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Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands-central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation-the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.

Cracks in civil structures are important signs of structural degradation and may indicate the inception of catastrophic failure. However, most of studies that have employed deep learning models for automatic crack detection are limited to high computational demand and require a large amount of labeled data. Long training time is not friendly to model update, and large amount of training data is usually unavailable in real applications. To bridge this gap, the innovation of this study lies in developing a hybrid method that comprises transfer learning (TL) and low‐rank dictionary learning (LRDL) for fast crack detection on concrete surfaces. Benefiting from the availability of preextracted features in TL and a limited number of parameters in LRDL, the training time can be significantly minimized without GPU acceleration. Experimental results showed that the time for training a dictionary only takes 25.33 s. Moreover, this new hybrid method reduces the demand for labeled data during training. It achieved an accuracy of 99.68% with only 20% labeled data. Three large‐scale images captured under varying conditions (e.g., uneven lighting conditions and very thin cracks) were further used to assess the crack detection performance. These advantages help to implement the proposed TL‐LRDL method on resource‐limited computers, such as battery‐powered UAVs, UGVs, and scarce processing capability of AR headsets. [ABSTRACT FROM AUTHOR]

Introduction Since transmission of HIV-1 mainly occurs at mucosal surfaces, HIV-1 vaccines should activate the mucosal arm of the immune system to prevent or contain viral transmission and the establishment [...], Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20-an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs--restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

Tumor vaccines, including DC vaccines (1), can activate potent cytotoxic T lymphocyte (CTL) responses against self tumor-associated antigens (TAA); however, they have been largely ineffective in causing tumor regression in [...], Regulatory T cells ([T.sub.reg] cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit [T.sub.reg] cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited [T.sub.reg] cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-α and were refractory to [T.sub.reg] cell--mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome [T.sub.reg] cell--mediated suppression in an antigen-specific manner, reducing the need to directly target [T.sub.reg] cells.

Background: Myopia (nearsightedness) is currently the most common human eye disorder, worldwide. In the recent years, several studies have addressed the role of microRNAs (miRNAs) in the pathogenesis of myopia. Objectives: The aim of this study was to perform a meta-analysis on the miRNA-expression profiling studies in myopia to identify commonly dysregulated miRNAs in myopic tissues. Method: Seven independent studies were included in the meta-analysis. A vote-counting strategy was employed as the meta-analysis method. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) functional enrichment analysis were performed to identify the pathways most strongly affected by the dysregulated mouse miRNAs. Results: According to the vote-counting method, eighteen miRNAs were reported in at least 2 studies with the consistent direction, of which 13 miRNAs were commonly upregulated in myopic samples compared with control samples, and five miRNAs were commonly downregulated. Subgroup analyses divided and compared the differentially expressed miRNAs according to species (human and animal) and ocular tissue types. The KEGG analysis showed that the dysregulated mouse miRNAs were most enriched in extracellular matrix-receptor interaction signal pathway. The most enriched GO process regulated by the dysregulated mouse miRNAs was cellular protein modification process. Conclusions: Our meta-analysis recommends several miRNAs may provide some clues of the potential biomarkers in myopia. Further mechanistic studies are warranted to elucidate the biological role of the dysregulated miRNAs in the development of myopia. [ABSTRACT FROM AUTHOR]