Salidroside Ameliorates Lung Injury Induced by PM 2.5by Regulating SIRT1-PGC-1α in Mice.

Objective: This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Methods: Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Results: Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1ß, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. Conclusion: SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5-induced lung injury.

Vaginal reconstruction with a double-sided biomembrane-a preclinical experimental study on large animals.

Tissue engineering techniques bring the promise of vaginal reconstruction with low invasiveness and fewer complications. However, existing biomaterial scaffolds remain limited in efficient vaginal recovery, focusing only on regenerating an epithelial layer, but muscle layers are missing or abnormal. The lack of a multi-tissue hierarchical structure in the reconstructed vagina leads to shrinking, stenosis, and fibrosis. Here, an acellular matrix named a double-sided biomembrane (DBM) is demonstrated for vaginal recovery. The regeneration of epithelial and muscle layers is achieved simultaneously since the smooth side of the DBM is helpful for guiding epithelial cell growth, while its loose and porous side guides muscle cell growth. In addition, the DBM demonstrates excellent mechanical properties similar to vaginal tissue, and hydrophilicity. Therefore, neovaginas were observed in the fourth and twelfth weeks after DBMs were transplanted to repair full-thickness vaginal defects (4 cm) that we established in large animals. The DBMs can effectively promote rapid epithelialization, the formation of large muscle bundles, higher rates of angiogenesis, and the restoration of physiological function in a neovagina. That is, the injured vagina achieves nearly complete recovery in anatomy and function, similar to a normal vagina. These preclinical results indicate that the DBM has prospects for vaginal injury repair.

Artificial intelligence in psychiatry research, diagnosis, and therapy.

Psychiatric disorders are now responsible for the largest proportion of the global burden of disease, and even more challenges have been seen during the COVID-19 pandemic. Artificial intelligence (AI) is commonly used to facilitate the early detection of disease, understand disease progression, and discover new treatments in the fields of both physical and mental health. The present review provides a broad overview of AI methodology and its applications in data acquisition and processing, feature extraction and characterization, psychiatric disorder classification, potential biomarker detection, real-time monitoring, and interventions in psychiatric disorders. We also comprehensively summarize AI applications with regard to the early warning, diagnosis, prognosis, and treatment of specific psychiatric disorders, including depression, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, addiction, sleep disorders, and Alzheimer's disease. The advantages and disadvantages of AI in psychiatry are clarified. We foresee a new wave of research opportunities to facilitate and improve AI technology and its long-term implications in psychiatry during and after the COVID-19 era.

Fc effector of anti-Aß antibody induces synapse loss and cognitive deficits in Alzheimer's disease-like mouse model.

Passive immunotherapy is one of the most promising interventions for Alzheimer's disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aß-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aß, antibody, and complement. Notably, anti-Aß antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aß-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aß-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.

Changes Observed in Potential Key Candidate Genes of Peripheral Immunity Induced by Tai Chi among Patients with Parkinson's Disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disease characterized by motor dysfunction. Although the inhibition of inflammation by Tai Chi has been demonstrated to involve a peripheral cytokine response and may play an important role in improving the motor function of PD patients, the related specific molecular mechanisms of the peripheral immune response to Tai Chi are not fully understood. The microarray dataset 'GSE124676' for the peripheral immune response to Tai Chi of PD patients was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened and analyzed using weighted gene co-expression network analysis (WGCNA). A total of 136 DEGs were found in the PD patients after Tai Chi, suggesting an effect of Tai Chi on the peripheral immunity of PD patients. The DEGs are mainly involved in neutrophil activation, T-cell activation, and NOD-like receptor and IL-17 signaling pathways. Furthermore, six key candidate genes (FOS, FOSB, JUNB, ZFP36, CAMP and LCN2) that are involved in peripheral inflammation and the inhibition of inflammation induced by Tai Chi were observed. The results in the present study could be conducive to comprehensively understanding the molecular mechanism involved in the effect of Tai Chi on peripheral inflammation in PD patients and providing novel targets for future advanced research.

UBR5 promotes tumor immune evasion through enhancing IFN-γ-induced PDL1 transcription in triple negative breast cancer.

Background: The up-regulation of PD-L1 is recognized as an adaption of cancer cells to evade immune surveillance and attack. However, the intrinsic mechanisms of the induction of PD-L1 by interferon-γ (IFN-γ) in tumor microenvironment remain incompletely characterized. Ubiquitin ligase E3 component N-recognition protein 5 (UBR5) has a critical role in tumorigenesis of triple negative breast cancer (TNBC) by triggering specific immune responses to the tumor. Dual targeting of UBR5 and PD-L1 exhibited superior therapeutic benefits in a preclinical TNBC model in short term. Methods: The regulation of UBR5 to PD-L1 upon IFN-γ stimulation was evaluated through in UBR5 deficiency, reconstitution or overexpression cell line models by quantitative PCR, immunohistochemistry and RNA-seq. The effects of PD-L1 regulation by UBR5 and double blockade of both genes were evaluated in mouse TNBC model. Luciferase reporter assay, chromatin immunoprecipitation-qPCR and bioinformatics analysis were performed to explore the transcription factors involved in the regulation of UBR5 to PD-L1. Results: E3 ubiquitin ligase UBR5 plays a key role in IFN-γ-induced PDL1 transcription in TNBC in an E3 ubiquitination activity-independent manner. RNA-seq-based transcriptomic analyses reveal that UBR5 globally affects the genes in the IFN-γ-induced signaling pathway. Through its poly adenylate binding (PABC) domain, UBR5 enhances the transactivation of PDL1 by upregulating protein kinase RNA-activated (PKR), and PKR's downstream factors including signal transducers and activators of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1). Restoration of PD-L1 expression in UBR5-deficient tumor cells recoups their malignancy in vivo, whereas CRISPR/Cas9-mediated simultaneous abrogation of UBR5 and PD-L1 expression yields synergistic therapeutic benefits than either blockade alone, with a strong impact on the tumor microenvironment. Conclusions: This study identifies a novel regulator of PDL1 transcription, elucidates the underlying molecular mechanisms and provides a strong rationale for combination cancer immunotherapies targeting UBR5 and PD-L1.

Interleukin-33 protects mice against hindlimb ischemic injury by enhancing endothelial angiogenesis.

Peripheral vascular disease usually leads to vascular injury and inflammatory reaction, and the main therapeutic measures are improving angiogenesis and restoring blood flow. Interleukin-33 (IL-33) is a pleiotropic cytokine implicated in immune responses and tissue repair. Here, we explore the effect of IL-33 in hindlimb ischemic injury and elucidate the potential mechanisms of action. The expression of IL-33 and its receptor ST2 were obviously elevated in ischemic hindlimb of mice underwent ligation surgery. Exogenous IL-33 apparently facilitated blood flow restoration in ischemic hindlimb, whereas ST2-deficient mice displayed severe defects in ischemic hindlimb repair. The activation of IL-33/ST2 signaling contributed to revascularization in ischemic hindlimb, which was related to modulation of proangiogenic function of endothelial cells. Further ex vivo and in vitro studies revealed that IL-33 clearly accelerated angiogenesis by Matrigel plug and tube formation assays. Mechanically, the angiogenic function of IL-33 is involved in regulation of Akt/eNOS pathway. All together, these findings imply that IL-33-mediated endothelial angiogenesis may represent a prospective effective therapy for hindlimb ischemic damage.

Self-Enhanced False Memory Across the Life Span.

OBJECTIVES: The role of self in veridical memory has been extensively studied, but what is the role of self in false memory development across the life span? The current study examined the impact of self-reference on associative false memory in children, younger adults, and older adults, and further investigated possible mechanisms concerning how self-reference might affect false memory in different age groups. METHODS: Combining a self-reference manipulation with the Deese/Roediger-McDermott (DRM) paradigm, children, younger adults, and older adults encoded DRM word lists as paired with their own name, another person's name, or a red square. Later their true and false recognition memory as well as recollection and familiarity were measured. RESULTS: A self-enhanced false memory effect was found in all age groups. That is, participants generated more false memories in the self-reference condition relative to the other-reference and neutral conditions. Furthermore, when examining its underlying memory mechanisms, we found that self-reference mainly increased false recollection in younger adults but facilitated familiarity of critical lures in older adults. DISCUSSION: Although self-reference increases false memory in both younger and older adults, the underlying mechanisms are different in that older adults have more self-relevant false familiarity while younger adults generate more self-relevant phantom recollection. The current study also has implications for eyewitness reports, suggesting that the self-relevance of memory may be one relevant factor to consider when evaluating potential risk factors of false memory.

Neuroprotection of N-benzyl Eicosapentaenamide in Neonatal Mice Following Hypoxic-Ischemic Brain Injury.

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic-ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic-ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53-PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

The immunodominant and neutralization linear epitopes for SARS-CoV-2.

Although vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulate the 3D structures and predict the B cell epitopes on the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches and validate epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induce antibody production, six of these are immunodominant epitopes in individuals, and 23 are conserved within SARS-CoV-2, SARS-CoV, and bat coronavirus RaTG13. We find that the immunodominant epitopes of individuals with domestic (China) SARS-CoV-2 are different from those of individuals with imported (Europe) SARS-CoV-2, which may be caused by mutations on the S (G614D) and N proteins. Importantly, we find several epitopes on the S protein that elicit neutralizing antibodies against D614 and G614 SARS-CoV-2, which can contribute to vaccine design against coronaviruses.

ncDRMarker: a computational method for identifying non-coding RNA signatures of drug resistance based on heterogeneous network.

BACKGROUND: Drug resistance is the primary cause of failure in the treatment of cancer. Identifying signatures of chemoresistance will help to overcome this problem. Current drug resistance studies focus on protein-coding genes and ignore non-coding RNAs (ncRNAs), rendering it a challenging task to systematically identify ncRNAs involved in drug resistance. METHODS: In this study, protein-protein, miRNA-target gene, miRNA-lncRNA interactions were integrated to construct a mRNA-miRNA-lncRNA network. Then, the random walk with restart (RWR) method was extended to the network for identifying ncRNA signatures of drug resistance. The leave-one-out cross validation (LOOCV) and receiver operating characteristic curve (ROC) were used to estimate the performance of ncDRMarker. Wilcoxon rank-sum test was used to validate the identified ncRNAs in NCI-60 cancer cell lines. KEGG pathway enrichment analysis was implemented to characterize the biological function of some identified ncRNAs. RESULTS: We performed this method on ten common clinical chemotherapy drugs and analyzed the results in detail. The region beneath the ROC was up to 0.881-0.951, which did not change significantly in the incomplete network, indicating the high performance and robustness of the method. Further, we confirmed the role of the identified ncRNAs in drug resistance, i.e., miR-92a-3p, a candidate chemoresistance ncRNA of tamoxifen and paclitaxel, can significantly classify cancer cell lines into sensitive or resistant to tamoxifen (or paclitaxel). We also dissected the mRNA-miRNA-lncRNA composite network and found that some hub ncRNAs, such as miR-124-3p, were involved in resistance of multiple drugs and engaged in many significant cancer-related pathways. Lastly, we have provided a ncDRMarker platform for users to identify candidate ncRNAs of drug resistance, which is available at http://bio-bigdata.hrbmu.edu.cn/ncDRMarker/index. CONCLUSIONS: Our findings suggest that ncDRMarker is an effective computational technique for prioritizing candidate ncRNAs of drug resistance. Additionally, the identified ncRNAs could be targeted to overcome drug resistance and help realize individualized treatment.

Superparamagnetic iron oxide nanoparticles conjugated with Aß oligomer-specific scFv antibody and class A scavenger receptor activator show therapeutic potentials for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aß oligomers (AßOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AßOs and promote Aß clearance may have great value for AD treatment. RESULTS: We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aß oligomer-specific scFv antibody W20 and class A scavenger receptor activator XD4 (W20/XD4-SPIONs). Besides the diagnostic value, W20/XD4-SPIONs retained the anti-Aß properties of W20 and XD4 by inhibiting Aß aggregation, attenuating AßO-induced cytotoxicity and increasing microglial phagocytosis of Aß. When applied to APP/PS1 mice, W20/XD4-SPIONs significantly rescued cognitive deficits and alleviated neuropathology of AD mice. CONCLUSION: These results suggest that W20/XD4-SPIONs show therapeutic benefits for AD. In combination with the early diagnostic property, W20/XD4-SPIONs present as a promising agent for early-stage AD diagnosis and intervention.

Acute Effects of Individual Exposure to Fine Particulate Matter on Pulmonary Function in Schoolchildren.

OBJECTIVE: This panel study aimed to determine the acute effects of exposure to fine particulate matter (PM 2.5) on schoolchildren's pulmonary function. METHODS: We selected 51 schoolchildren aged 9-12 years attending a full-time boarding school in Beijing, China, measured the indoor and outdoor PM 2.5 concentrations for five consecutive days, calculated the PM 2.5 time-weighted individual exposure levels based on the school micro-environmental concentrations and the time activity pattern recorded by schoolchildren, measured schoolchildren's pulmonary function on the fifth day. The survey was performed three times from December 2018 to April 2019. We used a linear mixed-effects model to evaluate the associations between PM 2.5 and pulmonary function. RESULTS: During the three surveys, the median PM 2.5 time-weighted individual exposure concentrations were 15.30 µg/m 3, 48.92 µg/m 3, and 42.89 µg/m 3, respectively. There was a significant difference between the three surveys in vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) and forced expiratory volume in one second/forced vital capacity (FEV 1/FVC) ( P < 0.05). The relevance analysis found that PM 2.5 had lag effect on schoolchildren's pulmonary function, each 10 µg/m 3increase in PM 2.5could cause largest decreases in FEF 25%-75%, FEV 1/FVC, FEF 75%, and FEV 1 on lag 0-1 d (80.44 mL/s, 35.85%, 78.58 mL/s, and 61.34 mL, respectively), and largest decreases in FEF 25% on lag 1 d (83.68 mL/s), in VC on lag 4 d (32.34 mL), and in FVC on lag 0-4 d (37.76 mL). Gender subgroup analysis revealed that the increase in PM 2.5 caused a decrease in FEV 1/FVC and VC on the day of physical examination only in boys, and on lag days it caused changes in different pulmonary function indicators, both for boys and girls, but most of the pulmonary function indicators decreased more in boys than in girls. CONCLUSION: Our findings show that acute PM 2.5 exposure has significant effects on pulmonary function within 0-4 d, on both small airway indicators and large airway indicators. Boys' pulmonary function is more sensitive to PM 2.5 than girls.

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. METHODS: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 µg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. RESULTS: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. CONCLUSIONS: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

Multifunctional Superparamagnetic Iron Oxide Nanoparticles Conjugated with Aß Oligomer-Specific scFv Antibody and Class A Scavenger Receptor Activator Show Early Diagnostic Potentials for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Diagnosing AD before symptoms arise will facilitate earlier intervention. The early diagnostic approaches are thus urgently needed. METHODS: The multifunctional nanoparticles W20/XD4-SPIONs were constructed by the conjugation of oligomer-specific scFv antibody W20 and class A scavenger receptor (SR-A) activator XD4 onto superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs' stability and uniformity in size were measured by dynamic light scattering and transmission electron microscopy. The ability of W20/XD4-SPIONs for recognizing Aß oligomers (AßOs) and promoting AßOs phagocytosis was assessed by immunocytochemistry and flow cytometry analysis. The blood-brain barrier permeability of W20/XD4-SPIONs was determined by a co-culture transwell model. The in vivo probe distribution of W20/XD4-SPIONs in AD mouse brains was detected by magnetic resonance imaging (MRI). RESULTS: W20/XD4-SPIONs, as an AßOs-targeted molecular MRI contrast probe, readily reached pathological AßOs regions in brains and distinguished AD transgenic mice from WT controls. W20/XD4-SPIONs retained the property of XD4 for SR-A activation and significantly promoted microglial phagocytosis of AßOs. Moreover, W20/XD4-SPIONs exhibited the properties of good biocompatibility, high stability and low cytotoxicity. CONCLUSION: Compared with W20-SPIONs or XD4-SPIONs, W20/XD4-SPIONs show the highest efficiency for AßOs-targeting and significantly enhance AßOs uptake by microglia. As a molecular probe, W20/XD4-SPIONs also specifically and sensitively bind to AßOs in AD brains to provide an MRI signal, demonstrating that W20/XD4-SPIONs are promising diagnostic agents for early-stage AD. Due to the beneficial effect of W20 and XD4 on neuropathology, W20/XD4-SPIONs may also have therapeutic potential for AD .

The immunodominant and neutralization linear epitopes for SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes a tremendous threat to global health. Although vaccines against the virus are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulated the three-dimensional structures of SARS-CoV-2 proteins with high performance computer, predicted the B cell epitopes on spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches, and then validated the epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induced antibody production, six of which were immunodominant epitopes in patients identified via the binding of epitopes with the sera from domestic and imported COVID-19 patients, and 23 were conserved within SARS-CoV-2, SARS-CoV and bat coronavirus RaTG13. We also found that the immunodominant epitopes of domestic SARS-CoV-2 were different from that of the imported, which may be caused by the mutations on S (G614D) and N proteins. Importantly, we validated that eight epitopes on S protein elicited neutralizing antibodies that blocked the cell entry of both D614 and G614 pseudo-virus of SARS-CoV-2, three and nine epitopes induced D614 or G614 neutralizing antibodies, respectively. Our present study shed light on the immunodominance, neutralization, and conserved epitopes on SARS-CoV-2 which are potently used for the diagnosis, virus classification and the vaccine design tackling inefficiency, virus mutation and different species of coronaviruses.

Yeast-Based Aß1-15 Vaccine Elicits Strong Immunogenicity and Attenuates Neuropathology and Cognitive Deficits in Alzheimer's Disease Transgenic Mice.

Immunotherapy focusing on reducing the amyloid-beta (Aß) burden is a promising treatment strategy for Alzheimer's disease (AD). Many clinical studies on AD immunotherapies have failed due to low safety and efficacy, calling for a highly potent AD vaccine which induces sufficient antibody titer while avoiding side effects. Here, we designed a yeast-based vaccine Y-5A15 comprising five copies of Aß1-15 displayed on the surface of yeast cell wall, and we subcutaneously immunized APP/PS1 mice three times. Our results demonstrated that the Y-5A15 remarkably enhanced the Aß epitope immunogenicity and elicited high antibody titers against Aß in AD mice. Importantly, Y-5A15 vaccination successfully reduced Aß levels, plaque burden and glial activation, rescued synaptic deficits and significantly ameliorated memory and cognitive decline in APP/PS1 transgenic mice, suggesting that the yeast-based Aß epitope vaccine has a promising potency for the treatment of AD.

A novel rapid modularized hepatitis B core virus-like particle-based platform for personalized cancer vaccine preparation via fixed-point coupling.

Personalized cancer vaccine which targets neoepitopes shows great promise for cancer treatment. However, rapid preparation is a critical challenge for clinical application of personalized cancer vaccine. Genetic recombination and chemical modification are a time-consuming "trial and error" pattern for making vaccines. Here we first constructed a platform for peptide vaccine preparation by inserting SpyCatcher into the major immunodominant region (MIR) of hepatitis B core protein (HBc) (1-183). The resulted recombinant protein HBc(1-183)-SpyCatcher (HBc(1-183)-S) assembled to virus-like particles (VLPs) and readily bound to SpyTag conjugated with OVA epitope peptides by just mixing, forming HBc(1-183)-S-OVA. HBc(1-183)-S-OVA VLPs effectively induced dendritic cell maturation. Our further results indicated that HBc(1-183)-S-OVA VLPs vaccination inhibited tumor growth in both prophylactic and treatment ways in E.G7-OVA tumor bearing mice by generating significant OVA-specific cytotoxic T lymphocyte responses. Our study provides a simple, rapid, efficient and universal HBc-based platform for the preparation of personalized cancer vaccine.

Interleukin-33 facilitates cutaneous defense against Staphylococcus aureus by promoting the development of neutrophil extracellular trap.

Neutrophil extracellular traps (NETs) are consisted of DNA fibers and granular proteins and the formation of NETs has been identified as a crucial element of innate immune defense. IL-33 is a member of the IL-1 family cytokines and has been known as a strong trigger of type-2 immunity. Growing studies imply that IL-33 is involved in host defense against microbial infection. Here, we investigate the underlying influence of IL-33 on NET formation in mice with S. aureus cutaneous infection. We found that the level of IL-33 was significantly elevated in skin lesions of S. aureus-infected mice. The alarmin IL-33 inspired host innate defense through activation of NADPH oxidase to produce reactive oxygen species (ROS). Besides mediating the direct bactericidal activity within phagolysosomes, ROS production in IL-33-primed neutrophils was also critical for induction of NET formation. Enhancement of NET production by IL-33 contributed to ensnaring S. aureus and bacterial killing activity in vitro and in vivo. All together, these findings set up an IL-33/ST2 axis modulating NET generation, which strengthens host defense of innate immunity against S. aureus infection.