Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors)

BACKGROUND: The nuclear hormone receptor (NR) superfamily complement in humans is composed of 48 genes with diverse roles in metabolic homeostasis, development, and detoxification. In general, NRs are strongly conserved between vertebrate species, and few examples of molecular adaptation (positive selection) within this superfamily have been demonstrated. Previous studies utilizing two-species comparisons reveal strong purifying (negative) selection of most NR genes, with two possible exceptions being the ligand-binding domains (LBDs) of the pregnane X receptor (PXR, NR1I2) and the constitutive androstane receptor (CAR, NR1I3), two proteins involved in the regulation of toxic compound metabolism and elimination. The aim of this study was to apply detailed phylogenetic analysis using maximum likelihood methods to the entire complement of genes in the vertebrate NR superfamily. Analyses were carried out both across all vertebrates and limited to mammals and also separately for the two major domains of NRs, the DNA-binding domain (DBD) and LBD, in addition to the full-length sequences. Additional functional data is also reported for activation of PXR and the vitamin D receptor (VDR; NR1I1) to gain further insight into the evolution of the NR1I subfamily. RESULTS: The NR genes appear to be subject to strong purifying selection, particularly in the DBDs. Estimates of the ratio of the non-synonymous to synonymous nucleotide substitution rates (the ω ratio) revealed that only the PXR LBD had a sub-population of codons with an estimated ω ratio greater than 1. CAR was also unusual in showing high relative ω ratios in both the DBD and LBD, a finding that may relate to the recent appearance of the CAR gene (presumably by duplication of a pre-mammalian PXR gene) just prior to the evolution of mammals. Functional analyses of the NR1I subfamily show that human and zebrafish PXRs show similar activation by steroid hormones and early bile salts, properties not shared by sea lamprey, mouse, or human VDRs, or by Xenopus laevis PXRs. CONCLUSION: NR genes generally show strong sequence conservation and little evidence for positive selection. The main exceptions are PXR and CAR, genes that may have adapted to cross-species differences in toxic compound exposure

Development of concave-convex imaging mirror system for a compact and achromatic full-field x-ray microscope

Jumpei Yamada, Satoshi Matsuyama, Shuhei Yasuda, Yasuhisa Sano, Yoshiki Kohmura, Makina Yabashi, Tetsuya Ishikawa, and Kazuto Yamauchi "Development of concave-convex imaging mirror system for a compact and achromatic full-field x-ray microscope", Proc. SPIE 10386, Advances in X-Ray/EUV Optics and Components XII, 103860C (6 September 2017); https://doi.org/10.1117/12.2272904

A Case of Immune-Related Aseptic Meningitis during Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma

Introduction: Immune checkpoint inhibitors are sometimes associated with immune-related adverse events during or after treatment. Among these, aseptic meningitis is a rare and serious complication. We report the first case of atezolizumab-induced aseptic meningitis, which occurred during treatment for advanced hepatocellular carcinoma (HCC). Case Presentation: A 74-year-old woman diagnosed with advanced HCC and treated with first-line atezolizumab plus bevacizumab developed anorexia, fatigue, and fever, after three treatment cycles. Cerebrospinal fluid examination showed slightly increased cell count and protein level but no infection or malignancy. Contrast enhancement along the cerebral sulcus was evident in contrast-enhanced magnetic resonance imaging, and the patient was diagnosed with aseptic meningitis associated with atezolizumab. Steroid therapy soon improved her clinical symptoms, and the contrast enhancement along the cerebral sulcus disappeared. Conclusion: Clinicians should monitor to avoid serious immune-related adverse events, such as aseptic meningitis, in patients during treatment of HCC with immune checkpoint inhibitors and make the diagnosis as soon as possible

An Autopsy Case of Ruptured Hepatic Angiosarcoma Treated by Transcatheter Arterial Embolization

An 80-year-old Japanese man presented to our hospital with intra-abdominal hemorrhage due to a ruptured liver tumor. Transcatheter arterial embolization (TAE) temporarily achieved hemostasis, but he died following re-rupture 4 days later. Based on autopsy findings, the liver tumor was diagnosed as hepatic angiosarcoma. Embolic agents used during embolization were identified within the hepatic small interlobular arteries. However, there were no findings of tumor cell necrosis or ischemic change in the angiosarcoma. In the present case, TAE alone did not induce ischemia-induced tumor necrosis, suggesting that TAE might be unsuitable to treat hepatic angiosarcoma. Treatment optimization for ruptured hepatic angiosarcoma is desired

6′,7′‐Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P‐glycoprotein

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109869/1/cptclpt1999363.pd

Development of precision Wolter mirrors for solar x-ray observations

Taro Sakao, Satoshi Matsuyama, Takumi Goto, Jumpei Yamada, Shuhei Yasuda, Kazuto Yamauchi, Yoshiki Kohmura, Ayumi Kime, Akira Miyake, Tadakazu Maezawa, Hirokazu Hashizume, Yoshinori Suematsu, Noriyuki Narukage, and Shin-nosuke Ishikawa "Development of precision Wolter mirrors for solar x-ray observations", Proc. SPIE 10386, Advances in X-Ray/EUV Optics and Components XII, 103860E (23 August 2017); https://doi.org/10.1117/12.2273507

Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders

The Japanese Clinical Practice Guideline for acute kidney injury 2016

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

Background and purposeThe Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine.MethodsMembers of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members.ResultsA total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs.ConclusionsBased on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals