BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1

Primary cilia are antenna-like organelles that contain specific proteins, and are crucial for tissue morphogenesis. Anterograde and retrograde trafficking of ciliary proteins are mediated by the intraflagellar transport (IFT) machinery. BROMI/TBC1D32 interacts with CCRK/CDK20, which phosphorylates and activates the ICK/CILK1 kinase, to regulate the change in direction of the IFT machinery at the ciliary tip. Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies, and mice defective in these genes are also known to demonstrate ciliopathy phenotypes. We here show that BROMI interacts not only with CCRK but also with CFAP20, an evolutionarily conserved ciliary protein, and with FAM149B1/JBTS36, a protein in which mutations cause Joubert syndrome. In addition, we show that FAM149B1 interacts directly with CCRK as well as with BROMI. Ciliary defects observed in CCRK-knockout (KO), BROMI-KO, and FAM149B1-KO cells, including abnormally long cilia and accumulation of the IFT machinery and ICK at the ciliary tip, resembled one another, and BROMI mutants that are defective in binding to CCRK and CFAP20 were unable to rescue the ciliary defects of BROMI-KO cells. These data indicate that CCRK, BROMI, FAM149B1, and probably CFAP20, all together regulate the IFT turnaround process under the control of ICK

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

The cancer stem cell (CSC) theory posits that a small population of cells with stem cell-like features is responsible for tumor growth, resistance, and recurrence in many malignancies. This theory could be a useful paradigm for designing innovative targeted drug therapies. Liver cancer is the fifth most common cancer worldwide, with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) as the predominant forms. Hepatic stem/progenitor cells are believed to be the origin of HCCs and CCAs; however, this remains a controversial topic. Aldehyde dehydrogenase (ALDH) is the main enzymatic system responsible for the clearance of acetaldehyde from the hepatocytes in the liver tissue. Therefore, ALDH1 has been suggested to be a potential, biological and CSC marker in liver cancers. We here provide an overview of the current state of knowledge of CSCs in liver and the role of ALDH1 in the development and progression of liver cancers and discuss its potential value as a prognostic and diagnostic biomarker

Scattered X-rays in Obscured Active Galactic Nuclei and their Implications for Geometrical Structure and Evolution

We construct a new sample of 32 obscured active galactic nuclei (AGNs) selected from the Second XMM-Newton Serendipitous Source Catalogue to investigate their multiwavelength properties in relation to the "scattering fraction", the ratio of the soft X-ray flux to the absorption-corrected direct emission. The sample covers a broad range of the scattering fraction (0.1%-10%). A quarter of the 32 AGNs have a very low scattering fraction (smaller than 0.5%), which suggests that they are buried in a geometrically thick torus with a very small opening angle. We investigate correlations between the scattering fraction and multiwavelength properties. We find that AGNs with a small scattering fraction tend to have low [O III]lambda5007/X-ray luminosity ratios. This result agrees with the expectation that the extent of the narrow-line region is small because of the small opening angle of the torus. There is no significant correlation between scattering fraction and far-infrared luminosity. This implies that a scale height of the torus is not primarily determined by starburst activity. We also compare scattering fraction with black hole mass or Eddington ratio and find a weak anti-correlation between the Eddington ratio and scattering fraction. This implies that more rapidly growing supermassive black holes tend to have thicker tori.Comment: 13 pages, 10 figures, accepted for publication in Ap

Usefulness of medium-Energy Collimator for Sentinel Node Lymphoscintigraphy Imaging in Breast Cancer Patients

金沢大学大学院医学系研究科小野口, 昌久This study was performed to investigate the usefulness of a general-purpose medium-energy (ME) collimator for the accurate localization of the sentinel lymph node (SLN) in breast cancer patients. Methods: We compared phantom images and lymphoscintigraphy images obtained under different conditions for a patient with breast cancer. Comparisons were performed between 2 cameras, between a low-energy high-resolution (LEHR) collimator and a general-purpose ME collimator, and between energy windows centered at 141 keV and at 146 keV. Profile curves and image contrast were evaluated along with the visual interpretation of images. The most suitable imaging time was selected from the relationship between contrast and the data acquisition time. Results: The images obtained with the general-purpose ME collimator and the energy window centered at 141 keV were of poorer quality than those obtained with the LEHR collimator and the same energy window. However, the quality of the images obtained with the general-purpose ME collimator improved when the energy window was centered at 146 keV. The method involving the general-purpose ME collimator and the energy window centered at 146 keV showed excellent image quality similar to that obtained with the LEHR collimator. The enhancement of contrast was confirmed at more than 3 cm away from the center of the injection site. Stable contrast was obtained with a data acquisition time of 5 min, with the general-purpose ME collimator, and with the energy window centered at 146 keV. Conclusion: The method involving the general-purpose ME collimator and the energy window centered at 146 keV has the merit of the lymph node not being concealed by a lead shield. This new method is expected to improve the rate of detection of SLN and has the potential for shortening the acquisition time

Synchronous malignant B-cell lymphoma and gastric tubular adenocarcinoma associated with paraneoplastic cutaneous vasculitis: hypereosinophilic syndrome with mixed cryoglobulinemia is an important sign of paraneoplastic syndrome

Gastric adenocarcinoma developing concomitantly with a lymphoma is rare. Furthermore, B-cell lymphoma, originating from lymph nodes, with eosinophilia is extremely rare. We report here a case with a synchronous diffuse large B-cell lymphoma (DLBCL) and an early adenocarcinoma of the stomach. In addition, this case seemed to be associated with paraneoplastic cutaneous vasculitis caused by hypereosinophilic syndrome (HES) with mixed cryoglobulinemia (MC). Many neoplastic diseases that affect internal organs display cutaneous manifestations, which may be the presenting signs and symptoms of the underlying malignancy. In particular, the association between cutaneous vasculitis and malignancy has been widely reviewed, and recently neoplasms have been suggested to produce antigens and the resultant immune complex formations, activating the serum complement, thus cause paraneoplastic vasculitis. In this case, severe eosinophilia and cryoglobulinemia with low complements were observed in a laboratory test. A biopsy specimen from a skin lesion revealed leukocytoclastic vasculitis with severe perivascular infiltration of eosinophils. The cutaneous vasuculitis was considered to be a manifestation of HES with MC, although there were no etiological factors of HES and MC. Therefore, the vasculitis seems to be a symptom of paraneoplastic syndrome in this case. Our finding suggests that the potential presence of malignancies should be kept in mind as a possible underlying disorder especially in the presence of HES with MC; this possibility is interesting also as regards at least part of the pathogenesis for paraneplastic syndrome

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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