Inhibition of AMPA receptor trafficking at hippocampal synapses by β-amyloid oligomers: the mitochondrial contribution

<p>Abstract</p> <p>Background</p> <p>Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer's disease (AD) <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>. An increasing body of work indicates that the oligomeric forms of β-amyloid (Aβ) molecules exert profound inhibition on synaptic functions and can cause a significant loss of neurotransmitter receptors from the postsynaptic surface, but the underlying mechanisms remain poorly understood. In this study, we investigated a potential contribution of mitochondria to Aβ inhibition of AMPA receptor (AMPAR) trafficking.</p> <p>Results</p> <p>We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP.</p> <p>Conclusions</p> <p>Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.</p

Immunogenic Cell Death Amplified by Co-localized Adjuvant Delivery for Cancer Immunotherapy

Despite their potential, conventional whole-cell cancer vaccines prepared by freeze-thawing or irradiation have shown limited therapeutic efficacy in clinical trials. Recent studies have indicated that cancer cells treated with certain chemotherapeutics, such as mitoxantrone, can undergo immunogenic cell death (ICD) and initiate antitumor immune responses. However, it remains unclear how to exploit ICD for cancer immunotherapy. Here, we present a new material-based strategy for converting immunogenically dying tumor cells into a powerful platform for cancer vaccination and demonstrate their therapeutic potential in murine models of melanoma and colon carcinoma. We have generated immunogenically dying tumor cells surface-modified with adjuvant-loaded nanoparticles. Dying tumor cells laden with adjuvant nanodepots efficiently promote activation and antigen cross-presentation by dendritic cells in vitro and elicit robust antigen-specific CD8α+ T-cells in vivo. Furthermore, whole tumor-cell vaccination combined with immune checkpoint blockade leads to complete tumor regression in 78% of CT26 tumor-bearing mice and establishes long-term immunity against tumor recurrence. Our strategy presented here may open new doors to "personalized" cancer immunotherapy tailored to individual patient's tumor cells. Keywords: cancer immunotherapy; cancer vaccine; Cell engineering; innunogenic cell death; nanoparticl

Robust Anti‐Tumor T Cell Response with Efficient Intratumoral Infiltration by Nanodisc Cancer Immunotherapy

Potent anti‐tumor T cell response and efficient intratumoral T cell infiltration are the major challenges for therapeutic cancer vaccines. To address these issues, a nanovaccine system is designed to promote anti‐tumor T cell responses, and intratumoral infiltration is examined in various murine tumor models. Subcutaneous vaccination with nanodiscs carrying human papillomavirus (HPV)‐16 E7 antigen elicits as high as ∼32% E7‐specific CD8α+ T cell responses in circulation, representing a 29‐fold improvement over the soluble peptide vaccination. Importantly, nanodisc vaccination also promotes robust intratumoral T cell infiltration and eliminates HPV16 E6/E7‐expressing TC‐1 tumors at mucosal sites, including lungs, inner lip, and intravaginal tissues. In a benchmark study with a live Listeria vaccine combined with anti‐PD‐1 IgG, nanodiscs plus anti‐PD‐1 immune checkpoint blockade elicits comparable levels of T cell responses with anti‐tumor efficacy. Furthermore, compared with Complete Freund’s Adjuvant combined with tetanus toxoid, nanodisc vaccination in HLA‐A02 mice generates >200‐fold stronger IFN‐γ+ T cell responses against a neoantigen from an HLA‐A02 melanoma patient. Overall, these results show that the nanodisc system is a promising cancer vaccine platform for inducing anti‐tumor T cell responses.Efficient infiltration of T cells in solid cancer is a major challenge for cancer immunotherapy. A nanoparticle vaccine system is developed to promote T cell infiltration into peripheral mucosal tissues and eliminate disseminated tumors. Nanodiscs are broadly applicable with a wide range of tumor antigens, thus providing a versatile and potent vaccine platform for eliciting T cell immunity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/3/adtp202000094.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/2/adtp202000094-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/1/adtp202000094_am.pd

Psychological Typhoon Eye in the 2008 Wenchuan Earthquake

BACKGROUND: On May 12, 2008, an earthquake measuring 8.0 on the Richter scale jolted Wenchuan, China, leading to 69,227 deaths and 374,643 injured, with 17,923 listed as missing as of Sept. 25, 2008, and shook the whole nation. We assessed the devastating effects on people's post-earthquake concern about safety and health. METHODOLOGY/PRINCIPAL FINDINGS: From June 4 to July 15, 2008, we surveyed a convenience sample of 2,262 adults on their post-earthquake concern about safety and health. Residents in non-devastated areas (Fujian and Hunan Provinces, and Beijing) and devastated areas (Sichuan and Gansu Provinces) responded to a questionnaire of 5 questions regarding safety measures, epidemic disease, medical workers, psychological workers, and medication. The ANOVAs showed a significant effect of residential devastation level on the estimated number of safety measures needed, the estimated probability of the outbreak of an epidemic, and the estimated number of medical and psychological workers needed (Ps<0.001). The post-earthquake concern decreased significantly as the level of residential devastation increased. Because of the similarity with the meteorological phenomenon of the eye of a typhoon, we dubbed these findings a "Psychological Typhoon Eye": the closer to the center of the devastated areas, the less the concern about safety and health a resident felt. CONCLUSIONS/SIGNIFICANCE: Contrary to common perception and ripple effect that the impact of an unfortunate event decays gradually as ripples spread outward from a center, a "Psychological Typhoon Eye" effect was observed where the post-earthquake concern was at its lowest level in the extremely devastated areas. The resultant findings may have implications for Chinese governmental strategies for putting "psychological comfort" into effect

One-step carbothermal synthesis of super nanoadsorbents for rapid and recyclable wastewater treatment

As a potential magnetic super adsorbent in wastewater treatment, Fe3O4 has been re-searched intensively up to date. However, its key problem of poor comprehensive magnetic properties is still challenging. In this work, an effective solution to this problem has been developed by a one-step carbothermal synthesis of Fe3O4 crystals, which are merited with pure-stoichiometry (FeO-phase free), high crystallinity, small-size (~10 nm), strong magnetism and sensitive magnetic response. The unveiled saturation magnetization of Fe3O4 nanoparticles reaches as high as 90.32 emu·g−1, and the fastest magnetic response time is as short as only 5 s. Such magnetic Fe3O4 super adsorbents exhibit outstanding performance when applied as an adsorbent for wastewater treatment. They can quickly and effectively adsorb methylene blue with an adsorption capacity of 62.5 mg·g−1, which is much higher than that of Fe3O4 adsorbents prepared by other methods reported in the literature. Importantly, this capacity is refreshable after removing the adsorbed methylene blue just by ultrasonic cleaning. With such combined outstanding magnetic properties and recyclable adsorption capacity, the problems associated with the conventional adsorbent solid–liquid separation could be resolved, thus making a forward development towards industrial wastewater treatment.This work was supported by the Natural Science Foundation of China (NSFC, 51404181); the Fok Ying Tung Education Foundation (171101); the Youth Innovation Team of Shaanxi Universities (2019-2022); the Top young talents project of “special support program for high level talents” in Shaanxi Province of China (2018-2023); the ANU Futures Scheme (Q4601024); and the Australian Research Council (DP190100295, LE190100014)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Synthetic High Density Lipoprotein Nanodiscs for Cancer Immunotherapy and Chemoimmunotherapy

Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumor exome sequencing have signaled the new era of personalized immunotherapy with patient-specific neo-antigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that synthetic high density lipoprotein-mimicking nanodiscs (sHDL) coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (i.e. CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumor growth. Nanodiscs eliminated established MC-38 and B16F10 tumors when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine. We also sought to develop alternative approaches for cancer therapy. For example, we demonstrated that by simply incorporating a hydrophobic anticancer drug withalongolide A-4,19,27-triacetate (WGA-TA) in sHDL nanodiscs, we could enhance the therapeutic outcome of WGA-TA and reduce the side effects due to the improved tumor targeted delivery of nanodiscs. In addition to direct killing of tumor cells, some chemotherapeutic drugs can cause immunogenic cell death and induce antitumor T cell responses, which also contribute to the anticancer efficacy and prompt a number of clinical trials on combination chemoimmunotherapy. However, it remains unclear how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy. Here we show that high-density lipoprotein (HDL)-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models. Delivery of DOX via nanodiscs triggered immunogenic cell death of cancer cells and exerted antitumor efficacy without any overt off-target side effects. Importantly, “priming” tumors with DOX-carrying nanodiscs elicited robust antitumor CD8+ T cell responses while broadening their epitope recognition to tumor-associated antigens, neoantigens, as well as intact whole tumor cells. Combination chemoimmunotherapy with nanodiscs plus anti-PD-1 therapy induced complete regression of established CT26 and MC38 colon carcinoma tumors in 80-88% of animals and protected survivors against tumor recurrence. Our work provides a new, generalizable framework for utilizing nanoparticle based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144119/1/ruikuai_1.pd

Drone Based RGBT Tracking with Dual-Feature Aggregation Network

In the field of drone-based object tracking, utilization of the infrared modality can improve the robustness of the tracker in scenes with severe illumination change and occlusions and expand the applicable scene of the drone object tracking task. Inspired by the great achievements of Transformer structure in the field of RGB object tracking, we design a dual-modality object tracking network based on Transformer. To better address the problem of visible-infrared information fusion, we propose a Dual-Feature Aggregation Network that utilizes attention mechanisms in both spatial and channel dimensions to aggregate heterogeneous modality feature information. The proposed algorithm has achieved better performance by comparing with the mainstream algorithms in the drone-based dual-modality object tracking dataset VTUAV. Additionally, the algorithm is lightweight and can be easily deployed and executed on a drone edge computing platform. In summary, the proposed algorithm is mainly applicable to the field of drone dual-modality object tracking and the algorithm is optimized so that it can be deployed on the drone edge computing platform. The effectiveness of the algorithm is proved by experiments and the scope of drone object tracking is extended effectively