統合失調症初回エピソードにおけるマイクロRNAの関与

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 辻 省次, 東京大学准教授 後藤 順, 東京大学教授 水口 雅, 東京大学教授 狩野 方伸, 東京大学准教授 垣内 千尋University of Tokyo(東京大学

Protective effects of Naringin in a rat model of spinal cord ischemia–reperfusion injury

Purpose: To evaluate the activity of naringin (NAR) in a rat model of spinal cord ischemic injury (SCII).Methods: Forty female rats were randomized into four groups: saline without  occlusion (control; group I), SCII (group II), 50 mg/kg NAR (group III), or 100 mg/kg NAR (group IV) for 7 days prior to SCI insult (pre-treatment). Neurological and locomotor functions, antioxidant activity, edema and inflammatory markers were determined.Results: Pre-treatment with NAR considerably lowered the incidence of spinal edema, lipid peroxidation products, and inflammatory markers (TNF-α, NF-p65, IL-1β, and IL-6). It also successfully reverted the antioxidative activity to near-normal levels and improved locomotor function by protecting spinal tissue from oxidative damage and inflammatory insults. NAR administration effectively downregulated the protein expression of TNF-α and NF-κB p65 subunit in spinal tissue, thus confirming its antiinflammatory activity.Conclusion: The results suggests that NAR exhibits neuroprotective effects by inhibiting free radical generation and downregulating inflammatory markers in an SCI rat model.Keywords: Naringin, Spinal cord injury, Locomotor function, Edema, Oxidative  stress, Inflammatio

Hardware Acceleration of Number Theoretic Transform in zk-SNARK

The proof in zk-SNARK has a fixed length and can be verified quickly, promoting the application of zero-knowledge proof in areas such as digital signature, blockchain, distributed storage, and outsourced computing. However, the generation of proofs is time-consuming and frequently used. As a result, NTT (number theoretic transform), one of the most time-consuming parts in proof-generation, needs to be accelerated significantly. However, the existing general NTT hardware acceleration methods cannot meet the requirements of large-bitwidth and large-scale in zk-SNARK. To address this issue, this paper proposes a highly pipelined architecture for NTT. First of all, large-bitwidth modular arithmetic is optimized and low-latency Montgomery modular multiplication hardware unit is designed. And then, the large-scale NTT tasks are divided into smaller sub-tasks through two-dimensional partitioning, which improves the parallelism of NTT computation and eliminates the data dependence among sub-tasks, thus reali-zing the pipeline among sub-tasks. Finally, the “data reordering” technique is introduced among multiple rounds of butterfly operations in a sub-task, which effectively alleviates the memory access requirements, thus realizing the bottom-level pipeline in each sub-task, among butterfly operations with different step sizes. This architecture can be flexibly scaled to different scales of FPGAs. The accelerator is prototyped on the AMD-Xilinx Alveo U50 card (UltraScale+XCU50 FPGA). To balance computing efficiency and flexibility, the OpenCL equipped with high-level synthesis (HLS) is used to implement the system. The evaluation results show that the NTT module performs 1.95 times faster than the one in PipeZK and the accelerator achieves 27.98 and 1.74 times speedup, 6.9 and 6 times energy efficiency improvement than AMD Ryzen 9 5900X respectively, when it is integrated into the well-known ZKP open-source project, bellman

CAEV Vif Hijacks ElonginB/C, CYPA and Cullin5 to Assemble the E3 Ubiquitin Ligase Complex Stepwise to Degrade oaA3Z2-Z3

Caprine arthritis encephalitis virus (CAEV) is a lentivirus that causes multisystemic chronic disorders in sheep and goats. It encodes Vif to counteract the restriction of Ovis aries A3Z2-Z3 (oaA3Z2-Z3) by inducing their degradation. Nevertheless, the mechanisms underlying the interplay between CAEV Vif and OaA3Z2-Z3 have yet to be elucidated. Here, we identified the cellular factors ElonginB/C, CYPA and Cullin5 as being hijacked by CAEV Vif as well as several functional domains of CAEV Vif required for degrading oaA3Z2-Z3. Moreover, we determined that CAEV Vif assembled E3 ubiquitin ligase stepwise via its SLE motif (170SLE172) to recruit ElonginB/C, the P21 site and the zinc finger motif (C132-C134-C154-C157) to recruit CYPA, as well as the hydrophobic domain (141IR142) to recruit Cullin5. And this CAEV Vif-mediated E3 ligase triggers the proteasomal degradation of oaA3Z2-Z3, which directly bind CAEV Vif through residues Y39 and L44. In particular, CYPA played an essential role in the process to regulate ligase assembly, which was analogous to CBF-β, the essential regulator for HIV-1 and SIV-mediated E3 ligase, indicating that there is a modular conservation and lineage-specific preference for cellular partners required by Vifs from different subgroups of lentiviruses. Taken together, these findings provide important insights regarding the CAEV Vif function and deepen our understanding of the arms race between the lentiviruses and their hosts

Circulating Monocytes Act as a Common Trigger for the Calcification Paradox of Osteoporosis and Carotid Atherosclerosis via TGFB1-SP1 and TNFSF10-NFKB1 Axis

BackgroundOsteoporosis often occurs with carotid atherosclerosis and causes contradictory calcification across tissue in the same patient, which is called the “calcification paradox”. Circulating monocytes may be responsible for this unbalanced ectopic calcification. Here, we aimed to show how CD14+ monocytes contribute to the pathophysiology of coexisting postmenopausal osteoporosis and carotid atherosclerosis.MethodsWe comprehensively analyzed osteoporosis data from the mRNA array dataset GSE56814 and the scRNA-seq dataset GSM4423510. Carotid atherosclerosis data were obtained from the GSE23746 mRNA dataset and GSM4705591 scRNA-seq dataset. First, osteoblast and vascular SMC lineages were annotated based on their functional expression using gene set enrichment analysis and AUCell scoring. Next, pseudotime analysis was applied to draw their differentiated trajectory and identify the key gene expression changes in crossroads. Then, ligand–receptor interactions between CD14+ monocytes and osteoblast and vascular smooth muscle cell (SMC) lineages were annotated with iTALK. Finally, we selected calcification paradox-related expression in circulating monocytes with LASSO analysis.ResultsFirst, we found a large proportion of delayed premature osteoblasts in osteoporosis and osteogenic SMCs in atherosclerosis. Second, CD14+ monocytes interacted with the intermediate cells of the premature osteoblast and osteogenic SMC lineage by delivering TGFB1 and TNFSF10. This interaction served as a trigger activating the transcription factors (TF) SP1 and NFKB1 to upregulate the inflammatory response and cell senescence and led to a retarded premature state in the osteoblast lineage and osteogenic transition in the SMC lineage. Then, 76.49% of common monocyte markers were upregulated in the circulating monocytes between the two diseases, which were related to chemotaxis and inflammatory responses. Finally, we identified 7 calcification paradox-related genes on circulating monocytes, which were upregulated in aging cells and downregulated in DNA repair cells, indicating that the aging monocytes contributed to the development of the two diseases.ConclusionsOur work provides a perspective for understanding the triggering roles of CD14+ monocytes in the development of the calcification paradox in osteoporosis- and atherosclerosis-related cells based on combined scRNA and mRNA data. This study provided us with an elucidation of the mechanisms underlying the calcification paradox and could help in developing preventive and therapeutic strategies

Improved reference genome of Aedes aegypti informs arbovirus vector control

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector