A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important ...lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid Ï-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the Ï-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (â¥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid Ï-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production.
Significance The sphingolipid backbone ceramide is the major lipid species in the stratum corneum and plays a pivotal function in skin permeability barrier formation. Acylceramide is an important epidermis-specific ceramide species. However, the details of acylceramide production, including its synthetic genes, reactions and their orders, and intracellular site for production, have remained unclear. In the present study, we identified the cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22) as the missing fatty acid Ï-hydroxylase required for acylceramide synthesis. We also determined that CYP4F22 is a type I endoplasmic reticulum membrane protein and that its substrate is ultra-long-chain fatty acids. Our findings provide important insights into the molecular mechanisms of not only acylceramide production but also skin permeability barrier formation.
Dysregulation of the G(1)/S transition in the cell cycle contributes to tumor development. The oncogenic transcription factors c-Jun and c-Myc are indispensable regulators at this transition, and ...their aberrant expression is associated with many malignancies. Degradation of c-Jun/c-Myc is a critical process for the G(1)/S transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 β (GSK3β). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this GSK3β modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 functions as a priming kinase of c-Jun and c-Myc. Knockdown of DYRK2 in human cancer cells shortened the G(1) phase and accelerated cell proliferation due to escape of c-Jun and c-Myc from ubiquitination-mediated degradation. In concert with these results, silencing DYRK2 increased cell proliferation in human cancer cells, and this promotion was completely impeded by codeprivation of c-Jun or c-Myc in vivo. We also found marked attenuation of DYRK2 expression in multiple human tumor samples. Downregulation of DYRK2 correlated with high levels of unphosphorylated c-Jun and c-Myc and, importantly, with invasiveness of human breast cancers. These results reveal that DYRK2 regulates tumor progression through modulation of c-Jun and c-Myc.
This study investigated the Holton‐Tan relationship between the equatorial quasi‐biennial oscillation (QBO) and the polar vortex as seen in the ERA‐40 reanalysis and ERA‐interim analysis (1980–2004, ...25 years) data sets and in ensemble simulated data sets (five members covering the period 1980–2004, 125 years) by using the Meteorological Research Institute chemistry climate model (MRI‐CCM) and focusing on the Northern Hemisphere winter. The primary tools employed were composite differences in zonal wind, temperature, and Eliassen‐Palm (EP) fluxes. Although not many global circulation models can simulate the QBO realistically, the MRI‐CCM, which includes the interaction between QBO dynamics and the ozone (hence heating) distribution, reproduces a self‐generated QBO that is fairly realistic. In agreement with the finding of previous studies, our results revealed that the conventional Holton‐Tan explanation that the equatorial winds in the lower stratosphere act as a waveguide for midlatitude planetary wave propagation cannot explain the winter circulation in either the ERA‐40 data or the simulation. Although the composite differences in zonal wind and temperature show a slight yet statistically significant Holton‐Tan effect, i.e., the stratospheric polar vortex is weaker and more disturbed under easterly QBO conditions, the EP flux diagnostics do not show more poleward propagation in the midlatitude stratosphere. Rather, planetary waves propagate more equatorward as well as more upward during the easterly phase of the QBO.
Summary Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of non-Hodgkin lymphoma according to the current WHO classification. This rare form of B-cell lymphoma is characterised ...by selective growth of tumour cells in the lumina of small vessels of various organs. Strange characteristics of IVLBCL, including the absence of marked lymphoadenopathy and the usually aggressive clinical behaviour, result in the delay of timely and accurate diagnosis and fatal complications. Thus, the prognosis of IVLBCL is extremely poor. The success achieved with the anti-CD20 chimeric monoclonal antibody, rituximab, represents an important milestone in the clinical practice of B-cell lymphoma. An advantage of adding rituximab to conventional chemotherapies has been shown, in the process of increasing our understanding of the clinical and pathological manifestations for IVLBCL. This Review describes the cutting edge of research on IVLBCL, and discusses the unsolved issues from biological and clinical perspectives to provide a better understanding of this rare lymphoma.
Background
Our aim is to evaluate the utility of liver function measured by modified albumin–bilirubin (mALBI) grade to predict eligibility for second-line therapies, including regorafenib and ...ramucirumab therapy, at initiation of sorafenib therapy for patients with hepatocellular carcinoma (HCC).
Methods
Participants in this retrospective, single-center study comprised 197 patients with sorafenib-treated HCC, Child–Pugh scores (CPs) 5–7 and performance status 0–1 treated between October 2009 and June 2019. The factors at initiation of sorafenib therapy, including mALBI grade and CPs, were analyzed with regard to second-line eligibility, regorafenib eligibility and ramucirumab eligibility, respectively.
Results
Proportions of eligibility for second-line therapies, regorafenib therapy and ramucirumab therapy were 48.7%, 35.5% and 18.3%. Modified ALBI grades 1 and 2a were contributing factors for second-line eligibility (odd ratios OR 16.7 and 5.6; 95% CI 6.5–43.3 and 2.6–12.2), regorafenib therapy (OR 13.9 and 6.9; 95% CI 5.6–34.4 and 2.9–16.2), and ramucirumab therapy (OR 9.5 and 4.8; 95% CI 2.9–30.8 and 1.6–14.4), with grade 2b defined as reference. Patients with mALBI grade 1 and CPs 5 exhibited especially high proportion of eligibility for regorafenib therapy (70.5%). In patients with mALBI grade 2b, those with CPs 5 displayed higher proportion of eligibility for second-line therapy and ramucirumab therapy (100% and 50%) than those with CPs 6 (31.8% and 11.4%).
Conclusions
Modified ALBI grade in combination with CPs at the initiation of sorafenib therapy would be useful to predict eligibility for second-line therapies.
We approached to find out the difference of Japanese and Western restaurant management, and Japanese restaurant managements between Kyoto, Osaka and Tokyo. In Japan, restaurants with long history ...tend to have good reputation as good restaurants and the good restaurants information are shared by mouth to mouth. On the other hand, good restaurants in Europe are judged by Michelin Guide and restaurants with famous chefs lead to be famous restaurants. Information about good restaurants in Japan are less visible than European restaurants. We studied restaurants in Japan, and compared the management between Japanese and Western restaurants and areal differences among Japanese restaurants. The differences of strategy and chef's career are observed between Japanese and Western restaurants. We also found that there are differences among Kyoto, Osaka and Tokyo in terms of history and career management of chefs.
Abstract
The ‘open’ and ‘compact’ regions of chromatin are considered to be regions of active and silent transcription, respectively. However, individual genes produce transcripts at different ...levels, suggesting that transcription output does not depend on the simple open-compact conversion of chromatin, but on structural variations in chromatin itself, which so far have remained elusive. In this study, weakly crosslinked chromatin was subjected to sedimentation velocity centrifugation, which fractionated the chromatin according to its degree of compaction. Open chromatin remained in upper fractions, while compact chromatin sedimented to lower fractions depending on the level of nucleosome assembly. Although nucleosomes were evenly detected in all fractions, histone H1 was more highly enriched in the lower fractions. H1 was found to self-associate and crosslinked to histone H3, suggesting that H1 bound to H3 interacts with another H1 in an adjacent nucleosome to form compact chromatin. Genome-wide analyses revealed that nearly the entire genome consists of compact chromatin without differences in compaction between repeat and non-repeat sequences; however, active transcription start sites (TSSs) were rarely found in compact chromatin. Considering the inverse correlation between chromatin compaction and RNA polymerase binding at TSSs, it appears that local states of chromatin compaction determine transcription levels.
In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable ...progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion–based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.
In our previous paper, it is proved that for any positive flow-spine
P
of a closed, oriented 3-manifold
M
, there exists a unique contact structure supported by
P
up to isotopy. In particular, this ...defines a map from the set of isotopy classes of positive flow-spines of
M
to the set of isotopy classes of contact structures on
M
. In this paper, we show that this map is surjective. As a corollary, we show that any flow-spine can be deformed to a positive flow-spine by applying first and second regular moves successively.
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