Evolutionary adaptation of visual pigments in geckos for their photic environment

家の守り神「ヤモリ」が夜でも色を見分けられるのはなぜ --ヤモリが持つ特殊な色覚能力の分子メカニズムを解明--. 京都大学プレスリリース. 2021-10-04.Vertebrates generally have a single type of rod for scotopic vision and multiple types of cones for photopic vision. Noteworthily, nocturnal geckos transmuted ancestral photoreceptor cells into rods containing not rhodopsin but cone pigments, and, subsequently, diurnal geckos retransmuted these rods into cones containing cone pigments. High sensitivity of scotopic vision is underlain by the rod’s low background noise, which originated from a much lower spontaneous activation rate of rhodopsin than of cone pigments. Here, we revealed that nocturnal gecko cone pigments decreased their spontaneous activation rates to mimic rhodopsin, whereas diurnal gecko cone pigments recovered high rates similar to those of typical cone pigments. We also identified amino acid residues responsible for the alterations of the spontaneous activation rates. Therefore, we concluded that the switch between diurnality and nocturnality in geckos required not only morphological transmutation of photoreceptors but also adjustment of the spontaneous activation rates of visual pigments

Mitochondrial Electron Transport Is the Cellular Target of the Oncology Drug Elesclomol

Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting

Synthesis of [11C]uric acid, using [11C]phosgene, as a possible biomarker in PET imaging for diagnosis of gout

The synthesis and in vivo evaluation of 11C -labeled uric acid ([11C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [11C]1 was achieved by reacting 5,6-diaminouracil (2) with 11C-labeled phosgene ([11C]COCl2). The radiochemical yield of [11C]1 was 37 ± 7% (decay-corrected based on [11C]COCl2) with specific radioactivities of 96-152 GBq/μmol at the end of synthesis (n = 6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30 min with >98% radiochemical purity. Second, the synthetic approach to [11C]1 was optimized using 5,6-diaminouracil sulfate (3) with [11C]COCl2 in the presence of 1,8-bis(dimethylamino)naphthalene. [11C]1 was synthesized in 36 ± 6% radiochemical yield, 89-142 GBq/μmol of specific radioactivities, and 98% radiochemical purity by this method (n = 5). This allowed the synthesis of [11C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [11C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [11C]1 has been developed, and preliminary PET evaluation of [11C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia. © 2011 Elsevier Ltd. All rights reserved

Pinopsin evolved as the ancestral dim-light visual opsin in vertebrates

脊椎動物の視覚進化モデルを修正 --暗所視と色覚はどっちが先か--. 京都大学プレスリリース. 2018-10-02.Pinopsin is the opsin most closely related to vertebrate visual pigments on the phylogenetic tree. This opsin has been discovered among many vertebrates, except mammals and teleosts, and was thought to exclusively function in their brain for extraocular photoreception. Here, we show the possibility that pinopsin also contributes to scotopic vision in some vertebrate species. Pinopsin is distributed in the retina of non-teleost fishes and frogs, especially in their rod photoreceptor cells, in addition to their brain. Moreover, the retinal chromophore of pinopsin exhibits a thermal isomerization rate considerably lower than those of cone visual pigments, but comparable to that of rhodopsin. Therefore, pinopsin can function as a rhodopsin-like visual pigment in the retinas of these lower vertebrates. Since pinopsin diversified before the branching of rhodopsin on the phylogenetic tree, two-step adaptation to scotopic vision would have occurred through the independent acquisition of pinopsin and rhodopsin by the vertebrate lineage

Different Characteristics of Cognitive Impairment in Elderly Schizophrenia and Alzheimer's Disease in the Mild Cognitive Impairment Stage

We compared indices of the revised version of the Wechsler Memory Scale (WMS-R) and scaled scores of the five subtests of the revised version of the Wechsler Adult Intelligence Scale (WAIS-R) in 30 elderly schizophrenia (ES) patients and 25 Alzheimer's disease (AD) patients in the amnestic mild cognitive impairment (aMCI) stage (AD-aMCI). In the WMS-R, attention/concentration was rated lower and delayed recall was rated higher in ES than in AD-aMCI, although general memory was comparable in the two groups. In WAIS-R, digit symbol substitution, similarity, picture completion, and block design scores were significantly lower in ES than in AD-aMCI, but the information scores were comparable between the two groups. Delayed recall and forgetfulness were less impaired, and attention, working memory and executive function were more impaired in ES than in AD-aMCI. These results should help clinicians to distinguish ES combined with AD-aMCI from ES alone

Sense of coherence as a predictor of onset of depression among Japanese workers: a cohort study

<p>Abstract</p> <p>Background</p> <p>The ability to predict future onset of depression is required for primary prevention of depression. Many cross-sectional studies have reported a correlation between sense of coherence (SOC) and the presence of depressive symptoms. However, it is unclear whether SOC can predict future onset of depression. Therefore, whether measures to prevent onset of depression are needed in for persons with low SOC is uncertain. Thus, the aim of this cohort study was to determine whether SOC could predict onset of depression and to assess the need for measures to prevent onset of depression for persons with low SOC.</p> <p>Methods</p> <p>A total of 1854 Japanese workers aged 20-70 years in 2005 who completed a sense of coherence (SOC) questionnaire were followed-up until August 2007 using their sick-pay records with medical certificates. Depression was defined as a description of "depression" or "depressive" as a reason for sick leave on the medical certificates. The day of incidence of depression was defined as the first day of the sick leave. Risk ratios of SOC for onset of depression were calculated using a multivariate Cox proportional hazards model.</p> <p>Results</p> <p>Of the 1854 participants, 14 developed depression during a mean of 1.8 years of follow-up. After adjustment for gender and age, the risk ratio of high SOC compared with low SOC for sick leave from depression was 0.18 (95% confidence interval [CI], 0.04 to 0.79). The area under the receiver operating characteristic curve of SOC was 0.70 (95% CI, 0.58 to 0.82).</p> <p>Conclusions</p> <p>The SOC may be able to predict onset of depression in Japanese workers. Measures to prevent onset of depression for persons with low SOC might be required in Japanese workplaces. Thus, SOC could be useful for identifying persons at high risk for future depression.</p

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces TH17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of TH1 and TH17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c+ dendritic cells and CD3+ T cells was seen, with a greater decrease in the CD11c+ population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of TH1- and TH17-mediated inflammatory diseases