Earthquake sources represent dynamic rupture within rocky materials at depth and often can be modeled as propagating shear slip controlled by friction laws. These laws provide boundary conditions on fault planes embedded in elastic media. Recent developments in observation networks, laboratory experiments, and methods of data analysis have expanded our knowledge of the physics of earthquakes. Newly discovered slow earthquakes are qualitatively different phenomena from ordinary fast earthquakes and provide independent information on slow deformation at depth. Many numerical simulations have been carried out to model both fast and slow earthquakes, but problems remain, especially with scaling laws. Some mechanisms are required to explain the power-law nature of earthquake rupture and the lack of characteristic length. Conceptual models that include a hierarchical structure over a wide range of scales would be helpful for characterizing diverse behavior in different seismic regions and for improving probabilistic forecasts of earthquakes.
earthquake; dynamic rupture; friction law; slow earthquake; hierarchical structure
Research works undertaken in the first author’s laboratory at the University of Tokyo over the past 30 years are highlighted. Finding of the occurrence of nonlinear waves (named Free-Surface Shock Waves) in the vicinity of a ship advancing at constant speed provided the start-line for the progress of innovative technologies in the ship hull-form design. Based on these findings, a multitude of the Computational Fluid Dynamic (CFD) techniques have been developed over this period, and are highlighted in this paper. The TUMMAC code has been developed for wave problems, based on a rectangular grid system, while the WISDAM code treats both wave and viscous flow problems in the framework of a boundary-fitted grid system. These two techniques are able to cope with almost all fluid dynamical problems relating to ships, including the resistance, ship’s motion and ride-comfort issues. Consequently, the two codes have contributed significantly to the progress in the technology of ship design, and now form an integral part of the ship-designing process.
ship hull-form; naval hydrodynamics; computational fluid dynamics; nonlinear waves; free-surface modelling
In 1976 we reported our first autopsied case with diffuse Lewy body disease (DLBD), the term of which we proposed in 1984. We also proposed the term “Lewy body disease” (LBD) in1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term to include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), which was proposed in 1996 on the basis of our reports of DLBD.
DLB is now known to be the second most frequent dementia following Alzheimer’s disease (AD).
In this paper we introduce our studies of DLBD and LBD.
Lewy body disease (LBD); diffuse Lewy body disease (DLBD); dementia with Lewy bodies (DLB); Parkinson’s disease (PD); Parkinson’s disease with dementia (PDD)
Remarkable progress has recently been made in molecular biology of double axis formation in Xenopus laevis. Leaving aside, for the time being, the problem of the gene expressions regulating Xenopus laevis development, here I show that pulse treatment could induce formation of a secondary axis in a fertilized Xenopus laevis egg. At 3 min after insemination, metal oxides were added to Xenopus fertilized eggs, and then twin embryos appeared. Zirconium oxide (ZrO2) was the most effective metal oxide for producing twin embryos. ZrO2 was added to the fertilized eggs, and 30 sec later, the eggs were dejellied with cysteine solution and washed within 7 min after insemination. The fertilized eggs began flattening at around 15 min after insemination. When the degree of flattening (the vertical length of the egg divided by the horizontal length) of the eggs at the 16- and 32-cell stages became less than 0.4 degrees, production of twin embryos occurred. Many flattened eggs at less than 0.4 degrees formed twin embryos. The third cleavage of eggs treated with metal oxides was meridional, while the normal third cleavage was horizontal.
Xenopus laevis; twinning; flattened eggs; Zirconium oxide; pulse treatment
Combination of bioaffinity and chromatography gave birth to affinity chromatography. A further combination with frontal analysis resulted in creation of frontal affinity chromatography (FAC). This new versatile research tool enabled detailed analysis of weak interactions that play essential roles in living systems, especially those between complex saccharides and saccharide-binding proteins. FAC now becomes the best method for the investigation of saccharide-binding proteins (lectins) from viewpoints of sensitivity, accuracy, and efficiency, and is contributing greatly to the development of glycobiology. It opened a door leading to deeper understanding of the significance of saccharide recognition in life. The theory is also concisely described.
frontal affinity chromatography; FAC; lectin profiling; PA-saccharide; galectin; concanavalin A
Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.
endocannabinoid; retrograde signaling; synapse; cannabinoid receptor; 2-arachidonylglycerol; anandamide
In Japan, efforts have been directed toward improving the detection of early gastric cancer by double contrast radiography and endoscopy, since early cancer has a good prognosis, resulting in Japan having the world’s best diagnostic system for early gastric cancer. The 5-year survival rate of gastric cancer patients in Japan is much higher than in Western countries by the development of endoscopic treatment for early gastric cancer. In February 2013, Japanese national health insurance cover for H. pylori eradication therapy was expanded to patients with H. pylori-associated gastritis, a type of chronic gastritis. H. pylori-associated gastritis causes gastric and duodenal ulcers and gastric polyps, therefore, providing treatment for this gastritis is likely to substantially decrease the prevalence of both gastric and duodenal ulcer and gastric cancer. Patients with gastritis are tested for H. pylori infection and those who are positive receive eradication therapy followed by periodic endoscopic surveillance. If such an approach is pursued further in Japan, gastric cancer deaths will show a dramatic decline after 10–20 years.
gastric cancer prevention; Helicobacter pylori (H. pylori); H. pylori-associated gastritis; elimination of gastric cancer
The history of pollinosis in Japan before the discovery of Japanese cedar pollinosis was presented in part I in this paper. Until early 1960s, it was believed that there was no pollinosis in Japan except one case of ragweed pollinosis.
The summary of how the Japanese cedar pollinosis was discovered and named was presented in part II, by referring to the paper in which we reported the presence of Japanese cedar pollinosis for the first time.
The epidemiology after the discovery of Japanese cedar pollinosis was presented in part III. The number of the patients suffering from Japanese cedar pollinosis gradually increased since the 1970s. The annual incidence rate of the pollinosis had correlations with the dispersed pollen count per year. The prevalence rate of the patients with Japanese cedar pollinosis increased from 16.2% in 1998 to 26.5% in 2008 by the nationwide survey. The prevalence rate of the patients with Japanese cedar pollinosis in Tokyo metropolitan area was 10% from 1983 to 1987, 19.4% in 1996, and 28.2% in 2006.
The prospects of current research and future studies were discussed in parts IV and V.
Japanese cedar; pollinosis; Japanese cedar pollinosis
Comprehensive whole-body counter surveys covering over 93% of the school children between the ages of 6 and 15 in Miharu town, Fukushima Prefecture, have been conducted for three consecutive years, in 2011, 2012 and 2013. Although the results of a questionnaire indicate that approximately 60% of the children have been regularly eating local or home-grown rice, in 2012 and 2013 no child was found to exceed the 137Cs detection limit of 300 Bq/body.
Fukushima Dai-ichi accident; radioactive cesium; whole-body counting; committed effective dose
Chaperone therapy is a newly developed molecular therapeutic approach to protein misfolding diseases. Among them we found unstable mutant enzyme proteins in a few lysosomal diseases, resulting in rapid intracellular degradation and loss of function. Active-site binding low molecular competitive inhibitors (chemical chaperones) paradoxically stabilized and enhanced the enzyme activity in somatic cells by correction of the misfolding of enzyme protein. They reached the brain through the blood-brain barrier after oral administration, and corrected pathophysiology of the disease. In addition to these inhibitory chaperones, non-competitive chaperones without inhibitory bioactivity are being developed. Furthermore molecular chaperone therapy utilizing the heat shock protein and other chaperone proteins induced by small molecules has been experimentally tried to handle abnormally accumulated proteins as a new approach particularly to neurodegenerative diseases. These three types of chaperones are promising candidates for various types of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases.
chaperone therapy; inhibitory chaperone; non-inhibitory chaperone; molecular chaperone; protein misfolding; lysosomal disease
The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. In 1994, we identified immunohistochemically a new zone between zG and zF of the rat adrenal gland. The zone appeared to be devoid of any significant endocrine functions specific to adrenocortical zones, therefore, we designated the zone as “undifferentiated cell zone (zU)”. Further, BrdU (5-bromo-2′-deoxyuridine)-incorporating cells (cells in S-phase) were concentrated at the outer region and the inner region of zU, and these cells proliferated and migrated bidirectionally: toward zG centrifugally and toward zF centripetally. We proposed that cells in and around zU are stem/progenitor cells of the rat adrenal cortex, maintaining functional zonation of the adrenal cortex. The view is consistent with observations reported recently that Sonic hedgehog (Shh), an important factor in embryonic development and adult stem cell maintenance, exists in zU of the rat adrenal gland and the Shh-containing cells seem to migrate bidirectionally.
adrenal cortex; steroidogenesis; aldosterone synthase cytochrome P450 (CYP11B2); steroid 11β-hydroxylase cytochrome P450 (CYP11B1); stem/progenitor cells of the adrenal cortex; functional zonation of the adrenal cortex
Assisted reproductive technology (ART) such as in vitro fertilization (IVF) and embryo transfer (ET) has been essential in the treatment of infertility. The world’s first IVF-ET baby was born in 1978 based on the technique developed by Dr. Robert Edwards and Dr. Patrick Steptoe.1) In Japan, the first IVF-ET birth was reported in 1983 by Prof. Masakuni Suzuki at Tohoku University School of Medicine.2,3)
IVF-ET is a procedure used to achieve pregnancy that consists of extracting oocytes from an infertile woman, fertilizing them in vitro, and transferring fertilized eggs into the patient’s uterine cavity (Fig. 1). Since the first report of successful IVF-ET, numerous techniques related to ART, such as cryopreservation of oocytes and embryos, gamete intrafallopian transfer (GIFT), and microinsemination, have been developed and refined (Table 1).
Herein we describe the history of basic research in IVF-ET that led to human applications, how the birth of the first IVF-ET baby was achieved in Japan, the current status of ART in Japan, issues related to ART, and future prospects for ART.
IVF in Japan; first successful IVF in Japan; early days of IVF
The ribosomal RNA gene (rDNA) repeats form a historically well-researched region in the chromosome. Their highly repetitive structure can be identified easily which has enabled studies on DNA replication, recombination, and transcription. The region is one of the most unstable regions in the genome because of deleterious recombination among the repeats. The ribosomal RNA gene repeats use a unique gene amplification system to restore the copy number after this has been reduced due to recombination. It has been shown that unstable features in the genome can accelerate cellular senescence that restricts the lifespan of a cell. Here, I will introduce a study by our group that shows how the stability of rDNA is maintained and affects lifespan. I propose that the ribosomal RNA gene repeats constitute a center from which the stability of the whole genome is regulated and the lifespan of the cell is controlled.
ribosomal RNA gene (rDNA); genome stability; cellular senescence; recombination; budding yeast; noncoding transcription
At least 150 different human proteins are anchored to the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI). GPI preassembled in the endoplasmic reticulum is attached to the protein’s carboxyl-terminus as a post-translational modification by GPI transamidase. Twenty-two PIG (for Phosphatidyl Inositol Glycan) genes are involved in the biosynthesis and protein-attachment of GPI. After attachment to proteins, both lipid and glycan moieties of GPI are structurally remodeled in the endoplasmic reticulum and Golgi apparatus. Four PGAP (for Post GPI Attachment to Proteins) genes are involved in the remodeling of GPI. GPI-anchor deficiencies caused by somatic and germline mutations in the PIG and PGAP genes have been found and characterized. The characteristics of the 26 PIG and PGAP genes and the GPI deficiencies caused by mutations in these genes are reviewed.
glycosylphosphatidylinositol; glycolipid; post-translational modification; somatic mutation; germline mutation; deficiency
The “reversion of cell fate from differentiated states back into totipotent or pluripotent states” has been an interest of many scientists for a long time. With the help of knowledge accumulated by those scientists, we succeeded in converting somatic cells to a pluripotent cell lineage by the forced expression of defined factors. These established induced pluripotent stem (iPS) cells have similar features to embryonic stem (ES) cells, including pluripotency and immortality. The iPS cell technology provides unprecedented opportunities for regenerative medicine and drug discovery.
iPS cell; reprogramming; pluripotent
One of the difficulties of the current giant impact model for the origin of the Moon is to explain the marked similarity in the isotopic compositions and the substantial differences in the major element chemistry. Physics of shock heating is analyzed to show that the degree of heating is asymmetric between the impactor and the target, if the target (the proto-Earth) had a magma-ocean but the impactor did not. The magma ocean is heated much more than the solid impactor and the vapor-rich jets come mainly from the magma-ocean from which the Moon might have been formed. In this scenario, the similarity and differences in the composition between the Moon and Earth would be explained as a natural consequence of a collision in the later stage of planetary formation. Including the asymmetry in shock heating is the first step toward explaining the chemical composition of the Moon.
giant impact; the Moon; magma ocean; shock heating; equation of state; Grüneisen parameter
Proteolytic processing of the amyloid precursor protein (APP) by β-secretase and γ-secretase leads to the generation and deposition of amyloid β (Aβ) in Alzheimer’s disease (AD). N-terminally or C-terminally truncated Aβ variants have been found in human cerebrospinal fluid and cultured cell media using immunoprecipitation and mass spectrometry. Unfortunately, the profile of plasma Aβ variants has not been revealed due to the difficulty of isolating Aβ from plasma. We present here for the first time studies of Aβ and related peptides in human plasma. Twenty-two Aβ-related peptides including novel peptides truncated before the β-secretase site were detected in human plasma and 20 of the peptides were identified by tandem mass spectrometry. Using an internal standard, we developed a quantitative assay for the Aβ-related peptides and demonstrated plasma dilution linearity and the precision required for their quantitation. The present method should enhance the understanding of APP processing and clearance in AD progression.
amyloid precursor protein; amyloid β; Alzheimer’s disease; immunoprecipitation; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; plasma
In modern life, we are surrounded by and filled with electromagnetic noise caused by the dominant use of energy in the form of electricity. This situation is brought about by the fact that the noise is not understood theoretically. A new practice of noise reduction was introduced for the construction of Heavy Ion Medical Accelerator in Chiba (HIMAC). The key concept is a symmetric three-line circuit that arranges power supplies, noise filters and magnets around a third central ground line. A continuous theoretical effort forced us to find a new circuit theory involving a multiconductor transmission-line system starting from Maxwell’s equations without any approximation. We discuss the essence of all of these experimental and theoretical developments with the hope to remove unnecessary electromagnetic noise not only from power supplies, but also from all electric devices. The newly derived circuit theory of multiconductor transmission lines is universal, and establishes the validity of the practice of noise reduction.
electromagnetic noise; new circuit theory; symmetric three-line circuit; normal mode; common mode; coefficients of potential
It has been pointed out by some researchers1,2) that road pavements are subjected to vertical stress due to vehicles on them as well as shear stress at the time of braking or acceleration of vehicles. In this paper, the results of elastic analysis to obtain the rigorous solution for an elastic two-layer system subjected to surface shear stress are described and it is shown that the effect of shear stresses applied at the surface gives rise to fairly large stresses in the system. On the basis of these findings, the author attempts to explain why pavement failure takes place frequently at places such as crossings and curved parts where pavements are subjected to high magnitude of surface shear stresses.
three-dimensional elasticity analysis; two-layer system; surface shear force; crossings and curved parts of road pavements; pavement failure
Antillatoxin 1 is a unique natural product that displays potent neurotoxic and neuritogenic activities through activation of voltage-gated sodium channels. The peptidic macrocycle of 1 was attached to a side chain with an exceptionally high degree of methylation. In this review, we discuss the total synthesis and biological evaluation of 1 and its analogues. First we describe an efficient synthetic route to 1. This strategy enabled the unified preparation of nine side chain analogues. Structure-activity relationship studies of these analogues revealed that subtle side chain modification leads to dramatic changes in activity, and detailed structural analyses indicated the importance of the overall size and three dimensional shape of the side chain. Based on these data, we designed and synthesized a photoresponsive analogue, proving that the activity of 1 was modulated via a photochemical reaction. The knowledge accumulated through these studies will be useful for the rational design of new tailor-made molecules to control the function and behavior of ion channels.
total synthesis; natural products; amino acids; ion channels; biological activity; structure-activity relationships
Glycoprotein quality control is categorized into three kinds of reactions; the folding of nascent glycoproteins, ER-associated degradation of misfolded or unassembled glycoproteins, and transport and sorting of correctly folded glycoproteins. In all three processes, N-glycans on the glycoproteins are used as tags that are recognized by intracellular lectins. We analyzed the functions of these intracellular lectins and their sugar-binding specificities. The results clearly showed that the A, B, and C-arms of high mannose-type glycans participate in the folding, transport and sorting, and degradation, respectively, of newly synthesized peptides. After correctly folded glycoproteins are transported to the Golgi apparatus, N-glycans are trimmed into Man3GlcNAc2 and then rebuilt into various complex-type glycans in the Golgi, resulting in the addition of diverse sugar structures that allow glycoproteins to play various roles outside of the cells.
lectin; specificity; quality control; folding; transport; ER-associated degradation
Borylated functional π-systems are useful building blocks to enable efficient synthesis of novel molecular architectures with beautiful structures, intriguing properties and unique functions. Introduction of boronic ester substituents to a variety of extended π-systems can be achieved through either iridium-catalyzed direct C–H borylation or the two-step procedure via electrophilic halogenation followed by palladium-catalyzed borylation. This review article focuses on our recent progress on borylation of large π-conjugated systems such as porphyrins, perylene bisimides, hexabenzocoronenes and dipyrrins.
transition-metal catalyst; C–H activation; boron; porphyrin; polyaromatic hydrocarbons; BODIPY
The wind velocity and temperature profiles observed in the middle atmosphere (altitude: 10–100 km) show perturbations resulting from superposition of various atmospheric waves, including atmospheric gravity waves. Atmospheric gravity waves are known to play an important role in determining the general circulation in the middle atmosphere by dynamical stresses caused by gravity wave breaking. In this paper, we summarize the characteristics of atmospheric gravity waves observed using the middle and upper atmosphere (MU) radar in Japan, as well as novel satellite data obtained from global positioning system radio occultation (GPS RO) measurements. In particular, we focus on the behavior of gravity waves in the mesosphere (50–90 km), where considerable gravity wave attenuation occurs. We also report on the global distribution of gravity wave activity in the stratosphere (10–50 km), highlighting various excitation mechanisms such as orographic effects, convection in the tropics, meteorological disturbances, the subtropical jet and the polar night jet.
atmospheric gravity wave; middle atmosphere; wave breaking; saturated spectrum; the MU radar; GPS radio occultation
Extensive research has recently been conducted on plant factory with artificial light, which is one type of closed plant production system (CPPS) consisting of a thermally insulated and airtight structure, a multi-tier system with lighting devices, air conditioners and fans, a CO2 supply unit, a nutrient solution supply unit, and an environment control unit. One of the research outcomes is the concept of resource use efficiency (RUE) of CPPS.
This paper reviews the characteristics of the CPPS compared with those of the greenhouse, mainly from the viewpoint of RUE, which is defined as the ratio of the amount of the resource fixed or held in plants to the amount of the resource supplied to the CPPS.
It is shown that the use efficiencies of water, CO2 and light energy are considerably higher in the CPPS than those in the greenhouse. On the other hand, there is much more room for improving the light and electric energy use efficiencies of CPPS. Challenging issues for CPPS and RUE are also discussed.
closed plant production system; plant factory; resource use efficiency
Non-communicable diseases (NCDs), such as diabetes mellitus and coronary heart disease, are chronic, non-infectious diseases of long duration. NCDs are increasingly widespread worldwide and are becoming a serious health and economic burden. NCDs arise from complex interactions between the genetic make-up of an individual and environmental factors. Several epidemiological studies have revealed that the perinatal environment influences health later in life, and have proposed the concept of developmental programming or developmental origin of health and disease (DOHaD). These studies suggest the importance of life course health care from fetal life, early childhood, adulthood, and through to old age. Recent progress in genomics, proteomics and diagnostic modalities holds promise for identifying high risk groups, predicting latent diseases, and allowing early intervention. Preemptive medicine is the ultimate goal of medicine, but to achieve it, the full participation of the public and all sectors of society is imperative.
non-communicable disease; developmental programming; life course health care; preemptive medicine; cohort study