A new turning point in glycosphingolipid research

Research on glycosphingolipids has advanced with the finding of their involvement in sphingolipidoses, blood group- and differentiation-related antigens, and receptors for bacteria and viruses. Recently, the molecular cloning of genes for the synthesis of glycosphingolipids has been performed extensively, and mice without sugar transferase-genes have been generated. These transferase-null mice have shown that the complex carbohydrate structures of glycosphingolipids are not essential for the embryogenesis, morphogenesis or development of animals, but that the accumulation of an intermediate, such as GM3 or ceramide, causes significant failure of neural development in knockout mice as to the GM2, GD3 and GlcCer synthase genes. On the other hand, the nonreducing terminal carbohydrates in either glycosphingolipids or glycoproteins have been confirmed to be related to carbohydrate-mediated phenomena using the same gene-manipulation technique, indicating that glycosphingolipids are some of the carriers for functionally important carbohydrates. Glycosphingolipids are certainly small molecules with hydrophobic ceramides, which carry both donor and acceptor groups of the hydrogen-bonding region with the potential ability to interact with several proteins on the raft structure in biomembranes, and their dynamic movement in the membranes was revealed by the flip-flop regulation of their synthesis in the Golgi apparatus and the transformation-associated alteration in the reactivity of the carbohydrate moiety with several ligands. Thus, research on the functional significance of glycosphingolipids should be carried out again regarding their physicochemical properties.     

Ethics and scientific publication

This article summarizes the major categories of ethical violations encountered during submission, review, and publication of scientific articles. We discuss data fabrication and falsification, plagiarism, redundant and duplicate publication, conflict of interest, authorship, animal and human welfare, and reviewer responsibility. In each section, pertinent historical background and citation of relevant regulations and statutes are provided. Furthermore, a specific case(s) derived from actual situations is(are) presented. These cases were chosen to highlight the complexities that investigators and journals must face when dealing with ethical issues. A series of discussion questions follow each case. It is our hope that by increasing education and awareness of ethical matters relevant to scientific investigation and publication, deviations from appropriate conduct will be reduced.     

Open access

正Aims and Scope:GPB publishes high-quality papers from the frontier research in the fields of genomics,proteomics,and bioinformatics.GPB's featured research areas include:Genomics:large-scale data acquisition,integrated studies and technology developments,concerning genome structures,variations,repeat contents and evolution.Other'omics'fields:epigenomics(DNA modifications,nucleosome positioning,histone     

Open access

Scientific communication is a misnomer. The process of scientific publication is much less a forum where information is exchanged for information than a market where information is exchanged for attention. Nevertheless, the exchange of information for attention is a somewhat peculiar market, since it seems much more natural to sell the information one has produced laboriously for money. Why publish a discovery, why share it with other researchers when knowledge is power?     

recA mutants of E. coli K12: A personal turning point

A first year graduate student, Ann Dee Margulies, changed my research career in 1962 by challenging me to direct her in the isolation of recombination-deficient mutants of Escherichia coli K-12. She succeeded in isolating two mutants, which conjugated with donor strains and received the donor DNA, but could not recombine that DNA with their own chromosomes. Ann Dee showed that both mutants were much more sensitive to UV radiation than was the wild type. Furthermore, she showed that one of these mutants carried a single mutation affecting both recombination and resistance. This work, published in 1965, was the first demonstration of the recA gene of E. coli. Subsequent work led to the discovery of many more recombination genes, the phenomenon of post replication-recombination repair, the invention of the SOS hypothesis and the discovery of genes encoding proteins with similar primary structure and function in all major groups of organisms. This article honors the memory of Ann Dee.     

A turning point in the knowledge of the structure-function-activity relations of elastin]

In this review are presented the last new results of our research group dealing with the molecular structures (atomic level) of tropoelastin, elastin and elastin derived peptides studied by using essentially methods of bioinformatics (theoretical predictions and molecular modelling) linked to experimental circular dichroism spectroscopic studies. We already had characterized both the local secondary structure and some parts of the tertiary structure of the tropoelastin and elastin molecules (human, bovine...), by using either theoretical predictions (local secondary structure, linear epitopes...) and/or experimental data (optical spectroscopic methods: Raman scattering, infrared absorption, circular dichroism). Except the cross-linking regions which are in helical conformations, the whole tropoelastin structure displays a lot of beta-reverse turns which usually belong to irregular structures in proteins. These turns play a key role in other regularly structures orientation (alpha-helix, beta-strand), thus they are very important in the native protein 3D architecture. It is particularly true for human tropoelastin, because its sequence is rich in glycines and prolines, and these residues are frequently met in beta-turns (a beta-turn is made of four consecutive residues which are stabilized by an hydrogen bond). Several types of beta-turns can be defined with the dihedral angles values phi and psi of the two central residues. Thus, by using a very recent updated set of propensities for the amino acid residues to belong to given types of reverse beta-turns (extracted from a reference set of known 3-D structures of globular proteins), we have determined, (by using our home made software COUDES), for all possible tetrapeptides of the human tropoelastin sequence, the distribution and the characterization of the possible type of turns. Thus, it is shown that the locations and/or the types of these reverse beta-turns reveal a regularity and are not all random. This confirms our hypothesis that intra-molecular elasticity of tropoelastin could be explained by the possibility of transitions between conformations involving short beta-strands and beta-turns. This result is of great interest in the construction (by using molecular biology) of elastic biomaterials derived from the elastin sequence (particularly, the elastin derived peptides corresponding to the sequence exon 21--(exon 24--exon 24...). Our study permit also to predict the conformations of specific elastin derived peptides which could have interesting biological activity. Peptides resulting from the degradation of elastin, the insoluble polymer of tropoelastin and responsible for the elasticity of vertebrate tissues, can induce biological effects and notably the regulation of matrix metalloproteinases (MMP-s) activity. Recently, it was proposed that some elastin derived hexapeptides resulting from circular permutations of VGVAPG (a three fold repetition sequence in exon 24 of human tropoelastin) possess MMP-1 production and activation regulation properties. This effect depends on the presence of the tropoelastin specific membraneous receptor 67 KDa EBP (Elastin Binding Protein). Our results obtained by using both circular dichroism spectroscopy and linear predictions confirmed the hypothesis of a structure dependent mechanism with a possibly occurring type VIII beta-turn on the first four residues of the GXXPG sequence consensus which is only present among all active peptides. Thus, we have performed extensive molecular dynamics studies, in both implicit and explicit solvent, on these active and inactive elastin derived hexapeptides. Using our own analysis method of pattern recognition of the types of the beta-reverse-turns followed during the molecular dynamics trajectory, we found that active and inactive peptides effectively form two well distinct conformational groups in which active peptides preferentially adopt conformation close to type VIII GXXP (beta-reverse-turn. The structural role of the C terminal G residue could also be explained. Additional molecular simulations on (VGVAPG)2 and (VGVAPG)3 show the formation of two or three GXXP tetrapeptides adopting a structure close to type VIII beta-reverse-turn, suggesting a local conformational preference for this motif. This observation of a specific structural single and/or repeated motif is in agreement with the circular dichroism spectra of the involved (VGVAPG)1, (VGVAPG)2 and (VGVAPG)3 peptides and then it can be proposed that their biological activities have to be linear. The final aim of this type of work is to understand more about the sequence/structure/function/activity relationships of those structured peptides in order to propose specific sequences (corresponding to specific structures) for best biological activity results.