| 1. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. 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.
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| 2. |
- Abe, K., et al.
(författare)
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Neutron tagging following atmospheric neutrino events in a water Cherenkov detector
- 2022
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Ingår i: Journal of Instrumentation. - : Institute of Physics (IOP). - 1748-0221. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- We present the development of neutron-tagging techniques in Super-Kamiokande IV using a neural network analysis. The detection efficiency of neutron capture on hydrogen is estimated to be 26%, with a mis-tag rate of 0.016 per neutrino event. The uncertainty of the tagging efficiency is estimated to be 9.0%. Measurement of the tagging efficiency with data from an Americium-Beryllium calibration agrees with this value within 10%. The tagging procedure was performed on 3,244.4 days of SK-IV atmospheric neutrino data, identifying 18,091 neutrons in 26,473 neutrino events. The fitted neutron capture lifetime was measured as 218 +/- 9 mu s.
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| 7. |
- Ishibashi, R, et al.
(författare)
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A novel podocyte gene, semaphorin 3G, protects glomerular podocyte from lipopolysaccharide-induced inflammation
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 25955-
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Tidskriftsartikel (refereegranskat)abstract
- Kidney diseases including diabetic nephropathy have become huge medical problems, although its precise mechanisms are still far from understood. In order to increase our knowledge about the patho-physiology of kidney, we have previously identified >300 kidney glomerulus-enriched transcripts through large-scale sequencing and microarray profiling of the mouse glomerular transcriptome. One of the glomerulus-specific transcripts identified was semaphorin 3G (Sema3G) which belongs to the semaphorin family. The aim of this study was to analyze both the in vivo and in vitro functions of Sema3G in the kidney. Sema3G was expressed in glomerular podocytes. Although Sema3G knockout mice did not show obvious glomerular defects, ultrastructural analyses revealed partially aberrant podocyte foot processes structures. When these mice were injected with lipopolysaccharide to induce acute inflammation or streptozotocin to induce diabetes, the lack of Sema3G resulted in increased albuminuria. The lack of Sema3G in podocytes also enhanced the expression of inflammatory cytokines including chemokine ligand 2 and interleukin 6. On the other hand, the presence of Sema3G attenuated their expression through the inhibition of lipopolysaccharide-induced Toll like receptor 4 signaling. Taken together, our results surmise that the Sema3G protein is secreted by podocytes and protects podocytes from inflammatory kidney diseases and diabetic nephropathy.
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| 12. |
- Betsholtz, C, et al.
(författare)
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The glomerular transcriptome and proteome
- 2007
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Ingår i: Nephron. Experimental nephrology. - : S. Karger AG. - 1660-2129. ; 106:2, s. E32-E36
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Tidskriftsartikel (refereegranskat)abstract
- Histopathology provides the current basis for classification and diagnosis of glomerular disorders. Molecular profiling methods, such as microarray analysis of mRNA expression, have rapidly emerged over the past years and are now applicable to minute amounts of tissue material, such as glomeruli from embryos or adult experimental animals, or from human renal needle biopsies. This review summarizes current efforts aiming at the determination of the glomerular transcriptome and proteome during development, in the healthy adult, and in disease. These studies are encouraging and show that comprehensive molecular profiling of the kidney glomerulus will most likely provide significant new insights into the normal structure and function of the glomerular filter, the molecular mechanisms of glomerular development, the diagnosis and classification of glomerular disease, and the pathogenic mechanisms underlying the stepwise breakdown of glomerular filter function that accompanies several common systemic disorders.
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| 15. |
- He, L, et al.
(författare)
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Glomerulus-specific mRNA transcripts and proteins identified through kidney expressed sequence tag database analysis
- 2007
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Ingår i: Kidney International. - 1523-1755 .- 0085-2538. ; 71:9, s. 889-900
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Tidskriftsartikel (refereegranskat)abstract
- The kidney glomerulus plays a crucial role in blood filtration but the molecular composition and physiology of the glomerulus is not well understood. We previously constructed and large-scale sequenced four mouse glomerular expressed sequence tag (EST) libraries from newborn and adult mouse glomeruli. Here, we compared glomerular EST profiles with whole kidney EST profiles, thereby identifying 497 transcripts corresponding to UniGene clusters that were glomerulus-enriched, that is expressed more abundantly in glomeruli than in whole kidney. These include several known protein-coding glomerulus-specific transcripts critical for glomerulus development and function, but also a large number of gene transcripts, which have not previously been shown to be expressed in the glomerulus, or implicated in glomerular functions. We used in situ hybridization to demonstrate glomerulus-specific RNA expression for six novel glomerular genes and the public Human Protein Atlas to verify glomerular protein expression for another two. The higher mRNA abundance for the eight genes in glomeruli compared with whole kidney was also verified by Taqman quantitative polymerase chain reaction. We surmise that the further characterization of these genes and proteins will increase our understanding of glomerular development and physiology.
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| 18. |
- Kawai, M., et al.
(författare)
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Comparison of the efficacy of salmeterol/fluticasone propionate combination in Japanese and Caucasian asthmatics
- 2007
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Ingår i: Respir Med. - : Elsevier BV. - 0954-6111. ; 101:12, s. 2488-94
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The effect of ethnicity on the efficacy of salmeterol (S)+fluticasone propionate (FP) has not been examined in Japanese and Caucasian asthmatics. In this study, the efficacy of combination treatment with S and FP from a single inhaler (SFC) was compared with concurrent treatment with S and FP administration from separate inhalers (S+FP) in Japanese and Caucasian asthmatics. METHODS: This was a randomised, double-blind, crossover study in male and female Japanese (n=18) and Caucasian (n=17) asthmatics (50-100% predicted FEV(1); >35% reversibility in sGaw). Subjects received SFC (S 50mcg/FP 250mcgb.i.d.) and S+FP (S 50mcgb.i.d.+FP 250mcgb.i.d.) for 14 days. sGaw and FEV(1) were determined 0-12h after the first and last doses. RESULTS: Treatment with both SFC and S+FP produced marked bronchodilation, which was maintained 0-12h after the first dose. Baseline sGaw and FEV(1) increased up to 51% and 180mL, respectively, in Japanese subjects over 2 weeks of treatment, with similar improvements in Caucasian subjects. On Day 14 the 0-12h S+FP:SFC treatment ratios (90% CI) for sGaw AUC and peak were 1.05 (0.98, 1.12) and 1.05 (0.97, 1.14), respectively, in Japanese subjects, and 0.99 (0.92, 1.07) and 0.98 (0.89, 1.07), respectively, in Caucasian subjects, with no difference between the two ethnic groups. CONCLUSIONS: The finding of a similar significant bronchodilator response in Japanese and Caucasian asthmatics following concurrent and combination treatment with salmeterol and FP suggests that the therapeutic response to these agents is comparable and independent of ethnicity in Japanese and Caucasian asthma patients.
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| 20. |
- Tamura, K, et al.
(författare)
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Fibronectin stimulates transcription of the platelet-derived growth factor beta-receptor in cultured rat aortic smooth muscle cells.
- 1998
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 251:3, s. 677-80
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Tidskriftsartikel (refereegranskat)abstract
- Fibronectin seems to play an important role in promoting the characteristic changes of vascular smooth muscle cells in diabetes mellitus including overexpression of the platelet-derived growth factor beta-receptor. To determine the regulatory mechanism of the beta-receptor by fibronectin, we have analyzed the effect of fibronectin on the expression of the beta-receptor in cultured rat aortic smooth muscle cells using the beta-receptor promoter/luciferase expression vector system. Fibronectin was found to stimulate the expression of the beta-receptor at the transcriptional level. Both a MEK1 inhibitor PD98059 and a tyrosine kinase inhibitor herbimycin A significantly inhibited the fibronectin-stimulated receptor transcription. Herbimycin A also completely inhibited the fibronectin-stimulated increase in tyrosine phosphorylation of focal adhesion kinase. These data suggest the involvement of the integrin-mediated mitogen-activated protein kinase pathway downstream of fibronectin stimulation in the activation process of the beta-receptor promoter.
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