細胞挙動を調節するための細胞適合性リン脂質ポリマーハイドロゲル多層膜

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 石原 一彦, 東京大学教授 吉田 亮, 東京大学准教授 坂田 利弥, 東京大学特任准教授 金野 智浩, 東京大学客員教授(東京医科歯科大学) 塙 隆夫University of Tokyo(東京大学

The Research on Operation of Obstructed Total Anomalous Pulmonary Venous Connection in Neonates

Objectives. Total anomalous pulmonary venous connection (TAPVC) is a rare congenital heart disease. This study aimed to evaluate the outcomes of TAPVC repair in neonates, controlling for anatomic subtypes and surgical techniques. Methods. Between 1997 and 2013, 88 patients (median age: 16 days) underwent repair for supracardiac (31), cardiac (18), infracardiac (36), or mixed (3) TAPVC. All the patients underwent emergency operation due to obstructed drainage. Supracardiac and infracardiac TAPVC repair included a side-to-side anastomosis between the pulmonary venous confluence and left atrium. Coronary sinus unroofing was preferred for cardiac TAPVC repair. Results. The early mortality rate was 2.3% (2/88 patients). The echocardiogram showed no obstruction in the pulmonary vein anastomosis, and flow rate was 1.1–1.42 m/s in the 3-year follow-up period. Conclusions. The accurate preoperative diagnosis, improved protection of heart function, use of pulmonary vein tissue to anastomose and avoid damage of the pulmonary vein, and delayed sternum closure can reduce the risk of mortality. The preoperative severity of pulmonary vein obstruction, the timing of the emergency operation, and infracardiac or mixed-type TAPVC can affect prognosis. Using our surgical technique, the TAPVC mortality among our patients was gradually reduced with remarkable results. However, careful monitoring of the patient with pulmonary vein restenosis and the timing and method of reoperation should also be given importance

Contributors to linkage between Arctic warming and East Asian winter climate

Previous modelling and observational studies have shown discrepancies in the interannual relationship of winter surface air temperature (SAT) between Arctic and East Asia, stimulating the debate about whether Arctic change can influence midlatitude climate. This study uses two sets of coordinated experiments (EXP1 and EXP2) from six different atmospheric general circulation models. Both EXP1 and EXP2 consist of 130 ensemble members, each of which in EXP1 (EXP2) was forced by the same observed daily varying sea ice and daily varying (daily climatological) sea surface temperature (SST) for 1982–2014 but with different atmospheric initial conditions. Large spread exists among ensemble members in simulating the Arctic–East Asian SAT relationship. Only a fraction of ensemble members can reproduce the observed deep Arctic warming–cold continent pattern which extends from surface to upper troposphere, implying the important role of atmospheric internal variability. The mechanisms of deep Arctic warming and shallow Arctic warming are further distinguished. Arctic warming aloft is caused primarily by poleward moisture transport, which in conjunction with the surface warming coupled with sea ice melting constitutes the surface-amplified deep Arctic warming throughout the troposphere. These processes associated with the deep Arctic warming may be related to the forcing of remote SST when there is favorable atmospheric circulation such as Rossby wave train propagating from the North Atlantic into the Arctic.publishedVersio

Generation of Kerr soliton microcomb in a normally dispersed lithium niobate microdisk resonator by mode trimming

Anomalous microresonator dispersion is mandatory for Kerr soliton microcomb formation, which depends critically on the geometry of the microresonator and can hardly be tuned after the structure is made. To date, cavity-based microcombs have only been generated with fundamental whispering gallery modes (WGMs) of anomalous dispersion in microresonators. Moreover, microcomb generation in highly Raman-active platforms such as lithium niobate (LN) microresonators frequently suffers from stimulated Raman scattering and mode crossing due to the existence of multiple families of high-order WGMs. Here, we reveal a unique Kerr soliton microcomb generation mechanism through mode trimming in a weakly perturbed LN microdisk resonator. Remarkably, the soliton comb is generated with fundamental WGMs of normal dispersion and free from the mode crossing and Raman scattering effects. A robust soliton with a spectrum spanning from 1450 nm to 1620 nm at an on-chip pump power of 35 mW. Our discovery offers a powerful solution to circumvent the stringent requirements on high-precision dispersion engineering and termination of Raman excitation for soliton generation in the high-Q microdisk.Comment: 16 pages,and 5 figure

Electro-optically tunable low phase-noise microwave synthesizer in an active lithium niobate microdisk

Photonic-based low-phase-noise microwave generation with real-time frequency tuning is crucial for a broad spectrum of subjects, including next-generation wireless communications, radar, metrology, and modern instrumentation. Here, for the first time to the best of our knowledge, narrow-bandwidth dual-wavelength microlasers are generated from nearly degenerate polygon modes in a high-Q active lithium niobate microdisk. The high-Q polygon modes formation with independently controllable resonant wavelengths and free spectral ranges is enabled by the weak perturbation of the whispering gallery microdisk resonators using a tapered fiber. The stable beating signal confirms the low phase-noise achieved in the tunable laser. Owing to the high spatial overlap factors between the two nearly degenerate lasing modes as well as that between the two lasing modes and the pump mode, gain competition between the two modes is suppressed, leading to stable dual-wavelength laser generation and in turn the low noise microwave source. The measured microwave signal shows a linewidth of ~6.87 kHz, a phase noise of ~-123 dBc/Hz, and an electro-optic tuning efficiency of -1.66 MHz/V.Comment: 13 pages, 5 figure

Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress

Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems

Long-term whole blood DNA preservation by cost-efficient cryosilicification

This work was supported by the National Natural Science Foundation of China (21972047 to W.Z., 52003086 to Q.L.), Guangdong Provincial Pearl River Talents Program (2019QN01Y314 to Q.L.), the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2019ZT08Y318 to W.Z.), Natural Science Foundation of Guangdong Province, China (2021A1515010724 to Q.L.), China Postdoctoral Science Foundation (2020M672625, 2021T140213 to Q.L.), Science and Technology Project of Guangzhou, China (202102020352 to W.Z., 202102020259 to Q.L.), the Fundamental Research Funds for the Central Universities of China. The authors thank the support from the Guangzhou Women and Children’s Medical Center and Laboratory Animal Research Center of the South China University of Technology. S.W. acknowledges funding from the Basque Government Industry Department under the ELKARTEK and HAZITEK programs.Deoxyribonucleic acid (DNA) is the blueprint of life, and cost-effective methods for its long-term storage could have many potential benefits to society. Here we present the method of in situ cryosilicification of whole blood cells, which allows long-term preservation of DNA. Importantly, our straightforward approach is inexpensive, reliable, and yields cryosilicified samples that fulfill the essential criteria for safe, long-term DNA preservation, namely robustness against external stressors, such as radical oxygen species or ultraviolet radiation, and long-term stability in humid conditions at elevated temperatures. Our approach could enable the room temperature storage of genomic information in book-size format for more than one thousand years (thermally equivalent), costing only 0.5 $/person. Additionally, our demonstration of 3D-printed DNA banking artefacts, could potentially allow 'artificial fossilization'.Publisher PDFPeer reviewe

Deciphering the contributions of cuproptosis in the development of hypertrophic scar using single-cell analysis and machine learning techniques

Hypertrophic scar (HS) is a chronic inflammatory skin disease characterized by excessive deposition of extracellular matrix, but the exact mechanisms related to its formation remain unclear, making it difficult to treat. This study aimed to investigate the potential role of cuproptosis in the information of HS. To this end, we used single-cell sequencing and bulk transcriptome data, and screened for cuproptosis-related genes (CRGs) using differential gene analysis and machine learning algorithms (random forest and support vector machine). Through this process, we identified a group of genes, including ATP7A, ULK1, and MTF1, as novel therapeutic targets for HS. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to confirm the mRNA expression of ATP7A, ULK1, and MTF1 in both HS and normal skin (NS) tissues. We also constructed a diagnostic model for HS and analyzed the immune infiltration characteristics. Additionally, we used the expression profiles of CRGs to perform subgroup analysis of HS. We focused mainly on fibroblasts in the transcriptional profile at single-cell resolution. By calculating the cuproptosis activity of each fibroblast, we found that cuproptosis activity of normal skin fibroblasts increased, providing further insights into the pathogenesis of HS. We also analyzed the cell communication network and transcription factor regulatory network activity, and found the existence of a fibroblast-centered communication regulation network in HS, where cuproptosis activity in fibroblasts affects intercellular communication. Using transcription factor regulatory activity network analysis, we obtained highly active transcription factors, and correlation analysis with CRGs suggested that CRGs may serve as potential target genes for transcription factors. Overall, our study provides new insights into the pathophysiological mechanisms of HS, which may inspire new ideas for the diagnosis and treatment

Revealing the roles of glycosphingolipid metabolism pathway in the development of keloid: a conjoint analysis of single-cell and machine learning

Keloid is a pathological scar formed by abnormal wound healing, characterized by the persistence of local inflammation and excessive collagen deposition, where the intensity of inflammation is positively correlated with the size of the scar formation. The pathophysiological mechanisms underlying keloid formation are unclear, and keloid remains a therapeutic challenge in clinical practice. This study is the first to investigate the role of glycosphingolipid (GSL) metabolism pathway in the development of keloid. Single cell sequencing and microarray data were applied to systematically analyze and screen the glycosphingolipid metabolism related genes using differential gene analysis and machine learning algorithms (random forest and support vector machine), and a set of genes, including ARSA,GBA2,SUMF2,GLTP,GALC and HEXB, were finally identified, for which keloid diagnostic model was constructed and immune infiltration profiles were analyzed, demonstrating that this set of genes could serve as a new therapeutic target for keloid. Further unsupervised clustering was performed by using expression profiles of glycosphingolipid metabolism genes to discover keloid subgroups, immune cells, inflammatory factor differences and the main pathways of enrichment between different subgroups were calculated. The single-cell resolution transcriptome landscape concentrated on fibroblasts. By calculating the activity of the GSL metabolism pathway for each fibroblast, we investigated the activity changes of GSL metabolism pathway in fibroblasts using pseudotime trajectory analysis and found that the increased activity of the GSL metabolism pathway was associated with fibroblast differentiation. Subsequent analysis of the cellular communication network revealed the existence of a fibroblast-centered communication regulatory network in keloids and that the activity of the GSL metabolism pathway in fibroblasts has an impact on cellular communication. This contributes to the further understanding of the pathogenesis of keloids. Overall, we provide new insights into the pathophysiological mechanisms of keloids, and our results may provide new ideas for the diagnosis and treatment of keloids