Existence of Oscillations in Cyclic Gene Regulatory Networks with Time Delay

This paper is concerned with conditions for the existence of oscillations in gene regulatory networks with negative cyclic feedback, where time delays in transcription, translation and translocation process are explicitly considered. The primary goal of this paper is to propose systematic analysis tools that are useful for a broad class of cyclic gene regulatory networks, and to provide novel biological insights. To this end, we adopt a simplified model that is suitable for capturing the essence of a large class of gene regulatory networks. It is first shown that local instability of the unique equilibrium state results in oscillations based on a Poincare-Bendixson type theorem. Then, a graphical existence condition, which is equivalent to the local instability of a unique equilibrium, is derived. Based on the graphical condition, the existence condition is analytically presented in terms of biochemical parameters. This allows us to find the dimensionless parameters that primarily affect the existence of oscillations, and to provide biological insights. The analytic conditions and biological insights are illustrated with two existing biochemical networks, Repressilator and the Hes7 gene regulatory networks

Roles of Trans and ω Fatty Acids in Health; Special References to Their Differences between Japanese and American Old Men

Omega and trans-fatty acids play important roles in atherogenesis of vascular system. In this review, we discuss such roles in health; there are much differences in coronary heart disease (CHD) rates between the US and Japan. Fatty acids profiles in the plasma are related to risks of CHD. There have been few studies that compared plasma levels of fatty acids, including trans-fatty acids, in people in Japan and the US. Plasma levels of long-chain omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) were higher in Japanese men, and omega-6 fatty acids (e.g., arachidonic acid [AA]) were lower compared with American men. American people had higher plasma levels of the major industrially produced trans-fatty acids (IP-TFAs; elaidic and inoelaidic acids), and levels of the potentially cardioprotective, primarily ruminant-derived trans-fatty acid, palmitoelaidic acid (POA) were higher in Japanese men. Plasma levels of saturated or monounsaturated fatty acids were also higher in American men. Only intakes of preference drinks have significant correlation with plasma levels of palmitoelaidic acid and linoelaidic acid. The higher levels of DHA and EPA, along with the lower levels of the IP-TFAs, are consistent with the markedly lower risk for coronary heart disease in Japan vs. the US

Intercellular exchange of Wnt ligands reduces cell population heterogeneity during embryogenesis

Wnt signaling is required to maintain bipotent progenitors for neural and paraxial mesoderm cells, the neuromesodermal progenitor (NMP) cells that reside in the epiblast and tailbud. Since epiblast/tailbud cells receive Wnt ligands produced by one another, this exchange may average out the heterogeneity of Wnt signaling levels among these cells. Here, we examined this possibility by replacing endogenous Wnt3a with a receptor-fused form that activates signaling in producing cells, but not in neighboring cells. Mutant mouse embryos show a unique phenotype in which maintenance of many NMP cells is impaired, although some cells persist for long periods. The epiblast cell population of these embryos increases heterogeneity in Wnt signaling levels as embryogenesis progresses and are sensitive to retinoic acid, an endogenous antagonist of NMP maintenance. Thus, mutual intercellular exchange of Wnt ligands in the epiblast cell population reduces heterogeneity and achieves robustness to environmental stress

Development of Youth Grassroot Employment Project in China and Employees\u27 Consciousness

本研究では、まず中国における若者を地方へ派遣する取り組みである地方就業プロジェクトの政策展開を整理し、国家政策としての位置付けや地方就業プロジェクトの全体像を明らかにした。次に、従事者に対して実施したアンケート調査から、①地方就業プロジェクト及び農村での就業に積極的な姿勢を示す若者の特徴、②任期終了後に地域での定住や起業、地域から出ても地域との関係保持意向を持つ従事者の特徴、③任期終了後の地域での定住や起業、地域との関係保持意向を促進させるための要点を考察した。その結果、政策展開を見ると、地方就業プロジェクトの国家政策としての重要性が高まっていること、各事業は互いに繋がりを持っており、人材を育成して、供給し合う仕組みが構築されていることなどが明らかとなった。従事者意識については、今後、より地方に若者を集めていくためには、農村に対するポジティブな印象や農業・農村に関する興味・関心の醸成が必要である。また、任期終了後の定住や起業、地域との関係保持を目指す上では、新卒者より一定程度の社会経験を有する人材をターゲットにすることが有効的であることが示唆された。さらに、従事者の地域との関係保持意向を促進するためには、生活及び労働環境の整備が重要であることも示唆された。樫原正澄先生退職記念

Different populations of Wnt-containing vesicles are individually released from polarized epithelial cells

Accumulating evidence suggests that exosomes are heterogeneous in molecular composition and physical properties. Here we examined whether epithelial cells secrete a heterogeneous population of exosomes, and if that is the case, whether epithelial cell polarity affects release of different populations of exosomes, especially that of those carrying Wnt. Sucrose-density ultracentrifugation and molecular marker analysis revealed that different populations of exosomes or exosome-like vesicles were released from MDCK cells depending on the cell polarity. Wnt3a associated with these vesicles were detectable in culture media collected from both apical and basolateral sides of the cells. Basolaterally secreted Wnt3a were co-fractionated with a typical exosomal protein TSG101 in fractions having typical exosome densities. In contrast, most of apically secreted Wnt3a, as well as Wnt11, were co-fractionated with CD63 and Hsp70, which are also common to the most exosomes, but recovered in higher density fractions. Wnt3a exhibiting similar floatation behavior to the apically secreted ones were also detectable in the culture media of Wnt3a-expressing L and HEK293 cells. The lipidation of Wnt3a was required for its basolateral secretion in exosomes but was dispensable for the apical one. Thus, epithelial cells release Wnt via distinct populations of vesicles differing in secretion polarity and lipidation dependency

Quantitative analyses reveal extracellular dynamics of Wnt ligands in Xenopus embryos

動く分子と動かない分子が協調して、安定した位置情報を素早く作り出す. 京都大学プレスリリース. 2021-06-04.The mechanism of intercellular transport of Wnt ligands is still a matter of debate. To better understand this issue, we examined the distribution and dynamics of Wnt8 in Xenopus embryos. While Venus-tagged Wnt8 was found on the surfaces of cells close to Wnt-producing cells, we also detected its dispersal over distances of 15 cell diameters. A combination of fluorescence correlation spectroscopy and quantitative imaging suggested that only a small proportion of Wnt8 ligands diffuses freely, whereas most Wnt8 molecules are bound to cell surfaces. Fluorescence decay after photoconversion showed that Wnt8 ligands bound on cell surfaces decrease exponentially, suggesting a dynamic exchange of bound forms of Wnt ligands. Mathematical modeling based on this exchange recapitulates a graded distribution of bound, but not free, Wnt ligands. Based on these results, we propose that Wnt distribution in tissues is controlled by a dynamic exchange of its abundant bound and rare free populations

Specific gene expression in unmyelinated dorsal root ganglion neurons in nonhuman primates by intra-nerve injection of AAV 6 vector

霊長類においてウイルスベクターを用いた痛覚神経への遺伝子導入に成功 --神経障害性疼痛治療への応用に期待--. 京都大学プレスリリース. 2021-08-12.Adeno-associated virus 6 has been proposed as a potential vector candidate for specific gene expression in pain-related dorsal root ganglion neurons, but this has not been confirmed in nonhuman primates. The aim of our study was to analyze the transduction efficiency and target specificity of this viral vector in the common marmoset by comparing with those in the rat. When green fluorescent protein-expressing serotype-6 vector was injected into the sciatic nerve, the efficiency of gene expression in dorsal root ganglion neurons was comparable in both species. We found that the serotype-6 vector was largely specific to the pain-related ganglion neurons in the marmoset as well as in the rat, whereas the serotype-9 vector resulted in contrasting effects in the two species. Neither AAV6 nor AAV9 resulted in DRG toxicity when administered via the sciatic nerve, suggesting this as a safer route of sensory nerve transduction than the currently used intrathecal or intravenous administrative routes. Furthermore, the adeno-associated virus 6 vector could be an optimal serotype for gene therapy for human chronic pain that has minimal effect on other somatosensory functions of dorsal root ganglion neurons

Immunology and Inflammation

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in mouse TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development

Three-dimensional analysis of trabecular bone structure of human vertebra in vivo using multi-detector row computed tomography -cross sectional and longitudinal studies-

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2002～2005課題番号: 14570852研究代表者: 高田 政彦（滋賀医科大学・医学部・講師）研究分担者: 今井 晋二（滋賀医科大学・医学部・助教授