ソニックスプレーイオン化法を用いた液体分離手段と質量分析の結合

取得学位：博士(理学)，学位授与番号：博乙第178号，学位授与年月日：平成11年3月25日,学位授与年：199

Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells

ACE発現ヒトiPS細胞を用いたSARS-CoV-2感染の個人差再現と原因究明. 京都大学プレスリリース. 2021-04-19.Stem cells show gender differences in COVID-19 risk. 京都大学プレスリリース. 2021-04-19.Genetic differences are a primary reason for differences in the susceptibility and severity of COVID-19. As induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in SARS-CoV-2 infection in vitro. We found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected w SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, budding of viral particles, and production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We performed SARS-CoV-2 infection experiments on ACE2-iPS/ embryonic stem (ES) cells from eight individuals. Male iPS/ES cells were more capable of producing the virus compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infection in vitro but also are a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences

Predicting the Start of the Aedes albopictus (Diptera: Culicidae) Female Adult Biting Season Using the Spring Temperature in Japan

Aedes albopictus (Skuse) (Diptera: Culicidae) is distributed widely and is common in much of Japan. In Japan, female adults begin to bite in between April and June, except in the southern subtropics where the mosquito has no dormant period. It is difficult to estimate the first Ae. albopictus biting day because it varies annually depending on the location. Over several years, we surveyed the mosquitoes at different locations that covered a range of warmer to cooler areas of Japan. We found an association between the timing of first biting day by Ae. albopictus and spring temperature. In spring months, the strongest correlation was found with mean April temperatures, followed by March. Based on these data, it may, therefore, be possible to apply a simple formula to predict the timing of the first biting day at various geographical locations in Japan. Forecasting maps were created using a simple prediction formula. We found that the first biting day for Ae. albopictus changed depending on early spring temperatures for each year. There was an approximate 20-d difference in first biting day between years with warmer and cooler springs. This prediction model will provide useful insight for planning and practice of Ae. albopictus control programs, targeting larvae and adults, in temperate regions globally.ArticleJournal of Medical Entomology.54(6):1519-1524(2017)journal articl

Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network

手と足の感覚は、実は脳の中でつながっていた --脳障害による活動変化の広がりを見ることで常識を覆す発見、脳機能・疾患機序の理解へ前進--. 京都大学プレスリリース. 2021-10-21.Concurrent genetic neuromodulation and functional magnetic resonance imaging (fMRI) in primates has provided a valuable opportunity to assess the modified brain-wide operation in the resting state. However, its application to link the network operation with behavior still remains challenging. Here, we combined chemogenetic silencing of the primary somatosensory cortex (SI) with tactile fMRI and related behaviors in macaques. Focal chemogenetic silencing of functionally identified SI hand region impaired grasping behavior. The same silencing also attenuated hand stimulation-evoked fMRI signal at both the local silencing site and the anatomically and/or functionally connected downstream grasping network, suggesting altered network operation underlying the induced behavioral impairment. Furthermore, the hand region silencing unexpectedly disinhibited foot representation with accompanying behavioral hypersensitization. These results demonstrate that focal chemogenetic silencing with sensory fMRI in macaques unveils bidirectional network changes to generate multifaceted behavioral impairments, thereby opening a pivotal window toward elucidating the causal network operation underpinning higher brain functions in primates

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

「何を買うんだっけ」と「どれにしよう」を処理する2つの脳回路を明らかに --霊長類の生体脳で神経経路を可視化・操作する技術で解明、高次脳機能の理解へ大きく前進--. 京都大学プレスリリース. 2021-06-24.The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates

Multiscale chemogenetic dissection of fronto-temporal top-down regulation for object memory in primates

見た物の記憶を保持する霊長類の脳ネットワークとメカニズムを解明 --認知症の記憶障害治療への応用に期待-- .京都大学プレスリリース. 2024-07-12.Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates

Regional flood dynamics in a bifurcating mega delta simulated in a global river model

In this paper we show the importance of bifurcation channels for flow in river mega deltas through the use of a new computational scheme implemented in the CaMa-Flood global hydrodynamic model. First, we developed a new river network map based on SRTM3 and HydroSHEDS which includes bifurcation channels. Next we implemented a new bifurcation scheme in CaMa-Flood capable of routing flow along this network and used the model to simulate the Mekong River. We show that in the Mekong delta such channels route about 50% of total flow, and that their representation is essential for realistic hydrodynamic simulations. A simulation without bifurcation channels was obviously unrealistic because no flow occurred between the mainstem and adjacent channels even when their water level difference was >6 m. The bifurcation channels are extracted from globally-available datasets, thus it is straightforward to expand the proposed scheme to global-scale studies

Chemogenetic attenuation of cortical seizures in nonhuman primates

「てんかん」の発生を時間的・空間的にピンポイントで抑える画期的な治療法を開発 --世界で初めてサルでの有効性を実証、臨床応用に向け大きく前進--. 京都大学プレスリリース. 2023-03-01.Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABAA receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model

GlacierMIP – A model intercomparison of global-scale glacier mass-balance models and projections

Global-scale 21st-century glacier mass change projections from six published global glacier models are systematically compared as part of the Glacier Model Intercomparison Project. In total 214 projections of annual glacier mass and area forced by 25 General Circulation Models (GCMs) and four Representative Concentration Pathways (RCP) emission scenarios and aggregated into 19 glacier regions are considered. Global mass loss of all glaciers (outside the Antarctic and Greenland ice sheets) by 2100 relative to 2015 averaged over all model runs varies from 18 ± 7% (RCP2.6) to 36 ± 11% (RCP8.5) corresponding to 94 ± 25 and 200 ± 44 mm sea-level equivalent (SLE), respectively. Regional relative mass changes by 2100 correlate linearly with relative area changes. For RCP8.5 three models project global rates of mass loss (multi-GCM means) of >3 mm SLE per year towards the end of the century. Projections vary considerably between regions, and also among the glacier models. Global glacier mass changes per degree global air temperature rise tend to increase with more pronounced warming indicating that mass-balance sensitivities to temperature change are not constant. Differences in glacier mass projections among the models are attributed to differences in model physics, calibration and downscaling procedures, initial ice volumes and varying ensembles of forcing GCMs