Generating Individual Trajectories Using GPT-2 Trained from Scratch on Encoded Spatiotemporal Data

Following Mizuno, Fujimoto, and Ishikawa's research (Front. Phys. 2022), we transpose geographical coordinates expressed in latitude and longitude into distinctive location tokens that embody positions across varied spatial scales. We encapsulate an individual daily trajectory as a sequence of tokens by adding unique time interval tokens to the location tokens. Using the architecture of an autoregressive language model, GPT-2, this sequence of tokens is trained from scratch, allowing us to construct a deep learning model that sequentially generates an individual daily trajectory. Environmental factors such as meteorological conditions and individual attributes such as gender and age are symbolized by unique special tokens, and by training these tokens and trajectories on the GPT-2 architecture, we can generate trajectories that are influenced by both environmental factors and individual attributes

BH4代謝病患者iPS細胞を用いた異常なドパミン合成の遺伝学的および薬理学的修復

京都大学0048新制・論文博士博士(医学)乙第13111号論医博第2129号新制||医||1022(附属図書館)(主査)教授 齊藤 博英, 教授 松原 和夫, 教授 林 康紀学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

<Award Paper of 4th Congress of Asian Pacific Society of Mountain Medicine (APSMM)>Glucose Intolerance by Interaction between Hypoxia Adaptation and Lifestyle Change in Highlanders in Tibet Plateau

Socioeconomic factors and hypoxia play major roles in the prevalence of glucose intolerance in highlanders. Hypoxemia and polycythemia were closely associated with glucose intolerance after adjustment for the effects of lifestyle changes in our study. Tibetan people may be vulnerable to glucose intolerance, with polycythemia as a sign of poor hypoxic adaptation. Epigenetics is also play a role in its vulnerability with quick lifestyle change. Prevention of lifestyle-related diseases and health education should be advocated, especially in high altitude dwellers with rapidly prevailing socioeconomic globalization

PPAR /RXR -Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice

peer reviewedAlzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD

Establishment of DYT5 patient-specific induced pluripotent stem cells with a GCH1 mutation

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 20-year-old dystonia patient with a GCH1 mutation (DYT5). Episomal vectors were used to introduce reprogramming factors (OCT3/4, SOX2, KLF4, L-MYC, LIN28, and p53 carboxy-terminal dominant-negative fragment) to the PBMCs. The generated iPSCs expressed pluripotency markers, and were capable of differentiating into derivates of all three germ layers in vitro. The iPSC line also showed a normal karyotype and preserved the GCH1 mutation. This cellular model can provide opportunities to perform pathophysiological studies for aberrant dopamine metabolism-related disorders

Genetic and pharmacological correction of aberrant dopamine synthesis using patient iPSCs with BH4 metabolism disorders.

患者由来iPS細胞とゲノム編集技術を用いて, BH4代謝病のドパミン合成異常の疾患モデル系構築に成功 : iPS細胞利用による代謝改善生理活性物質の同定と疾患再定義. 京都大学プレスリリース. 2016-10-28.Dopamine (DA) is a neurotransmitter in the brain, playing a central role in several disease conditions, including tetrahydrobiopterin (BH4) metabolism disorders and Parkinson's disease (PD). BH4 metabolism disorders present a variety of clinical manifestations including motor disturbance via altered DA metabolism, since BH4 is a cofactor for tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthesis. Genetically, BH4 metabolism disorders are, in an autosomal recessive pattern, caused by a variant in genes encoding enzymes for BH4 synthesis or recycling, including 6-pyruvoyltetrahydropterin synthase (PTPS) or dihydropteridine reductase (DHPR), respectively. Although BH4 metabolism disorders and its metabolisms have been studied, it is unclear how gene variants cause aberrant DA synthesis in patient neurons. Here, we generated induced pluripotent stem cells (iPSCs) from BH4 metabolism disorder patients with PTPS or DHPR variants, corrected the gene variant in the iPSCs using the CRISPR/Cas9 system, and differentiated the BH4 metabolism disorder patient- and isogenic control iPSCs into midbrain DA neurons. We found that by the gene correction, the BH4 amount, TH protein level and extracellular DA level were restored in DA neuronal culture using PTPS deficiency iPSCs. Furthermore, the pharmacological correction by BH4 precursor sepiapterin treatment also improved the phenotypes of PTPS deficiency. These results suggest that patient iPSCs with BH4 metabolism disorders provide an opportunity for screening substances for treating aberrant DA synthesis-related disorders