The Notch signaling pathway consists of several receptors and their ligands Delta and Jagged and is important for embryogenesis, cellular differentiation and proliferation. Activation of Notch receptors causes their cleavage yielding cytoplastic domains that translocate into the nucleus to induce target proteins such as the basic-loop-helix proteins Hes and Hey. Here we sought to clarify the significance of the Notch signaling pathway in acute kidney injury using a rat ischemia-reperfusion injury model and cultured NRK-52E cells. Analysis of the whole kidney after injury showed increased expression of Delta-1 and Hes-1 mRNA and protein along with processed Notch-2. Confocal microscopy, using specific antibodies, showed that Delta-1, cleaved Notch-2 and Hes-1 colocalized in the same segments of the injured renal proximal tubules. Recombinant Delta-1 significantly stimulated NRK-52E cell proliferation. Our study suggests that the Delta-1/Notch-2/Hes-1 signaling pathway may regulate the regeneration and proliferation of renal tubules during acute kidney injury.

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Real-time monitoring of the serum M2BPGi level after antiviral therapy for CHC patients could be a helpful screening tool for assessing the risk of HCC. M2BP and its glycan structure could be associated together with hepatocarcinogenesis.

Cell fate of hematopoietic progenitors is regulated by interaction between Notch proteins on progenitors and Notch ligands such as Jagged1 on stromal cells. Since acute myeloid leukemia (AML) originates from dysregulated hematopoietic progenitors, some abnormalities in the Notch-Jagged system may exist in AML cells. As the first step to clarify this, we examined the expression of Notch1 and Jagged1 proteins in eight AML cell lines and 15 fresh AML samples by immunoblotting. In the Notch1 protein, two bands, a 300 kDa band and a 120 kDa band, which appeared to be a full-length protein and a transmembrane fragment, respectively, were recognized in five AML cell lines and six fresh samples. In addition, three of the five cell lines showed a 110 kDa fragment, which appeared to be from an intracellular domain, namely an active form. One cell line showed aberrant sized fragments, which suggested a structural abnormality. Jagged1 protein was recognized in six cell lines and six fresh samples. In four cell lines and four fresh samples, both Notch1 and Jagged1 proteins were observed. In these cells, Notch1 and Jagged1 proteins may interact among themselves. We showed that Notch1 and Jagged1 proteins are widely expressed in AML cells. We hypothesize that some abnormalities in the Notch-Jagged system which cause the excessive self-renewal and the block of differentiation, may be involved in the abnormal proliferation of AML cells.

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.