862 research outputs found
Phytosphingosine degradation pathway includes fatty acid alpha-oxidation reactions in the endoplasmic reticulum
No full textAlthough normal fatty acids (FAs) are degraded via beta-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via alpha-oxidation. Phytosphingosine (PHS) is one of the long-chain bases (the sphingolipid components) and exists in specific tissues, including the epidermis and small intestine in mammals. In the degradation pathway, PHS is converted to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA alpha-oxidation. However, the detailed reactions and genes involved in the alpha-oxidation reactions of the PHS degradation pathway have yet to be determined. In the present study, we reveal the entire PHS degradation pathway: PHS is converted to C15: 0-COOH via six reactions [phosphorylation, cleavage, oxidation, CoA addition, cleavage (C1 removal), and oxidation], in which the last three reactions correspond to the alpha-oxidation. The aldehyde dehydrogenase ALDH3A2 catalyzes both the first and second oxidation reactions (fatty aldehydes to FAs). In Aldh3a2-deficient cells, the unmetabolized fatty aldehydes are reduced to fatty alcohols and are incorporated into ether-linked glycerolipids. We also identify HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like] as the major 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the FA alpha-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA alpha-oxidation in the peroxisomes, we have revealed the existence of FA alpha-oxidation in the endoplasmic reticulum in mammals
Extramammary Paget's disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies
No full textAlthough the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX intonu/numice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutationERBB2S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments
Normalized Energy Dissipation Rate in Shear Turbulence
No full textIn shear turbulence, a relationship between the normalized mean energy dissipation rate and the spectral equation is established. Simulations show that, as the Reynolds number increases, a term from the nonlinear interactions becomes constant, supporting the zeroth law of turbulence which states that the dissipation rate remains finite at high Reynolds numbers. The study also finds that the integral of the low-pass filtered energy flux is a critical factor for the zeroth law, rather than the constant flux assumed in the classic energy cascade picture. Additionally, in turbulence driven by a mean velocity gradient, dissipation is related to the scale of turbulence production.Journal of the Physical Society of Japan, 95(1), art. no. 013401; 2025journal articl
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