We have recently seen many successful applications of recurrent neural networks (RNNs) on electronic medical records (EMRs), which contain histories of patients' diagnoses, medications, and other ...various events, in order to predict the current and future states of patients. Despite the strong performance of RNNs, it is often challenging for users to understand why the model makes a particular prediction. Such black-box nature of RNNs can impede its wide adoption in clinical practice. Furthermore, we have no established methods to interactively leverage users' domain expertise and prior knowledge as inputs for steering the model. Therefore, our design study aims to provide a visual analytics solution to increase interpretability and interactivity of RNNs via a joint effort of medical experts, artificial intelligence scientists, and visual analytics researchers. Following the iterative design process between the experts, we design, implement, and evaluate a visual analytics tool called RetainVis, which couples a newly improved, interpretable, and interactive RNN-based model called RetainEX and visualizations for users' exploration of EMR data in the context of prediction tasks. Our study shows the effective use of RetainVis for gaining insights into how individual medical codes contribute to making risk predictions, using EMRs of patients with heart failure and cataract symptoms. Our study also demonstrates how we made substantial changes to the state-of-the-art RNN model called RETAIN in order to make use of temporal information and increase interactivity. This study will provide a useful guideline for researchers that aim to design an interpretable and interactive visual analytics tool for RNNs.
T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. ...In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed "bystander activation", has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4
T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4
T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer.
Cancer immunotherapies, including adoptive T cell transfer and immune checkpoint blockades, have recently shown considerable success in cancer treatment. Nevertheless, transferred T cells often ...become exhausted because of the immunosuppressive tumor microenvironment. Immune checkpoint blockades, in contrast, can reinvigorate the exhausted T cells; however, the therapeutic efficacy is modest in 70–80% of patients. To address some of the challenges faced by the current cancer treatments, here T‐cell‐membrane‐coated nanoparticles (TCMNPs) are developed for cancer immunotherapy. Similar to cytotoxic T cells, TCMNPs can be targeted at tumors via T‐cell‐membrane‐originated proteins and kill cancer cells by releasing anticancer molecules and inducing Fas‐ligand‐mediated apoptosis. Unlike cytotoxic T cells, TCMNPs are resistant to immunosuppressive molecules (e.g., transforming growth factor‐β1 (TGF‐β1)) and programmed death‐ligand 1 (PD‐L1) of cancer cells by scavenging TGF‐β1 and PD‐L1. Indeed, TCMNPs exhibit higher therapeutic efficacy than an immune checkpoint blockade in melanoma treatment. Furthermore, the anti‐tumoral actions of TCMNPs are also demonstrated in the treatment of lung cancer in an antigen‐nonspecific manner. Taken together, TCMNPs have a potential to improve the current cancer immunotherapy.
T‐cell‐membrane‐coated nanoparticles (TCMNPs) are developed for cancer immunotherapy. The TCMNPs can be targeted at tumors and kill cancer cells while being resistant to the pro‐tumoral factors in the tumor microenvironment. Indeed, the TCMNPs exhibit a higher therapeutic efficacy than current cancer treatments based on immune checkpoint blockade, and they are effective for the treatment of various tumors.
The nuclear factor of activated T cells (NFAT) family of transcription factors, which includes NFAT1, NFAT2, and NFAT4, are well-known to play important roles in T cell activation. Most of NFAT ...proteins are controlled by calcium influx upon T cell receptor and costimulatory signaling results increase of IL-2 and IL-2 receptor. NFAT3 however is not shown to be expressed in T cells and NFAT5 has not much highlighted in T cell functions yet. Recent studies demonstrate that the NFAT family proteins involve in function of lineage-specific transcription factors during differentiation of T helper 1 (Th1), Th2, Th17, regulatory T (Treg), and follicular helper T cells (Tfh). They have been studied to make physical interaction with the other transcription factors like GATA3 or Foxp3 and they also regulate Th cell signature gene expressions by direct binding on promotor region of target genes. From last decades, NFAT functions in T cells have been targeted to develop immune modulatory drugs for controlling T cell immunity in autoimmune diseases like cyclosporine A, FK506, etc. Due to their undesirable side defects, only limited application is available in human diseases. This review focuses on the recent advances in development of NFAT targeting drug as well as our understanding of each NFAT family protein in T cell biology. We also discuss updated detail molecular mechanism of NFAT functions in T cells, which would lead us to suggest an idea for developing specific NFAT inhibitors as a therapeutic drug for autoimmune diseases.
Recent work has suggested a microbial dysbiosis association between the lung and gut in respiratory diseases. Here, we demonstrated that gut microbiome modulation attenuated emphysema development. To ...modulate the gut microbiome, fecal microbiota transplantation (FMT) and diet modification were adopted in mice exposed to smoking and poly I:C for the emphysema model. We analyzed the severity of emphysema by the mean linear intercept (MLI) and apoptosis by the fluorescent TUNEL assay. Microbiome analysis was also performed in feces and fecal extracellular vesicles (EVs). The MLI was significantly increased with smoking exposure. FMT or a high-fiber diet (HFD) attenuated the increase. Weight loss, combined with smoking exposure, was not noted in mice with FMT. HFD significantly decreased macrophages and lymphocytes in bronchoalveolar lavage fluid. Furthermore, IL-6 and IFN-γ were decreased in the bronchoalveolar lavage fluid and serum. The TUNEL score was significantly lower in mice with FMT or HFD, suggesting decreased cell apoptosis. In the microbiome analysis, Bacteroidaceae and Lachnospiraceae, which are alleged to metabolize fiber into short-chain fatty acids (SCFAs), increased at the family level with FMT and HFD. FMT and HFD attenuated emphysema development via local and systemic inhibition of inflammation and changes in gut microbiota composition, which could provide a new paradigm in COPD treatment.
T cells generate antigen-specific immune responses to their cognate antigen as a hallmark of adaptive immunity. Despite the importance of antigen-specific T cells, here we show that antigen ...non-related, bystander memory-like CD4
T cells also significantly contribute to autoimmune pathogenesis. Transcriptome analysis demonstrates that interleukin (IL)-1β- and IL-23-prime T cells that express pathogenic T
17 signature genes such as RORγt, CCR6, and granulocyte macrophage colony-stimulating factor (GM-CSF). Importantly, when co-transferred with myelin-specific 2D2 TCR-transgenic naive T cells, unrelated OT-II TCR-transgenic memory-like T
17 cells infiltrate the spinal cord and produce IL-17A, interferon (IFN)-γ, and GM-CSF, increasing the susceptibility of the recipients to experimental autoimmune encephalomyelitis in an IL-1 receptor-dependent manner. In humans, IL-1R1
memory CD4
T cells are major producers of IL-17A and IFN-γ in response to IL-1β and IL-23. Collectively, our findings reveal the innate-like pathogenic function of antigen non-related memory CD4
T cells, which contributes to the development of autoimmune diseases.
Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are ...largely unknown. Here we show that Chi3l1 expression was increased in activated T cells, especially in Th2 cells. In addition, Chi3l1-deficient T cells are hyper-responsive to TcR stimulation and are prone to differentiating into Th1 cells. Chi3l1-deficient Th1 cells show increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice show reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, silencing of Chi3l1 expression in the lung using peptide-siRNA complex (dNP2-siChi3l1) efficiently inhibit lung metastasis with enhanced Th1 and CTL responses. Collectively, this study demonstrates Chi3l1 is a regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that is mainly expressed on activated T cells and regulatory T (Treg) cells that inhibits T-cell activation and regulates ...immune homeostasis. Due to the crucial functions of CTLA-4 in T-cell biology, CTLA-4-targeted immunotherapies have been developed for autoimmune disease as well as cancers. CTLA-4 is known to compete with CD28 to interact with B7, but some studies have revealed that its downstream signaling is independent of its ligand interaction. As a signaling domain of CTLA-4, the tyrosine motif plays a role in inhibiting T-cell activation. Recently, the lysine motif has been shown to be required for the function of Treg cells, emphasizing the importance of CTLA-4 signaling. In this review, we summarize the current understanding of CTLA-4 biology and molecular signaling events and discuss strategies to target CTLA-4 signaling for immune modulation and disease therapy.
Regulatory T cells play a key role in immune tolerance to self‐antigens, thereby preventing autoimmune diseases. However, no drugs targeting Treg cells have been approved for clinical trials yet. ...Here, a chimeric peptide is generated by conjugation of the cytoplasmic domain of CTLA‐4 (ctCTLA‐4) with dNP2 for intracellular delivery, dNP2‐ctCTLA‐4, and evaluated Foxp3 expression during Th0, Th1, Treg, and Th17 differentiation dependent on TGF‐β. The lysine motif of ctCTLA‐4, not tyrosine motif, is required for Foxp3 expression for Treg induction and amelioration of experimental autoimmune encephalomyelitis (EAE). Transcriptome analysis reveals that dNP2‐ctCTLA‐4‐treated T cells express Treg transcriptomic patterns with properties of suppressive functions. In addition, the molecular interaction between the lysine motif of ctCTLA‐4 and PKC‐η is critical for Foxp3 expression. Although both CTLA‐4‐Ig and dNP2‐ctCTLA‐4 treatment in vivo ameliorated EAE progression, only dNP2‐ctCTLA‐4 requires Treg cells for inhibition of disease progression and prevention of relapse. Furthermore, the CTLA‐4 signaling peptide is able to induce human Tregs in vitro and in vivo as well as from peripheral blood mononuclear cells (PBMCs) of multiple sclerosis patients. These results collectively suggest that the chimeric CTLA‐4 signaling peptide can be used for successful induction of regulatory T cells in vivo to control autoimmune diseases, such as multiple sclerosis.
In this study, it is described how the synthetic peptide dNP2‐ctCTLA‐4 can induce Foxp3+ Tregs in mice and human peripheral blood mononuclear cells (PBMCs), ameliorate experimental autoimmune encephalomyelitis (EAE) progression with long‐term regulation and prevent disease relapse. On the basis of these findings, this peptide is an attractive drug candidate to increase Tregs in autoimmune diseases, such as multiple sclerosis.
All-solution processing of large-area organic electronics requires multiple steps of patterning and stacking of various device components. Here, we report the fabrication of highly integrated arrays ...of polymer thin-film transistors and logic gates entirely through a series of solution processes. The fabrication is done using a three-dimensional crosslinker in tetrahedral geometry containing four photocrosslinkable azide moieties, referred to as 4Bx. 4Bx can be mixed with a variety of solution-processable electronic materials (polymer semiconductors, polymer insulators, and metal nanoparticles) and generate crosslinked network under exposure to UV. Fully crosslinked network film can be formed even at an unprecedentedly small loading, which enables preserving the inherent electrical and structural characteristics of host material. Because the crosslinked electronic component layers are strongly resistant to chemical solvents, micropatterning the layers at high resolution as well as stacking the layers on top of each other by series of solution processing steps is possible.
PDF
