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- Imanishi, T., et al.
(författare)
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Integrative annotation of 21,037 human genes validated by full-length cDNA clones
- 2004
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 2:6, s. 856-875
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Tidskriftsartikel (refereegranskat)abstract
- The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.
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| 2. |
- Badelek, B, et al.
(författare)
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The photon collider at TESLA
- 2004
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Ingår i: International Journal of Modern Physics A. - 0217-751X. ; 19:30, s. 5097-5186
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Forskningsöversikt (refereegranskat)abstract
- High energy photon colliders (gammagamma,gammae) are based on e(-)e(-) linear colliders where high energy photons are produced using Compton scattering of laser light on high energy electrons just before the interaction point. This paper is a part of the Technical Design Report of the linear collider TESLA.(1) Physics program, possible parameters and some technical aspects of the photon collider at TESLA are discussed.
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| 4. |
- Wang, X., et al.
(författare)
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Involvement of the MKK6-p38? cascade in ?-radiation-induced cell cycle arrest
- 2000
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 20:13, s. 4543-4552
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Tidskriftsartikel (refereegranskat)abstract
- The p38 group of kinases belongs to the mitogen-activated protein (MAP) kinase superfamily with structural and functional characteristics distinguishable from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although there is a high degree of similarity among members of the p38 group in terms of structure and activation, each member appears to have a unique function. Here we show that activation of p38-? (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for ?-irradiation- induced G2 arrest. Activation of the MKK6-p38? cascade is sufficient to induce G2 arrest in cells, and expression of dominant negative alleles of MKK6 or p38? allows cells to escape the DNA damage-induce G2 delay. Activation of p38? is dependent on ATM and leads to activation of Cds1 (also known as Chk2). These data suggest a model in which activation of ATM by ? irradiation leads to the activation of MKK6, p38?, and Cds1 and that activation of both MKK6 and p38? is essential for the proper regulation of the G2 checkpoint in mammalian cells.
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| 5. |
- Bergström, Christel A. S., 1973-
(författare)
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Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process.
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| 10. |
- Han, S. H., et al.
(författare)
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Studies of dynamic critical behaviour in YBa2Cu3O7-delta single crystals
- 2000
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Ingår i: Physica. C, Superconductivity. - 0921-4534 .- 1873-2143. ; 341, s. 1855-1856
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Tidskriftsartikel (refereegranskat)abstract
- Up to now, the value of the dynamic critical exponent z is still an open question. We have studied this exponent in the intermediate (XY) critical regime in zero field for a set of high quality YBa2Cu3O7-delta Single crystals in terms of Fisher-Fisher-Huse (FFH) dynamic scaling, and using previously obtained values for the critical exponents cu of the de critical conductivity fluctuations. In this regime (i.e. the absence of Coulomb interactions), one would expect model-E dynamics (z = 1.5) to apply with the conserved charge-density conjugate to the phase fluctuations. However, we find the dynamic critical exponent to be z = 2, which is in agreement with the suggestion of FFH that due to plasma fluctuations, fully relaxational dynamics, model A (z = 2), should be appropriate.
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