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Abstract 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 Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ, antibody, and complement. Notably, anti-Aβ antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aβ-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, Aβ-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.

Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aβ oligomers (AβOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AβOs and promote Aβ clearance may have great value for AD treatment. Results We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aβ 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-Aβ properties of W20 and XD4 by inhibiting Aβ aggregation, attenuating AβO-induced cytotoxicity and increasing microglial phagocytosis of Aβ. 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.

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. 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. 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-1β, 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. SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5 -induced lung injury. [ABSTRACT FROM AUTHOR]

Abstract Background Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau294–305, an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau294–305-targeted approach may have beneficial effects in the treatment of AD and FTD. Methods In this study, we genetically fused tau294–305 epitope to the hepatitis B virus core protein (HBc) major immunodominant region (MIR) (with the resultant protein termed T294-HBc), and we subcutaneously immunized a Tau.P301S transgenic mouse model of FTD and AD with T294-HBc four times. The levels and characteristics of antibodies induced by T294-HBc were determined by enzyme-linked immunosorbent assay. The effect of T294-HBc on the cognitive deficits of Tau.P301S mice was tested using the Morris water maze test, novel object recognition, and a Y-maze test. Western blot analysis and IHC were applied to measure the effect of T294-HBc on tau pathologies and neuroinflammation in the mouse brains. Results The results showed that T294-HBc self-assembled into HBc chimeric virus-like particles (VLPs) with tau294–305 displayed on the surface and that it induced high antibody titers specifically against the mis-disordered truncated tau. Further investigation showed that these antibodies simultaneously bound to microtubule-binding regions 1–4 (MTBR1–4) [tau263–274, tau294–305, tau325–336, tau357–368 and tau294–305(P301S)]. Moreover, T294-HBc VLP vaccination significantly ameliorated memory and cognitive decline; reduced the levels of AT8-positive tau, truncated tau monomer, and oligomer; attenuated microgliosis and astrogliosis; and rescued synaptic deficits in Tau.P301S transgenic mice. Conclusions T294-HBc VLP vaccine elicited strong immune response and alleviated cognitive deficits and neuropathology progression in Tau.P301S mice, indicating that the T294-HBc VLP vaccine has promising therapeutic potential for the treatment of AD and FTD.

Abstract Background β-Amyloid peptide (Aβ) oligomers are initial factors used to induce Alzheimer’s disease (AD) development, and Aβ monomers have normal physiological function. The antibodies or vaccines against Aβ monomers have serious problems, such as side effects and low curative effects. Therefore, it is essential to specifically target Aβ oligomers rather than monomers for the treatment of AD. Methods The mimotopes of Aβ oligomers were obtained by panning the phage-displayed random peptide libraries using oligomer-specific antibodies as targets and expressed on the surface of EBY100 Saccharomyces cerevisiae to generate yeast cell base vaccines. One vaccine (AOE1) induced antibodies specifically against Aβ oligomers and was selected for further study. The APP/PS1 mice were subcutaneously immunized with AOE1 eight times. The levels and characteristics of antibodies induced by AOE1 were determined by enzyme-linked immunosorbent assay. The effect of AOE1 on the cognitive deficits of AD mice was tested by novel object recognition (NOR) and Y-maze. Dot blot analysis, Western blot analysis, and immunohistochemistry were applied to measure the effects of AOE1 on Aβ pathologies, neuroinflammation, and microhemorrhages in the brains of AD mice. Results Eight mimotope candidates of Aβ oligomers were selected and expressed on EBY100 S. cerevisiae. Only AOE1 vaccine containing mimotope L2 induced antibodies that specifically recognized Aβ42 oligomers rather than monomers. AOE1 immunization significantly increased the AD mice’s exploration times for the novel object in the NOR test and the choices for new arms in the Y-maze test, and it reduced levels of Aβ oligomers and glial activation in the AD mouse brains. No activation of Aβ-specific T cells and microhemorrhages was observed in their brains following AOE1 vaccination. Conclusions AOE1 is the first vaccine applying the oligomer-specific mimotope as an immunogen, which could induce antibodies with high specificity to Aβ oligomers. AOE1 immunization attenuated Aβ pathologies and cognitive deficits in AD mice, decreased the overactivation of glial cells, and did not induce microhemorrhage in the brains of AD mice. These findings suggest that AOE1 may be a safer and more effective vaccine for AD treatment.

Immunotherapy focusing on reducing the amyloid-beta (Aβ) 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 Aβ1-15 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 Aβ epitope immunogenicity and elicited high antibody titers against Aβ in AD mice. Importantly, Y-5A15 vaccination successfully reduced Aβ 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 Aβ epitope vaccine has a promising potency for the treatment of AD.

Background:. The prevalence of childhood asthma has been increasing in China. This study aimed to compare the prevalence, diagnosis, and treatment of asthmatic children from urban and rural areas in Beijing, China. Methods:. Schools, communities, and kindergartens were randomly selected by cluster random sampling from urban and rural areas in Beijing. Parents were surveyed by the same screening questionnaires. On-the-spot inquiries, physical examinations, medical records, and previous test results were used to diagnose asthmatic children. Information on previous diagnoses, treatments, and control of symptoms was obtained. Results:. From 7209 children in rural areas and 13,513 children in urban areas who completed screening questionnaires, 587 children were diagnosed as asthma. The prevalence of asthma in rural areas was lower than in urban areas (1.25% vs. 3.68%, χ2 = 100.80, P < 0.001). The diagnosis of asthma in rural areas was lower than in urban areas (48.9% vs. 73.9%, χ2 = 34.6, P < 0.001). Compared with urban asthmatic children (56.5%), only 35.6% of rural asthmatic children received inhaled corticosteroids (P < 0.05). The use of bronchodilators was also lower in rural areas than in urban areas (56.5% vs. 66.4%, χ2 = 14.2, P < 0.01). Conclusion:. The prevalence of asthma in children was lower in rural areas compared with children in the urban area of Beijing. A considerable number of children were not diagnosed and inadequately treated in rural areas.

Uterine abnormalities infertility can be treated with implantable patches for tension‐free healing. However, the existing clinical patches are still limited in effective uterus recovery, resulting in low pregnancy and live birth rates. Herein, a novel engineered, and biocompatible Janus collagen patch (JCOP) is developed to achieve excellent uterine defect recovery and increase effective live births. The JCOP can highly match the structure, micromorphology, and mechanical properties of a natural uterus due to homologous‐like tissue homogeneity. JCOP's rough surface and loose‐extracellular‐matrix‐like porosity promote fibroblast adhesion and tissue regeneration, whereas its smooth surface reduces fibroblast adhesion and prevents visceral adhesions. Additionally, it exhibits exceptional resistance to swelling and deformation along with stable mechanical strength for long‐term preservation in the body and can withstand the highest uterine pressure in a humid interior environment attributed to its superior structural layout. Moreover, JCOP@bF, a functional JCOP linked to basic fibroblast growth factor (bFGF) via a specific collagen‐binding domain, significantly promotes repair of the injured uterus, restores the ability of the endometrium to accept embryos, and supports their development to a viable stage in a rat model of uterine damage. This study shows great promise for treating infertility caused by uterine damage. [ABSTRACT FROM AUTHOR]

To assist in addressing the problem where an aluminum alloy formwork (AAF) deforms more greatly under the action of lateral pressure and therefore does not meet the requirements of plaster-free engineering, we propose a method for determining the geometric parameters of this formwork based on a PSO algorithm and BP neural network with ABAQUS as the platform. The influence of six geometric parameters of the formwork on the maximum deflection value of the panel under the action of lateral pressure is studied using finite element analysis. The maximum deflection value of the panel is used as the index, and the influence of each factor is analyzed with an orthogonal test, and a set of optimal geometric parameters is obtained via extreme difference analysis and analysis of variance. The sample data are obtained via finite element simulation, and the PSO-BP neural network model is established using the six factors of the orthogonal test as input values and the maximum deflection of the panel as the output value, and the optimal geometric parameters are optimized using the PSO algorithm. The results indicate that the maximum deflection for the panel in the orthogonal scheme is 1.446 mm. The PSO-BP neural network prediction model demonstrates greater accuracy and a 31.74% reduction in running time compared to the BP neural network prediction model. The optimized PSO-BP neural network prediction model scheme reveals a maximum panel deflection of 1.296 mm, a 10.37% decrease compared to the orthogonal solution. These findings offer technical guidance and a foundation for optimizing AAF designs, presenting practical applications. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) has been implicated as a key proinflammatory cytokine involved in the pancreatic islet inflammation of type 2 diabetes mellitus (T2DM). Excess IL-1β impairs islet function by inducing insulin resistance and β-cell apoptosis. Therefore, specifically reducing IL-1β activity provides a therapeutic improvement for T2DM by sustaining the inhibition of IL-1β-mediated islet inflammation. In this study, we developed an IL-1β-targeted epitope peptide vaccine adjuvanted with polylactic acid microparticles (1βEPP) and applied it to a diabetic KK-Ay mouse model. Results showed that the 1βEPP elicited high antibody responses, which neutralized the biological activity of IL-1β, and induced barely detectable inflammatory activity. 1βEPP immunization reduced body weight gain, protected KK-Ay mice from hyperglycemia, improved glucose tolerance and insulin sensitivity, and decreased the serum levels of free fatty acids, total cholesterol and triglyceride. Moreover, 1βEPP restored β-cell mass; inhibited β-cell apoptosis; decreased the expression of IL-1β; and interrupted NF-κB activation by reducing IKKβ and pRelA levels. These studies indicated that the IL-1β-targeted vaccine may be a promising immunotherapeutic for T2DM treatment.

Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with cardiovascular morbidity and mortality, which share the common feature of PM2.5-induced vascular inflammation; however, the underlying mechanisms of how PM2.5 triggers increased inflammatory response in vascular endothelial cells are not well understood. After treating mouse aortic endothelial cells (MAECs) with different concentrations of PM2.5, we assessed interleukin (IL)-6 and four and a half LIM domains 2 (FHL2) expression in cell supernatant by enzyme-linked immunosorbent assay and Western blot, respectively, as well as activation of nuclear factor (NF)-κB and immune-response signaling pathways. Additionally, changes in pathway activation, IL-6 expression, and autophagy were evaluated under PM2.5 exposure, following FHL2 knockdown with small interfering RNA. Our results indicated that PM2.5 exposure induced FHL2 expression and IL-6 secretion, as well as activation of pathways associated with immune response. Additionally, following FHL2 knockdown, the activation of NF-κB-related pathways and IL-6 secretion was inhibited under PM2.5 exposure, although the Akt- and p38-signaling pathways were not affected. Furthermore, PM2.5 exposure induced autophagy, whereas autophagy inhibition eventually inhibited PM2.5-induced FHL2 expression. These findings suggested a novel link between autophagy induced FHL2 upregulation and IL-6 production in MAECs under PM2.5 exposure.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]