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Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14+phagocytes. Exofacial PIPs on the surfaces of early and late-apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P3antibody, AKT- and PLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or by CD14 knockout in phagocytes. We further confirmed that exofacial PIP+thymocytes increased dramatically after in vivo irradiation and that exofacial PIP+cells represented more significant populations in tissues ofCd14−/−than WT mice, especially after induction of apoptosis. Our findings reveal exofacial PIPs to be previously unknown cell death signals recognized by CD14+phagocytes.

Vascular smooth muscle cell (VSMC) proliferation is a hallmark of neointimal hyperplasia (NIH) in atherosclerosis and restenosis post-balloon angioplasty and stent insertion. Although numerous cytotoxic and cytostatic therapeutics have been developed to reduce NIH, it is improbable that a multifactorial disease can be successfully treated by focusing on a preconceived hypothesis. We, therefore, aimed to identify key molecules involved in NIH via a hypothesis-free approach. We analyzed four datasets (GSE28829, GSE43292, GSE100927, and GSE120521), evaluated differentially expressed genes (DEGs) in wire-injured femoral arteries of mice, and determined their association with VSMC proliferation

Atopic dermatitis is a chronic skin inflammatory disease mediated by Th2-type immune responses. Although intestinal immune responses have been shown to play a critical role in the development or prevention of atopic dermatitis, the precise influence of intestinal immunity on atopic dermatitis is incompletely understood. We show here that orally tolerized mice are protected from experimental atopic dermatitis induced by sensitization and epicutaneous (EC) challenge to ovalbumin. Although the expression of Th2-type cytokines in the small intestine of orally tolerized and EC-challenged mice did not change significantly, these mice showed decreased inflammatory responses in the small intestine with restoration of microbial change elicited by the EC challenge. Interestingly, an increase in small intestinal eosinophils was observed with the EC challenge, which was also inhibited by oral tolerance. The role of small intestinal eosinophils and microbiota in the pathogenesis of experimental atopic dermatitis was further substantiated by decreased inflammatory mediators in the small intestine and attenuated Th2-type inflammation in the skin of eosinophil-deficient and microbiota-ablated mice with EC challenges. Based on these data, we propose that the bidirectional interaction between the skin and the intestine has a role in the pathogenesis of atopic dermatitis and that modulation of the intestinal microenvironments could be a therapeutic approach to atopic dermatitis.

Despite the high prevalence of chronic dermatitis and the accompanied intractable itch, therapeutics that specifically target itching have low efficacy. Increasing evidence suggests that TLRs contribute to immune activation and neural sensitization; however, their roles in chronic itch remain elusive. Here, we show that the RBL-2H3 mast cell line expresses TLR4 and that treatment with a TLR4 antagonist opposes the LPS dependent increase in mRNA levels of Th2 and innate cytokines. The pathological role of TLR4 activation in itching was studied in neonate rats that developed chronic itch due to neuronal damage after receiving subcutaneous capsaicin injections. Treatment with a TLR4 antagonist protected these rats with chronic itch against scratching behavior and chronic dermatitis. TLR4 antagonist treatment also restored the density of cutaneous nerve fibers and inhibited the histopathological changes that are associated with mast cell activation after capsaicin injection. Additionally, the expression of IL-1β, IL-4, IL-5, IL-10, and IL-13 mRNA in the lesional skin decreased after TLR4 antagonist treatment. Based on these data, we propose that inhibiting TLR4 alleviated itch in a rat model of chronic relapsing itch, and the reduction in the itch was associated with TLR4 signaling in mast cells and nerve fibers.

Increasing evidence suggests that serum lipids are associated with depressive symptoms. However, previous studies have mostly employed a cross-sectional design and assessed middle-aged or older adult populations, making it difficult to discern the impact of lipid changes early in life on the development of depression. Accordingly, we sought to investigate changes in blood cholesterol levels during adolescence and the development of depressive symptoms in early adulthood. This prospective cohort study included participants aged 15–16 years from the JS High School Study (JSHS), with an average follow-up of 6 years. Participants had no diagnosed depression at baseline. Multivariable linear regression models were used to estimate associations between changes in total cholesterol during adolescence and depressive symptoms in adulthood. Changes in total cholesterol during adolescence were classified as “consistently low,” “decreased,” “moderate,” “increased,” or “consistently high”. In men, depressive symptoms were higher in the consistently low (β = 3.20, p = 0.036) and increased total cholesterol groups (β = 3.48, p = 0.017), compared with the moderate group. In the consistently high group, although a positive linear association was observed, it lacked statistical significance (β = 2.71, p = 0.067). While similar tendencies were noted in women, the associations were not statistically significant. Consistently low or increased total cholesterol levels during adolescence may pose an increased risk of depressive symptoms in early adulthood. These findings suggest that different strategies should be adopted to manage the lipid risk factors with consideration of age and sex.

In this work, we address the issues of missing modalities that have arisen from the Visual Question Answer-Difference prediction task and find a novel method to solve the task at hand. We address the missing modality-the ground truth answers-that are not present at test time and use a privileged knowledge distillation scheme to deal with the issue of the missing modality. In order to efficiently do so, we first introduce a model, the "Big" Teacher, that takes the image/question/answer triplet as its input and outperforms the baseline, then use a combination of models to distill knowledge to a target network (student) that only takes the image/question pair as its inputs. We experiment our models on the VizWiz and VQA-V2 Answer Difference datasets and show through extensive experimentation and ablation the performances of our method and a diverse possibility for future research., To appear in CVPR MULA Workshop

Background In eukaryotic cells, biogenesis of proteins destined to the secretory pathway begins from the cytosol. Nascent chains are either co-translationally or post-translationally targeted to the endoplasmic reticulum (ER) and translocated across the membrane through the Sec61 complex. For the post-translational translocation, the Sec62/Sec63 complex is additionally required. Sec63, however, is also shown to mediate co-translational translocation of a subset of proteins, the types and characteristics of proteins that Sec63 mediates in translocation still await to be defined. Methods To overview the types of proteins that require Sec63 for the ER translocation, we prepared Sec63 mutant lacking the first 39 residues (Sec63_ΔN39) in yeast and assessed initial translocation efficiencies of diverse types of precursors in the sec63_ΔN39 strain by a 5 min metabolic labeling. By employing Blue-Native gel electrophoresis (BN-PAGE), stability of the SEC complex (Sec61 plus Sec62/Sec63 complexes) isolated from cells carrying the Sec63_ΔN39 mutant was examined. Results Among the various translocation precursors tested, we found that proper sorting of single- and double-pass membrane proteins was severely impaired in addition to post-translational translocation precursor in the sec63_ΔN39 mutant strain. Stability of the SEC complex was compromised upon deletion of the N-terminal 39 residues. Conclusions The N-terminus of Sec63 is important for stability of the SEC complex and Sec63 is required for proper sorting of membrane proteins in vivo. General significance Sec63 is essential on insertion of membrane proteins.

The N-terminal signal sequence (SS) on proteins targeted to the endoplasmic reticulum (ER) is surprisingly diverse in hydrophobicity, in the number of preceding N-terminal residues (N-length), and in charged residues flanking the sequence. However, it remains unclear how these sequences despite their heterogeneity bind to the same site and open the Sec61 translocon. We assessed varying features of SSs and their efficiencies in initiating translocation across the ER by using 5-min radiolabeling in yeast. We found that while hydrophobic SSs with a short N-length efficiently initiated translocation in Sec62 mutant, Sec63 mutant and Sec72 deletion strains, most SSs showed varying degrees of translocation defect in these strains. In particular, Sec71 was required for internal hydrophobic SSs to efficiently initiate translocation. These results suggest that different combinations of Sec62, Sec63, Sec71 and Sec72 dynamically associate with the Sec61 translocon for the optimal binding of incoming SSs of broad characteristics and the initiation of protein translocation in vivo.

Recent state-of-the-art active learning methods have mostly leveraged Generative Adversarial Networks (GAN) for sample acquisition; however, GAN is usually known to suffer from instability and sensitivity to hyper-parameters. In contrast to these methods, we propose in this paper a novel active learning framework that we call Maximum Classifier Discrepancy for Active Learning (MCDAL) which takes the prediction discrepancies between multiple classifiers. In particular, we utilize two auxiliary classification layers that learn tighter decision boundaries by maximizing the discrepancies among them. Intuitively, the discrepancies in the auxiliary classification layers' predictions indicate the uncertainty in the prediction. In this regard, we propose a novel method to leverage the classifier discrepancies for the acquisition function for active learning. We also provide an interpretation of our idea in relation to existing GAN based active learning methods and domain adaptation frameworks. Moreover, we empirically demonstrate the utility of our approach where the performance of our approach exceeds the state-of-the-art methods on several image classification and semantic segmentation datasets in active learning setups., Comment: 11 pages, Accepted to IEEE-TNNLS

We analyzed responsiveness of KRAS-mutated CRC cell lines with distinctive MSI status against mitogen-activated protein kinase (MEK) inhibitor (selumetinib; AZD) and/or B-raf proto-oncogene (BRAF) kinase inhibitor (vemurafenib; PLX). The viability of MSI-high (MSI-H) KRAS-mutated LS174T cells treated with AZD or PLX was 24.5 ± 0.9% or 71.4 ± 3.6%, respectively, and the viability of microsatellite stable (MSS) KRAS-mutated SW480 cells for AZD or PLX was 57.4 ± 3.1% or 43.1 ± 1.8%, respectively. These observations imply that the therapeutic efficacy of MEK kinase inhibitors or BRAF kinase inhibitors against KRAS-mutated colon cancer cells may differ between MSI-H and MSS. However, a combination of both inhibitors synergistically inhibits the proliferation of KRAS-mutated colon cancer cells regardless of MSI status. The underlying synergistic cytotoxic efficacy of AZD/PLX combination on KRAS-mutated colon cancer cells with different MSI status was further substantiated by markedly decreased phosphorylation of ERK in both LS74T and SW480 cell lines upon AZD and PLX treatment. Based on these collective data, we propose that MSI status should be considered when MEK kinase inhibitor or BRAF kinase inhibitor is treated for KRAS-mutated colon cancer, and that combination of both inhibitors synergistically inhibit proliferation of KRAS-mutated colon cancer cells independent of MSI status.

In order to summarize a content video properly, it is important to grasp the sequential structure of video as well as the long-term dependency between frames. The necessity of them is more obvious, especially for unsupervised learning. One possible solution is to utilize a well-known technique in the field of natural language processing for long-term dependency and sequential property: self-attention with relative position embedding (RPE). However, compared to natural language processing, video summarization requires capturing a much longer length of the global context. In this paper, we therefore present a novel input decomposition strategy, which samples the input both globally and locally. This provides an effective temporal window for RPE to operate and improves overall computational efficiency significantly. By combining both Global-and-Local input decomposition and RPE together, we come up with GL-RPE. Our approach allows the network to capture both local and global interdependencies between video frames effectively. Since GL-RPE can be easily integrated into the existing methods, we apply it to two different unsupervised backbones. We provide extensive ablation studies and visual analysis to verify the effectiveness of the proposals. We demonstrate our approach achieves new state-of-the-art performance using the recently proposed rank order-based metrics: Kendall’s \(\tau \) and Spearman’s \(\rho \). Furthermore, despite our method is unsupervised, we show ours perform on par with the fully-supervised method.

We analyzed responsiveness of KRAS-mutated CRC cell lines with distinctive MSI status against mitogen-activated protein kinase (MEK) inhibitor (selumetinib; AZD) and/or B-raf proto-oncogene (BRAF) kinase inhibitor (vemurafenib; PLX). The viability of MSI-high (MSI-H) KRAS-mutated LS174T cells treated with AZD or PLX was 24.5 ± 0.9% or 71.4 ± 3.6%, respectively, and the viability of microsatellite stable (MSS) KRAS-mutated SW480 cells for AZD or PLX was 57.4 ± 3.1% or 43.1 ± 1.8%, respectively. These observations imply that the therapeutic efficacy of MEK kinase inhibitors or BRAF kinase inhibitors against KRAS-mutated colon cancer cells may differ between MSI-H and MSS. However, a combination of both inhibitors synergistically inhibits the proliferation of KRAS-mutated colon cancer cells regardless of MSI status. The underlying synergistic cytotoxic efficacy of AZD/PLX combination on KRAS-mutated colon cancer cells with different MSI status was further substantiated by markedly decreased phosphorylation of ERK in both LS74T and SW480 cell lines upon AZD and PLX treatment. Based on these collective data, we propose that MSI status should be considered when MEK kinase inhibitor or BRAF kinase inhibitor is treated for KRAS-mutated colon cancer, and that combination of both inhibitors synergistically inhibit proliferation of KRAS-mutated colon cancer cells independent of MSI status.

Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3–74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.

Eosinophils are terminally differentiated cytotoxic effector cells that have a role in parasitic infections and allergy by releasing their granule-derived cytotoxic proteins. However, an increasing number of recent observations indicate that eosinophils are not only associated with the pathogenesis of a wide range of diseases, but also contribute to the maintenance of homeostatic responses in previously underappreciated diverse tissues, such as the gastrointestinal (GI) tract and adipose tissue. In this review, we describe biological characteristics of eosinophils, as their developmental properties, permissive proliferation and survival, degranulation activity, and migration properties enable them to distribute to both homeostatic and inflamed tissues. We describe pathologic aspects of eosinophils with a role in asthma and in various GI diseases, including eosinophilic GI disorders, inflammatory bowel disease, and radiation-induced enteropathy. Finally, we discuss the beneficial role of eosinophils, which contribute to the resolution of pathogenic conditions and to the modulation of homeostatic biologic responses.

Although colorectal cancer is one of the most lethal cancer types in the world, its metastasis to the ovary is rare, compared to metastasis to other organs. Consequently, the genomic basis for colon-to-ovary metastasis remains unstudied, due to limited available patients, and thus there have been no attempts to construct individual-specific networks. Due to its rarity, the small sample size makes common mutations difficult to find. To overcome this problem, we herein attempted to apply a biological connectivity map called a sample-specific network (SSN), to reveal common biological functions in three samples. Our three samples were compared to a clinical dataset contained in The Cancer Genome Atlas (TCGA) Colorectal Adenocarcinoma (COAD), showing different mutational spectra, compared to matched samples based on age, gender, microsatellite instability (MSI) status, and tumor, node, metastasis (TNM) stage. The SSNs for the three samples revealed significant correlations of the mutation statuses of several apoptosis genes, in contrast to the TCGA-matched samples. Further analysis of a targeted-gene panel sequencing dataset for colon-to-ovary metastasis of primary tumor samples also confirmed significant correlations of the mutational statuses among apoptosis genes. In summary, using SSN, we successfully identified a common function (apoptosis) among our three patients having colon-to-ovary metastasis, despite no common mutations in the three patients. Such computational analyses could facilitate productive study of rare cancers and other diseases.

Defective gut immune reactions have been implicated in the development of atopic dermatitis (AD), whereas oral tolerance (OT), that is, the immune unresponsiveness induced by oral antigen administration, protects mice against AD. To investigate this protective role of OT, the transcriptomic profiles of skin were obtained by RNA sequencing from mice that were epicutaneously sensitized, orally tolerized prior to epicutaneous sensitization, or neither (control). Oral tolerance inhibited the upregulation of keratin- and allergic inflammation-associated genes that occurred in the epicutaneously sensitized group. Compared to the controls, mice that were orally tolerized and epicutaneously sensitized showed an upregulation of genes that regulate inflammation or keratinocyte differentiation. Knocking down two of those genes, SCGB1A1 and TSC22D3, upregulated Th2 inflammatory mediators and downregulated a cornified cell envelope-related gene. Based on our findings, OT may protect skin against allergic inflammation by promoting the expression of genes that regulate Th2 inflammatory responses and skin barrier function.

In article number 2004979, Dongwoo Khang, YunJae Jung, and co‐workers investigate the innate and adaptive immune response triggered by protein corona surrounding nanotubes. It was confirmed that conformational changes of protein structures driven by conjugation of nanotubes elicit immune activation of neutrophil and natural killer cells. The elevation of these innate immune cells subsequently induces the activation of T cells. This suggested mechanism can provide a platform technology for activating the innate immune cells that could be readily adapted to immunotherapies in the near future. [Image: see text]

Increasing evidence suggests that serum lipids are associated with depressive symptoms. However, previous studies have mostly employed a cross-sectional design and assessed middle-aged or older adult populations, making it difficult to discern the impact of lipid changes early in life on the development of depression. Accordingly, we sought to investigate changes in blood cholesterol levels during adolescence and the development of depressive symptoms in early adulthood. This prospective cohort study included participants aged 15-16 years from the JS High School Study (JSHS), with an average follow-up of 6 years. Participants had no diagnosed depression at baseline. Multivariable linear regression models were used to estimate associations between changes in total cholesterol during adolescence and depressive symptoms in adulthood. Changes in total cholesterol during adolescence were classified as "consistently low," "decreased," "moderate," "increased," or "consistently high". In men, depressive symptoms were higher in the consistently low (β = 3.20, p = 0.036) and increased total cholesterol groups (β = 3.48, p = 0.017), compared with the moderate group. In the consistently high group, although a positive linear association was observed, it lacked statistical significance (β = 2.71, p = 0.067). While similar tendencies were noted in women, the associations were not statistically significant. Consistently low or increased total cholesterol levels during adolescence may pose an increased risk of depressive symptoms in early adulthood. These findings suggest that different strategies should be adopted to manage the lipid risk factors with consideration of age and sex.

Background/aim Colon cancer is prone to distant metastases to other sites and the risk of recurrence is relatively high. Therefore, the identification of liver metastasis-related factors is important for the diagnosis or treatment of colon cancer. The aim of this study was to identify the metastasis-related factors that are differentially expressed in synchronous solitary liver metastasis compared to primary colon cancer. Materials and methods Tissues of primary colon cancer and associated with liver metastases of five patients were used for mass spectrometry. Identified proteins were validated by western blotting. The in silico analysis was performed using the STRING database and GeneMANIA. Results We identified 58 differentially expressed proteins (DEPs), including 51 under-expressed and 7 over-expressed proteins among a total of 164 identified proteins. Major hubs of protein-protein networks were ACTC1, PRDX6, TPI1, and ALDH1A1. DEPs were located in the extracellular region and cytoplasm and were involved in the regulation of enzymatic activity. The metabolic process was significantly enriched in biological processes and an involvement in the KEGG pathway. Conclusion These DEPs can potentially be used as biomarkers for the diagnosis of liver metastasis and they may provide a new strategy for developing anti-metastatic liver drugs in colon cancer patients.

Background Oral tolerance is immune unresponsiveness induced by oral administration of innocuous antigens. Oral administration of allergens has been shown to be effective for suppressing IgE production in allergic responses. However, whether oral tolerance has a role in protection from allergic skin inflammation has not been fully investigated. Here, we evaluated the potential protective role of oral tolerance in a murine model of atopic dermatitis (AD) and investigated the underlying immunologic mechanisms. Methods Mice were fed with ovalbumin (OVA) in drinking water then epicutaneously sensitized by repeated application of OVA to tape-stripped skin. Skin biopsies were analyzed for immunohistopathologic features. Levels of antibodies in sera and intestinal washes were measured by ELISA. Flow cytometry and real-time PCR analysis of the skin and mesenteric lymph nodes (MLN) were performed to investigate the immunologic effects of oral tolerance in epicutaneous (EC) sensitization-induced allergic responses. Results Induction of oral tolerance effectively inhibited inflammatory responses provoked by EC sensitization. Tolerogenic immune mediators were significantly increased in the skin and MLN of EC-sensitized mice following induction of oral tolerance. A marked increase in Il5 and Il13 expression and infiltration of eosinophils and type 2 innate lymphoid cells (ILC2) in the skin of EC-sensitized mice were significantly inhibited by oral tolerance. Conclusions Oral tolerance plays a protective role in the development of AD in a murine model by modulating immune microenvironments to be more favorable for immune regulation. This modulation involves inhibition of ILC2 infiltration in skin lesions.

Recently, sphingolipid derivatives, such as ceramide and sphingosine‑1‑phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation. This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation. Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF‑7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length. Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal‑regulated kinases (ERK) as shown by western blotting. In addition, CerS6 overexpression reduced MCF‑7 cell proliferation. This effect was partially reversed by co‑treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6‑mediated decrease in MCF‑7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF‑7 cell proliferation as measured by MTT assay. Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database. In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16‑ceramide, which is generated by CerS6.