👤 Takashi Ebihara

The lymphatic system maintains tissue fluid balance, and FOXC2 mutations cause lymphoedema-distichiasis syndrome, which is characterized by lymphatic valve defects. Although oscillatory shear stress regulates FOXC2 expression, other extracellular regulators remain unclear. In this study, we identified LPA4 and LPA6, two Gα12/Gα13-coupled receptors for the bioactive lipid lysophosphatidic acid (LPA), as key regulators of FOXC2 expression and lymphatic valve development. Lymphatic endothelial cell-specific (LEC-specific) Lpa4 Lpa6-deficient mice exhibited impaired lymphatic valve formation and maintenance, which resembled phenotypes of LEC-specific Foxc2-deficient mice, including abnormal lymphatic vessel patterning. Mechanistically, lymphatic endothelial Lpa4/Lpa6 ablation reduced FOXC2 expression in vitro and in vivo. NF-κB was found to be essential for LPA-induced FOXC2 expression through the LPA4/LPA6-Gα12/Gα13-Rho kinase signaling axis. Accordingly, pharmacological inhibition of NF-κB and Rho kinase impaired lymphatic valve maintenance in mice. These results suggested that lymphatic endothelial LPA4 and LPA6 synergistically regulate FOXC2 expression through NF-κB activation and play an important role in lymphatic valve formation and maintenance. Our findings provide a molecular basis for lymphatic vessel development with a therapeutic potential for targeting lymphatic system-associated diseases. Show less

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-β, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-β plasma level was elevated in line with increased severity compared with HCs, as were IFN-β downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-β (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression. Show less

The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. Show less