaccharides mainly depends on gut commensal-derived CAZymes. RESULTS: We report a novel species isolated from the chicken intestine, designated as Paenibacillus jilinensis sp. nov. and with YPG26T (= CCTCC M2020899T) as the type strain. The complete genome of P. jilinensis YPG26T is made up of a single circular chromosome measuring 3.97 Mb in length and containing 49.34% (mol%) G + C. It carries 33 rRNA genes, 89 tRNA genes, and 3871 protein-coding genes, among which abundant carbohydrate-degrading enzymes (CAZymes) are encoded. Moreover, this strain has the capability to antagonize multiple pathogens in vitro. We identified putative 6 BGCs encoding bacteriocin, NRPs, PKs, terpenes, and protcusin by genome mining. In addition, antibiotic susceptibility testing showed sensitivity to all antibiotics tested. CONCLUSIONS: This study highlights the varieties of CAZymes genes and BGCs in the genome of Paenibacillus jilinensis. These findings confirm the beneficial function of the gut microbiota and also provide a promising candidate for the development of new carbohydrate degrading enzymes and antibacterial agents.

Nightmare frequency and psychopathological problems in a large sample of Chinese adolescents.

PURPOSE: Nightmares are common, especially in pediatric populations and psychiatric patients. Nightmares are associated with daytime distress and negative health outcomes. The data on the prevalence and psychopathological profiles of nightmares in Chinese adolescents are limited. This study examined age and gender differences in nightmare frequency and associated psychopathological problems in a large sample of Chinese adolescents. METHODS: A total of 11,831 adolescent students (mean age = 14.9, 12-18 years) participated in the baseline survey of Shandong Adolescent Behavior and Health Cohort. Participants completed a self-administered questionnaire to report their nightmare frequency, trait anger, hopelessness, and multiple domains of behavioral/emotional problems. Univariate and multivariate analyses were performed to examine psychopathological problems in relation to nightmare frequency. RESULTS: Of the sample, 45.2% reported having nightmares at least once in the past month and 7.9% at least once/week. Girls reported more frequent nightmares than boys. Nightmare frequency significantly declined with age for both boys and girls. Mean scores on trait anger, hopelessness, attention, internalizing problems, and externalizing problems significantly increased with nightmare frequency. Frequent nightmares (at least once/week) were significantly associated with 2-4-fold increased likelihood of behavioral/emotional problems after adjusting for adolescent and family covariates. CONCLUSION: Nightmares are prevalent in Chinese adolescents. Frequent nightmares are associated with multiple domains of psychopathological problems. Assessment and intervention of frequent nightmares should be incorporated into routine clinical practice and mental health services in adolescents.

A Longitudinal Study of Insomnia, Daytime Sleepiness, and Academic Performance in Chinese Adolescents.

BACKGROUND: Longitudinal data on the associations between sleep disturbances, daytime sleepiness, and daily functioning are limited in the general adolescent population. This study examined the cross-sectional and longitudinal associations between insomnia, excessive daytime sleepiness (EDS), and subject-specific academic performance in a large sample of Chinese adolescents. METHOD: Data were derived from the Shandong Adolescent Behavior and Health Cohort (n = 7,072) study. A self-administered questionnaire was used to assess insomnia, EDS, academic performance (overall, Chinese, mathematics, and English), behavioral and emotional problems, and family demographics. The cross-sectional analysis was conducted with baseline data while the longitudinal analysis was conducted with both baseline and 1-year follow-up data. Logistic regression analyses and mediation models were performed to examine the associations between insomnia, EDS, and academic performance. RESULTS: Logistic regression analyses revealed that insomnia and EDS had significant cross-sectional associations with overall performance and mathematics performance after controlling for age, gender, ever smoking, ever alcohol drinking, frequent snore, sleep duration, chronic disease, anxious/depressive symptoms, parents' education, parents' occupation, and family economic status. Both insomnia (OR = 1.20, 95% CI: 1.00-1.45) and EDS (OR = 1.22, 95% CI: 1.03-1.45) at baseline were significantly associated with poor mathematics performance 1 year later. The effect of insomnia at baseline on poor academic performance 1 year later was mediated by EDS except for the Chinese subject after controlling for the covariates. CONCLUSIONS: Insomnia and daytime sleepiness are significantly associated with poor academic performance, particularly in mathematics. EDS mediates the association between insomnia and poor academic performance. Further research is warranted to investigate the effects of sleep disturbance and daytime sleepiness on the learning process and performance across academic subjects.

Akkermansia muciniphila Suppresses High-Fat Diet-Induced Obesity and Related Metabolic Disorders in Beagles.

Obesity is one of the prevalent chronic diseases in human and companion animals usually associated with several metabolic disorders. The gut commensal bacterium Akkermansia muciniphila (A. muciniphila) is known for its therapeutic effects on metabolic disorders and inflammations. Here, we isolated the A. muciniphila AKK2 strain from the feces of interferon-inducible protein 204-/- (IFI204-/-) mice and further evaluated its anti-obesity effects on high-fat diet (HFD)-fed C57BL/6J mice and beagles. The results showed that it effectively controlled weight gain. Microbiome analysis using 16S rRNA gene sequencing revealed that HFD alters gut microbiota composition and A. muciniphila AKK2 increases the Firmicutes/Bacteroidetes (F/B) ratio in beagles. Furthermore, we prepared microcapsules containing A. muciniphila AKK2, and tolerance tests showed the encapsulation maintained high viability and stability in an aerobic environment and simulated the secretion of gastrointestinal fluids. Overall, this study widens the spectrum of A. muciniphila applications to prevent obesity.

GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1-Cxcr2 axis.

Gasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1ß secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1-Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1ß production, the critical role of IL-1ß was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1ß production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1-Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1-Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy.

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug's clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson's disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.

Nearly dispersionless multicolor metasurface beam deflector for near eye display designed by a physics-driven deep neural network.

Dispersion is one of the most important issues in see-through near eye displays with waveguide technology. In particular, the nanophotonics design is challenging but demanding. In this paper, we propose a design method for a multilayer achromatic metasurface structure for near eye display application by a physics-driven generative neural network. Two in-coupling metagratings under different projector illuminations are presented and numerically verified with the absolute diffraction efficiency over 89%. A beam splitter, which provides a balance between compactness and visual comfort in a single-projector-binocular display, is also designed. Finally, we apply this method to an out-coupling metasurface with the capability of enlarging the visible region by threefold.