Roles of Selenoprotein M (SELENOM) in Hypothalamic Leptin Signaling and Calcium Regulation.

Ph.D. Thesis. University of Hawaiʻi at Mānoa 2018

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis.

Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available.ImportanceTo fully comprehend the diverse functions of a protein, it is essential to understand the functionality of individual residues. Current methods are highly dependent on evolutionary sequence conservation, which is usually limited by sampling size. Sequence conservation-based methods are further confounded by structural constraints and multifunctionality of proteins. Here we present a method that can systematically identify and annotate functional residues of a given protein. We used a high-throughput functional profiling platform to identify essential residues. Coupling it with homologous-structure comparison, we were able to annotate multiple functions of proteins. We demonstrated the method with the PB1 protein of influenza A virus and identified novel functional residues in addition to its canonical function as an RNA-dependent RNA polymerase. Not limited to virology, this method is generally applicable to other proteins that can be functionally selected and about which homologous-structure information is available

桓武天皇の皇統意識

本稿では、桓武天皇即位前後の政治動向、及び即位後に行われた長岡遷都・郊祀などを手かがりにして桓武天皇の皇統意識を再検討する。神護景雲四（七七〇）年八月、称徳天皇の遺宣によって天智の孫である光仁（白壁王）が即位し、皇位継承の嫡流となった。奈良時代後半における皇位継承の闘争によって多くの有力後継者は皇位継承の序列から排除され、生き残ったのは高齢の天武傍系の皇族及び天智系の二世王のみである。光仁が選ばれた理由は、聖武の血を引く井上内親王との間に生まれた他戸親王の皇位継承によって、聖武系の血統を継続させる可能性が見込まれたからである。また、志貴皇子（光仁の父）は「吉野の盟約」のメンバーである重要性も他の研究で明らかになった。しかし光仁が即位して間もなく井上・他戸母子が廃され、三十五歳の桓武（山部）は皇太子となった。桓武は光仁の長男であり、称徳朝では一般官僚として出世した。桓武の即位にとって、母方の渡来系血統は大きなマイナス要素であり、後の桓武朝の政治を揺るがす要因の一つでもある。桓武の即位後、天皇としての正統性を主張するため、中国の「辛酉革命・甲子革令」に基づいて年号を「天応」に改元した。この間、新京長岡に遷都し、延暦四年に中国風の郊祀を倣った天神祭祀を行い、皇位継承の正統性を強化した。一方、桓武の即位に不満を抱く人々が謀反や魘魅などのクーデターを起こし、有力な皇族を含めて多数の人が刑罰を受け、さらに種継の暗殺事件によって、桓武の同母弟である早良親王や甥の五百枝王も皇統継承の候補者から外れた。政治事件における一連の粛清の結果、桓武から息子の安殿親王への直系継承となる条件が揃った。光仁の改葬・延暦年間の山陵祭祀における天智・志貴・光仁への追慕や弟の早良親王の排除・安殿の立太子など、桓武は直系による皇統継承を強く意識したと見られる。延暦六年に行った郊祀は、光仁を配主としたことから、光仁―桓武―安殿（延暦六年元服）までの父方血統のみで構成する新たな皇位継承の秩序を完成したと見られる。This paper discusses the imperial consciousness of the Emperor Kanmu from prior to and immediately after accession to the throne to transfer of the capital to Heian-kyo in 794.In 770, Prince Shirakabe, the grandchild of Emperor Tenchi, was enthroned as Emperor Konin after Emperor Shotoku died. Although the imperial line had succeeded from Emperor Tenmu, there had been a string of power struggles, and Prince Shirakabe, a descendent of Emperor Tenchi, became Emperor Konin following the order of succession. After enthronement, Emperor Konin named Imperial Princess Inoe Empress and Imperial Prince Osabe Crown Prince. Due to the humble background of Emperor Kanmu’s mother as a naturalized clansman, there was no hope for the Emperor to become crown prince even after his father, Prince Shirakabe, was enthroned, but he aimed to succeed as a government bureaucrat. However, he charged Imperial Princess Inoe with high treason for cursing and removed the Empress and Crown Prince Osabe.The Emperor Kanmu’s accession to the throne was a great epoch in history. With the transfer of the capital, the Nara period completely ended and the Heian period commenced. He was enthroned in Heijyo-kyo and the capital was moved to Nagaoka-kyo in A.D. 784. It is thought that the transfer of the national capital to Nagaoka-kyo was conducted to eliminate outdated thinking and concepts and to enhance the authority of the emperor. The Heian period attached great importance to the Providence Theory; Kanototori is one of the zodiac signs in Chinese astrology and is said to be the year of revolution. It is believed that Emperor Kanmu strongly admired China; he imitated Tang emperors and performed Koshi two times.Some people, however, were dissatisfied with Kanmu’s policies and launched a coup d’état. Many of the royal family members were subjected to criminal punishment. After transferring the capital to Nagaoka-kyo, Fujiwara no Tanetsugu was assassinated. After this incident, the Imperial Prince Sawara and Ioe were completely removed from the line of succession of the Imperial Throne. The succession to the Imperial Throne shall devolved on a direct line to Imperial Prince Aden. After the death of Emperor Kanmu, the princes ascended to the throne in order; the reforms by Emperor Heizei, the next emperor after Kanmu, were no less positive than the reforms by Kanmu. A new order of succession to the throne composed only of paternal bloodline was completed

Toward Multi-Level Governance in China? Coping with complex public affairs across jurisdictions and organizations

This special issue argues for the applicability of the conceptual framework of Multi-Level Governance to the political–administrative regime of China, provided significant adaptations and qualifications are developed. The application of Multi-Level Governance to China enables to account for global influences as well as for the involvement of non-governmental actors in public policy making. More radically, we suggest in this introductory article that the development of Multi-Level Governance may be interpreted as a way of enhancing the societal legitimacy of the political regime under the conditions of new authoritarianism. We conclude this article by drawing a fascinating yet possibly hazardous and overstretched parallel; that is, the development of Multi-Level Governance may be part and parcel of a process of building political legitimacy in China, just as it may be a way of exploring paths for the renewal of beleaguered traditional liberal democracy in Europe. Albeit along profoundly different trajectories, China and Europe might adopt Multi-Level Governance arrangements for a very purposive course of action: enhancing the legitimacy of the respective and very diverse political systems and buttressing their very foundations. This suggests a strongly normative and purposive application of Multi-Level Governance

An Electrostatically Preferred Lateral Orientation of SNARE Complex Suggests Novel Mechanisms for Driving Membrane Fusion

Biological membrane fusion is a basic cellular process catalyzed by SNARE proteins and additional auxiliary factors. Yet, the critical mechanistic details of SNARE-catalyzed membrane fusion are poorly understood, especially during rapid synaptic transmission. Here, we systematically assessed the electrostatic forces between SNARE complex, auxiliary proteins and fusing membranes by the nonlinear Poisson-Boltzmann equation using explicit models of membranes and proteins. We found that a previously unrecognized, structurally preferred and energetically highly favorable lateral orientation exists for the SNARE complex between fusing membranes. This preferred orientation immediately suggests a novel and simple synaptotagmin-dependent mechanistic trigger of membrane fusion. Moreover, electrostatic interactions between membranes, SNARE complex, and auxiliary proteins appear to orchestrate a series of membrane curvature events that set the stage for rapid synaptic vesicle fusion. Together, our electrostatic analyses of SNAREs and their regulatory factors suggest unexpected and potentially novel mechanisms for eukaryotic membrane fusion proteins

Towards A Unified Neural Architecture for Visual Recognition and Reasoning

Recognition and reasoning are two pillars of visual understanding. However, these tasks have an imbalance in focus; whereas recent advances in neural networks have shown strong empirical performance in visual recognition, there has been comparably much less success in solving visual reasoning. Intuitively, unifying these two tasks under a singular framework is desirable, as they are mutually dependent and beneficial. Motivated by the recent success of multi-task transformers for visual recognition and language understanding, we propose a unified neural architecture for visual recognition and reasoning with a generic interface (e.g., tokens) for both. Our framework enables the principled investigation of how different visual recognition tasks, datasets, and inductive biases can help enable spatiotemporal reasoning capabilities. Noticeably, we find that object detection, which requires spatial localization of individual objects, is the most beneficial recognition task for reasoning. We further demonstrate via probing that implicit object-centric representations emerge automatically inside our framework. Intriguingly, we discover that certain architectural choices such as the backbone model of the visual encoder have a significant impact on visual reasoning, but little on object detection. Given the results of our experiments, we believe that visual reasoning should be considered as a first-class citizen alongside visual recognition, as they are strongly correlated but benefit from potentially different design choices

Studies on Metadiscourse since the 3rd Millennium

Metadiscourse refer to linguistic resources that are used to refer to the act and the context of writing about some subject matter. Study of metadiscourse provides a gateway for understanding interactional features of texts or speech, looking beyond the ideational dimension of texts at how writers characterize the world and function interpersonally. The ability of writers to use metadiscourse effectively, to control the level of personality in their texts by offering a credible representation of themselves and their ideas, is seen as a defining feature of successful writing (Hyland, 2008). This paper provides a literature review of the theories in modelling metadiscourse and the studies investigating metadiscourse for the past 15 years, and propose future research directions based on the review. Keywords: Metadiscourse, interactional features, literature revie

Automaticity in processing spatial-numerical associations: Evidence from a perceptual orientation judgment task of Arabic digits in frames.

Human adults are faster to respond to small/large numerals with their left/right hand when they judge the parity of numerals, which is known as the SNARC (spatial-numerical association of response codes) effect. It has been proposed that the size of the SNARC effect depends on response latencies. The current study introduced a perceptual orientation task, where participants were asked to judge the orientation of a digit or a frame surrounding the digit. The present study first confirmed the SNARC effect with native Chinese speakers (Experiment 1) using a parity task, and then examined whether the emergence and size of the SNARC effect depended on the response latencies (Experiments 2, 3, and 4) using a perceptual orientation judgment task. Our results suggested that (a) the automatic processing of response-related numerical-spatial information occurred with Chinese-speaking participants in the parity task; (b) the SNARC effect was also found when the task did not require semantic access; and (c) the size of the effect depended on the processing speed of the task-relevant dimension. Finally, we proposed an underlying mechanism to explain the SNARC effect in the perceptual orientation judgment task