Idiopathic pulmonary fibrosis-specific Bayesian network integrating extracellular vesicle proteome and clinical information.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by severe lung fibrosis and a poor prognosis. Although the biomolecules related to IPF have been extensively studied, molecular mechanisms of the pathogenesis and their association with serum biomarkers and clinical findings have not been fully elucidated. We constructed a Bayesian network using multimodal data consisting of a proteome dataset from serum extracellular vesicles, laboratory examinations, and clinical findings from 206 patients with IPF and 36 controls. Differential protein expression analysis was also performed by edgeR and incorporated into the constructed network. We have successfully visualized the relationship between biomolecules and clinical findings with this approach. The IPF-specific network included modules associated with TGF-ß signaling (TGFB1 and LRC32), fibrosis-related (A2MG and PZP), myofibroblast and inflammation (LRP1 and ITIH4), complement-related (SAA1 and SAA2), as well as serum markers, and clinical symptoms (KL-6, SP-D and fine crackles). Notably, it identified SAA2 associated with lymphocyte counts and PSPB connected with the serum markers KL-6 and SP-D, along with fine crackles as clinical manifestations. These results contribute to the elucidation of the pathogenesis of IPF and potential therapeutic targets.

Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.

Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota.

The gut microbiome is an important determinant in various diseases. Here we perform a cross-sectional study of Japanese adults and identify the Blautia genus, especially B. wexlerae, as a commensal bacterium that is inversely correlated with obesity and type 2 diabetes mellitus. Oral administration of B. wexlerae to mice induce metabolic changes and anti-inflammatory effects that decrease both high-fat diet-induced obesity and diabetes. The beneficial effects of B. wexlerae are correlated with unique amino-acid metabolism to produce S-adenosylmethionine, acetylcholine, and L-ornithine and carbohydrate metabolism resulting in the accumulation of amylopectin and production of succinate, lactate, and acetate, with simultaneous modification of the gut bacterial composition. These findings reveal unique regulatory pathways of host and microbial metabolism that may provide novel strategies in preventive and therapeutic approaches for metabolic disorders.

Panomicon: A web-based environment for interactive, visual analysis of multi-omics data.

Multi-omics analyses, combining transcriptomics, genomics, proteomics, and so on, have led to important insights in many areas of biology and medicine. To support these analyses, software that can handle the difficulties associated with multi-omics datasets is crucial. Here, we describe Panomicon, a web-based, interactive analysis environment for multi-omics data. Building on Toxygates, a tool previously created to study single-omics data that features interactive clustering, heatmaps, and user data uploads, Panomicon introduces improvements for the storage and handling of additional omics types, as well as tools for the generation and visualization of interaction networks between different types of omics data. Panomicon is a new type of environment for the collaborative study of multi-omics data, both for users uploading data to our server and for groups wishing to host their own deployment of Panomicon. We demonstrate Panomicon's capabilities by revisiting a microRNA-mRNA interaction networks study in a non-small cell lung cancer dataset.

Constructing an In Silico Three-Class Predictor of Human Intestinal Absorption With Caco-2 Permeability and Dried-DMSO Solubility.

Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried-dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application.

An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8+ T Cells in Nonhuman Primates.

The priming, boosting, and restoration of memory cytotoxic CD8+ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid-based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid-based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-α and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic-polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response-boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer.

Essential Role of CARD14 in Murine Experimental Psoriasis.

Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card14-/- mice. Comparison of the early gene signature of the skin between IMQ-cream-treated Card14-/- mice and Tlr7-/-Tlr9-/- mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type-specific analysis of these mice identified skin Langerinhigh Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of Vγ4+ T cells producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis.