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In eucaryotes, most genomic DNA is stored as chromatin wrapped around a core histone. The intranuclear phenomena of transcription, replication and repair that act directly on genomic DNA take place with an accompanying change in the structure of chromatin. This wide-reaching chromatin remodelling can be said to control the intranuclear phenomena; for example, transcription activity is dependent on the structure of chromatin, as chromatin changes proximity to the DNA by a factor of 2500X. The activation range of transcription factors acting on naked DNA is up to 10X, so it follows that chromatin remodelling is primarily responsible for controlling transcription. (Fig.1)
Fig. 1 Chromatin Remodelling
Chromatin remodelling is generally carried out by histone modification factor and ATP-dependent remodelling factor acting in turn upon chromatin. 1) From immunoprecipitation experiments among others, it has come to be understood that histone modification factor and chromatin remodelling factor, acting from their separate promoters, carry out chromatin remodelling through various methods. 2) Through these step-by-step operations, chromatin takes various shapes—mononucleosomes, 30nm chromatin fibres and also goes through higher level structure changes—and through the dynamic conversions between these forms controls transcription, replication and other such intranuclear phenomena. 3) Among the various factors that participate in chromatin remodelling, histone modification factor, by means of acetylation, phosphorylation, methylation, ubiquitination and the reverse of these respective processes, forms a unique chemical modification pattern on the tails of histone H3 and H4 amino termini. This pattern works as a recognizable code that is used to further recruit factors involved in chromatin remodelling; the so-called ‘histone control hypothesis’. 4), 5) ATP-dependent remodelling factor complexes such as SW1/SNF, NURF and Mi-2 have also been identified. These use energy from ATP hydrolysis to bring about a loosening of chromatin structure. ATP-dependent remodelling factor has not only an ATP-ase domain, but also a bromodomain, SANT domain, chromodomain, and ATP hook among others, and is thought to be carried to regions of chromatin by the action of these domains. Also involved in transcription extension, FACT and DSIF appear to have chromatin remodelling activity.
How has structural biology contributed to chromatin remodelling research? The literature contains many reports of the tertiary structure of acetylating histone modification enzymes, for example, HAT domain at Tetrahymena pyriformis GCN5, and these reports have provided important information for recognizing histone tails by their amino acid arrangement. 7) [[Where is reference 6?]] While there are no reports on histone deacetylation enzyme, there are reports on the tertiary structure of the analog extreme thermophile HDLP (histone deacetylaselike protein). 8) While the original function of this latter enzyme in thermophilic bacteria is not clearly known. ithas in vitro deacetylation activity, the same as the eucaryotic histone deacetylation enzyme. In addition it has a factor in common with toricostatin A and SAHA (suberoylanilidehydroxamicacid) in that they all work as inhibitors. For that reason, through the study of the tertiary structure of HDLP, it is possible to offer a reasonable explanation of the organization of the structure of the histone deacetylase enzyme. The chemically modified histone tail works as a recognition code for, among others, the chromatin remodelling factor. Structural biology has played an important role here in providing such evidence in support of the ‘histone code hypothesis’. Among HAT, ATP-dependent remodelling factor, coactivator, and TFIID subunit TAF, there exist partially homologous bromine domains, with homology ranging from 110 amino acids upwards. The bromine domain structure of coactivator P/CAF has been determined by NMR, and a hydrophobic pocket found within this structure. Binding assays using NMR indicate that a peptide in the tail of the acetylated H3 binds to this hydrophobic pocket. Furthermore, it can be inferred that there are two bromine domain crystal structures lined up in tandem on the biggest subunit (TAFII250) of general transcription factor TF110. These domains have binding activity with acetylated histone H4 tails. It has also been shown that the chromodomain of heterochromatinprotein1 binds to the methylated tail of histone H3. Research has been conducted on the NMR structure of the chromodomain of mouse chromatin modifier protein 1. 9)
Chromatin remodelling factor recognizes the histone tail code via regions such as the bromodomain, and although it accesses specific regions of the nucleosome directly, it is often recruited indirectly via a DNA associated transcription factor. The transcription repression factor Mad, containing bHLH (basichelix-loop-helix)-zip as a DNA binding domain, recruits the Sin3 complex (containing histone acetlyase enzyme as a subunit) to chromatin. The complex of Sin3’s PAH2 domain and Mad’s transcription repression domain has been analysed by NMR, and the recruitment of the deacetylation complex to regions of chromatin is currently under discussion. 10)
DNA methylation and chromatin structure control.
After cell division, for the purpose of preservation, long-term chromatin structural transition takes place. As is generally seen in upper level eukaryotes, CpG methylation is also thought to participate in this preservation. This methylation is a chemical modification found uniquely in vertebrates and is a stereotypical example of a preserving epigenetic phenomenon in post-division somatic cells. The preservation of the methylation pattern is carried out by the methylase Dnmt1 bound to the replication apparatus, and is thought to occur by methylation at the same time as replication. DNA methylation brings about stability in regions of dense genomic DNA and, by its action, transcription repression and a reduction in the mutation rate are also seen. There is also a clear correlation between genomic DNA methylation, genomic imprinting, X chromosome inactivation and tumorigenisis.
Fig.2 MBD1 methylase DNA binding domain and DNA replication complex tertiary structure
The major functions of DNA methylation are revealed by methylated DNA binding protein study. In mammals, five types of DNA binding protein have been found: MBD1 through 4 and MeCP2, which all show high levels of homology at the N terminus DNA binding domain. Many of these proteins interact with the histone deacetylase containing Sin3 complex and Mi2-Nurd, etc., producing recruitment to chromatin of the Sin3 complex and Mi2-Nurd. Thus, in the same way as the aforementioned Mad, these proteins function as recruitment factors for chromatin remodelling factor.
The tertiary structure of methylated DNA binding domain has been determined. The Wakefield group’s MeCP2 11) and the authors’ MBD1 12) methylated DNA binding domain’s tertiary structure have been reported previously. In addition, the authors have also carried out structural analysis of MBD1’s DNA binding domain with methylated DNA. (Fig. 2) 13)
The four-strand alpha/beta sheet structure of the MBD1 methylated DNA binding domain is composed of antiparallel beta sheets and helix bound together by loops, and binds to methylated DNA obliquely via the major groove. The L1 loop, unable to form a stable tertiary structure, forms unique conformations within complexes and partially binds to the sugar-phosphate backbone of DNA, making contact over a large area. The 2 methyl groups of the methylated CpG region recognize and bind to hydrophobic pockets formed by 5 highly conserved residues. Within these residues, 2 arginine residues pair with guanine bases via hydrogen bonds. The only interaction between DNA bases and protein is by two neighbouring base pairs. As a result of this, the interaction between protein and DNA is restricted to the major groove, and does not extend to the minor groove or the reverse side of the DNA. This kind of unique tertiary structure not only explains why methylated DNA binding domain binds with only CpG, but also explains how it is able to bind with nucleosome DNA. On the outer face of nucleosomic DNA, the major groove is exposed, without being hidden by core histone, as can be seen from analysis of the crystal structure. However, the core histone tail is wrapped around most of the minor groove.
Japanese to English: Japanese Universities - General article Detailed field: General / Conversation / Greetings / Letters
Source text - Japanese (1/6)
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Translation - English
The University Crisis
At present Japanese universities are in crisis. The reasons for this are, firstly, a crisis of the subject matter of education (at the same time as being a crisis of people's attitude towards students due to upbringing), secondly, a crisis of teachers and researchers themselves, and thirdly, a crisis of the human society which created these problems.
As of now, all universities are educating for the purpose of acquiring qualifications. In order to maintain student numbers in the midst of a declining birth rate, universities have turned to selling themselves on the premise that students will be secured employment on graduation, by the means of teaching students skills and imparting knowledge which they can use immediately in the workplace. However, this kind of education for the purpose of acquiring qualifications can also be carried out at vocational schools or quickly introduced at any other university, so it bears no connection to the individuality of the university. Therefore, to try and attract students, in addition to the increasingly specific qualification-oriented courses, universities are competing by educating students to deal with the class composition of Japanese society.
Universities can't function without teaching students about developments in research in their field of study and establishing the logic that relates to these developments. It may well be necessary to make adjustments to the education system to attract students, but perfecting these adjustments is wrongly taking precedence, and essential educational content is being neglected.
What is important is to educate students to recognize the logical connections between concepts, and the relevance of these concepts to society. When this recognition begins it can truly be said that one understands the matter in question. However, a tendency is appearing in which the focus is on how to teach (as opposed to actual content), appealing to some ideal image whilst putting emphasis on the fragmentary, transitory aspects of education. This ‘digital thinking’ causes an inability to grasp the nature of causal relationships between objects or to appreciate their meaning to society.
People deal with other people directly, and as one person to another in a mutually respectful environment collaborate and cooperate, learn together and forge ‘humanity’ as we know it. To promote this is a fundament of education, and is the polar opposite of a system of market economy in which exchange of goods and money is what keeps the wheels turning. If universities take this market economy road, they will forgo their position as a seat of learning.
The present crisis in universities is due to a forced reform in which market principles are being brought into all areas of society, cutting out enterprises and fields which don’t turn a profit. At present, this principle of stock price supremacy - increasing the value of stocks and thus turning a profit over all else- is being pushed on universities, money is becoming the number one goal and justification for the existence of the enterprise. As universities and educational institutions increasingly become public limited companies, there is a tendency to treat the students as products for sale, goods to be made and profited from, with stock price supremacy becoming the fundamental goal.
All universities need to return to first principles, and realize that what props up society is people, and focus on fostering individuals who can create a peaceful society within a peaceful country. Only by taking such a stand will this crisis of universities be overcome.
Japanese to English: Japanese tax issues Detailed field: General / Conversation / Greetings / Letters
Source text - Japanese --------------------------------------------------------------------------------
Translation - English The perfect tax system would bring the wealthy from foreign countries.
Thirdly, as previously touched upon in paragraph three, I think the Japanese tax system is a problem. Tax in Japan is too high.
If tax in Japan were to become slightly less than in other industrial countries, the prosperity of Japan would be guaranteed. If not just personal income tax but corporate tax were also to fall, businesses would not run from Japan. Rather, foreign enterprise would steadily come to Japan, and the number of paper companies and suchlike would probably also increase. If tax were to fall, although the tax revenue from each individual company would be small, the total annual tax revenue, coming from many companies, would increase, so rather than a loss, there would be an overall profit. Incidentally, major companies from around the world would probably bring their headquarters, even if only in name, to the many empty rooms left in buildings around Tokyo since the time of the bubble economy.
Furthermore, if very wealthy people from around the world were to start coming to Japan, Japan's future would become more and more secure. To begin with, Japan is a very safe country, and for that reason alone is attractive to wealthy people. Japanese parents not having to employ a bodyguard for, or travel with children to school is miraculous to parents from Europe and America. In light of this fact, if tax were low, wealthy people would move to Japan, bringing their wealth and their families. This would be an excellent protective measure for Japan, as well as very advantageous in bridging the worldwide information gap.
There is another merit for Japan arising from this: Problems such as depopulation may be resolved by the arrival of wealthy people. Wealthy people have the ability to live in sparsely populated areas. Rich families, such as the Rockefellers, tend to have their main home in sparsely populated areas. Why? Well, wealthy people can use personal helicopters and private jets, and can avoid inconvenience by hiring servants. Indeed, living in a nice natural environment with lakes and rivers away from other people means privacy is not infringed upon and provides an ideal location for the rich.
In Japan, problems arise precisely because people who are not rich live in areas of depopulation, thus, be it in Hokkaido or anywhere else, getting rich people to live in depopulated areas is a good idea. Ideally rich Japanese would also move into those areas. Karuizawa was originally a sparsely populated area. Rich foreigners moved in and began to buy second homes, as then did Japanese, resulting in the development of that area. Thus far Hokkaido has not developed as the threat of a Soviet invasion was present, but now that threat is nonexistent.
The easiest path to follow for Japan's survival is to lower tax, and I think that ultimately saving Japan depends on whether or not the rate of tax can be lowered.
Kyuu Eikan, Watanabe Shinichi, The Era of the Asian Financial World-Farewell America, pp. 179-181.
My background is in science, therefore most of the translating and editing/proofreading work I do is with Japanese research into English, most recently for the prestigious ‘Science’ and ‘Nature’ journals, however I also translate more general business correspondence, websites, and newspaper articles and proofread a wide range of material.
I am used to working to deadlines for clients seeking to put out work in target publications that accept work of only the highest standard. All the translation work I have taken on has been delivered punctually and has met these high standards, as can be corroborated by previous clients and outsourcing companies (references available on request).