CD40 and IFN-γ dependent T cell activation by human bronchial epithelial cells

We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/ BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-γ resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-γ, but only weakly compared with those without IFN-γ. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-γ- dependent manners under the presence of third party cells that transduce co-stimulatory signals

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling

The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but, after sex determination, it is upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late-onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by finetuning Notch signaling

Effect of aspirin treatment on serum levels of lipoprotein (a) : analysis from the apolipoprotein (a) isoforms

We have found that aspirin lowers elevated serum lipoprotein(a) [Lp(a)] levels via reduction of the transcriptional activity of apolipoprotein(a) [apo(a)] gene with suppression of apo(a) mRNA expression. In the present study, we evaluated the effect of aspirin treatment on serum Lp(a) level and analyzed its relation to type of apo(a) isoform. Serum levels of Lp(a) were measured by turbidimetric immunoassay before and after the oral administration of aspirin therapy (81 mg/day) in 57 patients with coronary artery disease or cerebral infarction. Apo(a) isoforms were determined by immunoblotting method. In patients with high serum Lp(a) levels (more than 30 mg/dl), aspirin reduced serum Lp(a) levels to approximately 80 % of the baseline after one month. Their levels sustained significantly low even after six months. The effect of aspirin in reducing elevated serum Lp(a) levels were stronger in patients with smaller-sized type or double-band type of apo(a) isoforms. The transcriptional efficiency of apo(a) gene is thought to be increased in patients with these apo(a) isoforms. Therefore, these findings suggest that aspirin reduces apo(a) gene transcription preferentialy in patients with high transcriptional efficiency of this gene

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD

The Interaction of LFA-1 on Mononuclear Cells and ICAM-1 on Tubular Epithelial Cells Accelerates TGF-β1-Induced Renal Epithelial-Mesenchymal Transition

The epithelial-mesenchymal transition (EMT) of renal epithelial cells (RTECs) has pivotal roles in the development of renal fibrosis. Although the interaction of lymphocyte function-associated antigen 1 (LFA-1) on leukocytes and its ligand, intracellular adhesion molecule 1 (ICAM-1), plays essential roles in most inflammatory reactions, its pathogenetic role in the EMT of RTECs remains to be clarified. In the present study, we investigated the effect of the interaction of LFA-1 on peripheral blood mononuclear cells (PBMCs) and ICAM-1 on HK-2 cells after stimulation with TGF-β1 on the EMT of RTECs. ICAM-1 was highly expressed in HK-2 cells. After TGF-β1 stimulation, the chemokines CCL3 and CXCL12 increased on HK-2 cells. After co-culture of PBMCs and HK-2 cells pre-stimulated with TGF-β1 (0.1 ng/ml) (HK-2-TGF-β1 (0.1)), the expression of the active form of LFA-1 increased on PBMCs; however, total LFA-1 expression did not change. The expression of the active form of LFA-1 on PBMCs did not increase after co-culture with not CCL3 but CXCL12 knockdown HK-2-TGF-β1 (0.1). The expression of epithelial cell junction markers (E-cadherin and occludin) further decreased and that of mesenchymal markers (vimentin and fibronectin) further increased in HK-2-TGF-β1 (0.1) after co-culture with PBMCs for 24 hrs (HK-2-TGF-β1 (0.1)-PBMCs). The phosphorylation of ERK 1/2 but not smad2 and smad3 increased in HK-2-TGF-β1 (0.1)-PBMCs. The snail and slug signaling did not increase HK-2-TGF-β1 (0.1)-PBMCs. Although the migration and invasion of HK-2 cells induced full EMT by a high dose (10.0 ng/ml) and long-term (72–96 hrs) TGF-β1 stimulation increased, that of HK-2-TGF-β1 (0.1)-PBMCs did not increase. These results suggested that HK-2 cells stimulated with TGF-β1 induced conformational activation of LFA-1 on PBMCs by increased CXCL12. Then, the direct interaction of LFA-1 on PBMCs and ICAM-1 on HK-2 cells activated ERK1/2 signaling to accelerate the part of EMT of HK-2 cells induced by TGF-β1

Carcinogenicity of cobalt, antimony compounds, and weapons-grade tungsten alloy

The complete evaluation of the carcinogenicity of cobalt, antimony compounds, and weapons-grade tungsten alloy will be published in Volume 131 of the IARC Monographs.[Excerpt] In March, 2022, a Working Group of 31 scientists from 13 countries met remotely at the invitation of the International Agency for Research on Cancer (IARC) to finalise their evaluation of the carcinogenicity of nine agents: cobalt metal (without tungsten carbide or other metal alloys), soluble cobalt(II) salts, cobalt(II) oxide, cobalt(II,III) oxide, cobalt(II) sulfide, other cobalt(II) compounds, trivalent antimony, pentavalent antimony, and weapons-grade tungsten (with nickel and cobalt) alloy. For cobalt metal and the cobalt compounds, particles of all sizes were included in the evaluation. These assessments will be published in Volume 131 of the IARC Monographs.1 Cobalt metal and soluble cobalt(II) salts were classified as “probably carcinogenic to humans” (Group 2A) based on “sufficient” evidence for cancer in experimental animals and “strong” mechanistic evidence in human primary cells. Cobalt(II) oxide and weapons-grade tungsten alloy were classified as “possibly carcinogenic to humans” (Group 2B) based on “sufficient” evidence in experimental animals. Trivalent antimony was classified as “probably carcinogenic to humans” (Group 2A), based on “limited” evidence for cancer in humans, “sufficient” evidence for cancer in experimental animals, and “strong” mechanistic evidence in human primary cells and in experimental systems. Cobalt(II,III) oxide, cobalt(II) sulfide, other cobalt(II) compounds, and pentavalent antimony were each evaluated as “not classifiable as to its carcinogenicity to humans” (Group 3).[...

A multilevel dataset of microplastic abundance in the world’s upper ocean and the Laurentian Great Lakes

A total of 8218 pelagic microplastic samples from the world’s oceans were synthesized to create a dataset composed of raw, calibrated, processed, and gridded data which are made available to the public. The raw microplastic abundance data were obtained by different research projects using surface net tows or continuous seawater intake. Fibrous microplastics were removed from the calibrated dataset. Microplastic abundance which fluctuates due to vertical mixing under different oceanic conditions was standardized. An optimum interpolation method was used to create the gridded data; in total, there were 24.4 trillion pieces (8.2 × 104 ~ 57.8 × 104 tons) of microplastics in the world’s upper oceans

International studies of ice sheet and bedrock at Dome Fuji, East Antarctica

The Tenth Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Wed. 4 Dec. / 2F Auditorium, National Institute of Polar Researc

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target