Elucidating disease-associated mechanisms triggered by pollutants via the epigenetic landscape using large-scale ChIP-Seq data.

BACKGROUND: Despite well-documented effects on human health, the action modes of environmental pollutants are incompletely understood. Although transcriptome-based approaches are widely used to predict associations between chemicals and disorders, the molecular cues regulating pollutant-derived gene expression changes remain unclear. Therefore, we developed a data-mining approach, termed "DAR-ChIPEA," to identify transcription factors (TFs) playing pivotal roles in the action modes of pollutants. METHODS: Large-scale public ChIP-Seq data (human, n = 15,155; mouse, n = 13,156) were used to predict TFs that are enriched in the pollutant-induced differentially accessible genomic regions (DARs) obtained from epigenome analyses (ATAC-Seq). The resultant pollutant-TF matrices were then cross-referenced to a repository of TF-disorder associations to account for pollutant modes of action. We subsequently evaluated the performance of the proposed method using a chemical perturbation data set to compare the outputs of the DAR-ChIPEA and our previously developed differentially expressed gene (DEG)-ChIPEA methods using pollutant-induced DEGs as input. We then adopted the proposed method to predict disease-associated mechanisms triggered by pollutants. RESULTS: The proposed approach outperformed other methods using the area under the receiver operating characteristic curve score. The mean score of the proposed DAR-ChIPEA was significantly higher than that of our previously described DEG-ChIPEA (0.7287 vs. 0.7060; Q = 5.278 × 10-42; two-tailed Wilcoxon rank-sum test). The proposed approach further predicted TF-driven modes of action upon pollutant exposure, indicating that (1) TFs regulating Th1/2 cell homeostasis are integral in the pathophysiology of tributyltin-induced allergic disorders; (2) fine particulates (PM2.5) inhibit the binding of C/EBPs, Rela, and Spi1 to the genome, thereby perturbing normal blood cell differentiation and leading to immune dysfunction; and (3) lead induces fatty liver by disrupting the normal regulation of lipid metabolism by altering hepatic circadian rhythms. CONCLUSIONS: Highlighting genome-wide chromatin change upon pollutant exposure to elucidate the epigenetic landscape of pollutant responses outperformed our previously described method that focuses on gene-adjacent domains only. Our approach has the potential to reveal pivotal TFs that mediate deleterious effects of pollutants, thereby facilitating the development of strategies to mitigate damage from environmental pollution.

Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells.

Many therapeutic antibodies (Abs) and mRNA vaccines, both targeting SARS-CoV-2 spike protein (S-protein), have been developed and approved in order to combat the ongoing COVID-19 pandemic. In consideration of these developments, a common concern has been the potential for Ab-dependent enhancement (ADE) of infection caused by inoculated or induced Abs. Although the preventive and therapeutic effects of these Abs are obvious, little attention has been paid to the influence of the remaining and dwindling anti-S-protein Abs in vivo. Here, we demonstrate that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. Although sera collected from mRNA-vaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. None of the sera examined exhibited neutralizing activity against infection with the Omicron strain. Rather, some ADE of Omicron infection was observed in some sera. These results suggest the possible emergence of adverse effects caused by these Abs in addition to the therapeutic or preventive effect.

The potential of COVID-19 patients' sera to cause antibody-dependent enhancement of infection and IL-6 production.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many vaccine trials have been initiated. An important goal of vaccination is the development of neutralizing antibody (Ab) against SARS-CoV-2. However, the possible induction of antibody-dependent enhancement (ADE) of infection, which is known for other coronaviruses and dengue virus infections, is a particular concern in vaccine development. Here, we demonstrated that human iPS cell-derived, immortalized, and ACE2- and TMPRSS2-expressing myeloid cell lines are useful as host cells for SARS-CoV-2 infection. The established cell lines were cloned and screened based on their function in terms of susceptibility to SARS-CoV-2-infection or IL-6 productivity. Using the resulting K-ML2 (AT) clone 35 for SARS-CoV-2-infection or its subclone 35-40 for IL-6 productivity, it was possible to evaluate the potential of sera from severe COVID-19 patients to cause ADE and to stimulate IL-6 production upon infection with SARS-CoV-2.

Genomic style: yet another deep-learning approach to characterize bacterial genome sequences.

Motivation: Biological sequence classification is the most fundamental task in bioinformatics analysis. For example, in metagenome analysis, binning is a typical type of DNA sequence classification. In order to classify sequences, it is necessary to define sequence features. The k-mer frequency, base composition and alignment-based metrics are commonly used. On the other hand, in the field of image recognition using machine learning, image classification is broadly divided into those based on shape and those based on style. A style matrix was introduced as a method of expressing the style of an image (e.g. color usage and texture). Results: We propose a novel sequence feature, called genomic style, inspired by image classification approaches, for classifying and clustering DNA sequences. As with the style of images, the DNA sequence is considered to have a genomic style unique to the bacterial species, and the style matrix concept is applied to the DNA sequence. Our main aim is to introduce the genomics style as yet another basic sequence feature for metagenome binning problem in replace of the most commonly used sequence feature k-mer frequency. Performance evaluations showed that our method using a style matrix has the potential for accurate binning when compared with state-of-the-art binning tools based on k-mer frequency. Availability and implementation: The source code for the implementation of this genomic style method, along with the dataset for the performance evaluation, is available from https://github.com/friendflower94/binning-style. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (II): apoptosis of antiproliferactive principle (24,25-dihydrowithanolide D) against ATL cell lines and structure-activity relationships with withanolides isolated from solanaceous plants.

Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4ß-hydroxy group as well as a 5ß,6ß-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.

Case of peritoneal dissemination of colon cancer in which PET/CT was useful in determining the indicated surgical procedure.

The right half of the colon was resected in a 70-year-old woman in August 2002 for ascending colon cancer. The peritoneum was also resected because of metastasis (Stage IV). Since tumor markers gradually increased, positron emission tomography (PET)/ computed tomography (CT) revealed peritoneal dissemination. Abdominal pain appeared 40 months after surgery. Barium enema findings revealed an ileal constriction approximately 25 cm from the anastomosed site toward the anus. Repeat PET/CT revealed peritoneal dissemination coinciding with ileal constriction. CT did not reveal well-defined tumor shadows. The patient was diagnosed with constriction associated with peritoneal metastasis and underwent surgery. Surgical findings revealed a roughly 2-cm peritoneal metastatic focus and ileal constriction. The site was resected and anastomosed. Postoperative progress was favorable; the patient was discharged and enjoys a favorable quality of life through outpatient adjuvant chemotherapy. PET/CT is suggested to be useful in observing the progress of peritoneal dissemination and may be of assistance in determining the course of treatment.