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http://www.webmedcentral.com/images/Header_Logo.giftext/html2010-09-09T21:08:41+01:00http://www.webmedcentral.com/Dr. Oleg E TolmachovHypothesis, Inserting Bacterial Natural Transformation Protein Complexes Into Human Cells For Efficient Gene Therapy Using Naked Dna
http://www.webmedcentral.com/article_view/577
Naked DNA is a non-toxic vector for therapeutic gene delivery. However, current methods of transfection with naked DNA reach a limited range of susceptible tissues and have a low efficiency. The transfection of clinically important post-mitotic cells is particularly challenging because in these cells DNA need to pass the nuclear barrier. Thus, new principles for the transfer of naked DNA into human cells are required and can be found among the genetic exchange mechanisms in bacteria, where gene entry into cells via pick-up and transfer of naked DNA is known as “transformation”. In a number of bacteria, dedicated molecular machinery facilitates cell entry of free DNA by the process of “natural transformation”. In transformation-competent bacterial cells, specialised protein complexes mediate the binding of free double-stranded DNA, its fragmentation, cell entry and conversion to single-stranded DNA. I propose to exploit bacterial natural transformation machinery for a two-step transfection of human cells with therapeutic naked DNA. Firstly, the bacterial transformation protein complexes are inserted into the plasma membranes or nuclear envelopes of the target human cells and, secondly, the double-stranded vector DNA is supplied for the processing by the installed DNA transfer apparatus. I hypothesize that non-toxic bacterial transformation complexes residing in their new human milieu can promote the ultra-efficient transfer of exogenous therapeutic naked DNA. As the introduction of DNA into mammalian cells by non-viral means is called “transfection”, I propose to name the bacterial transformation complexes functioning in their new eukaryotic surroundings as “transfectosomes”. The initial step of the gene delivery should exploit the modern methods of extraneous protein insertion into mammalian cells, such as cell painting, engineering of cell permeable proteins with targeted intracellular localization, physical techniques of protein transfer like electroinsertion and electroporation. Sequence-selective natural transformation systems are known and can be taken advantage of to exclude undesired (e.g. gene silencing) portions of vector DNA from entering human nucleoplasm. Improved transfectosomes can possibly be engineered for better establishment and performance in human membranes. The hypothesis can be tested by comparing the naked DNA transfer efficiency into the transfectosome-bearing and the naive human cells in ex-vivo and in-vivo gene therapy settings. Immunogenicity of the transfectosomes can be modulated by protein engineering. As the delivered fragments of single-stranded DNA are highly recombinogenic, the confirmation of the hypothesis can lead to a breakthrough in gene repair therapy of dominantly inherited familial hypercholesterolemia, polycystic kidney disease and trinucleotide repeat disorders.text/html2010-09-23T16:32:47+01:00http://www.webmedcentral.com/Dr. Manjari S MukherjeeCommon Gene Polymorphisms in the Mother of a Child Born with Neural Tube Defect and Down Syndrome
http://www.webmedcentral.com/article_view/651
The purpose of this communication is to report an unusual case of an infant affected with both neural tube defect (NTD) and Down syndrome (DS). Genetic risk factors in the mother were investigated. As impaired folate metabolism is implicated in the etiology of NTD and DS, folate gene polymorphisms were determined in the case-mother. These included methylene tetrahydrofolate reductase gene (MTHFR) 677C>T, methionine synthase gene (MTR) 2756A>G, betaine homocysteine methyl transferase gene (BHMT) 742G>A, thymidylate synthase gene enhancer region (TSER) – 3 or 2 tandem repeats of 28-bp and TS gene, 6-bp deletion in 3’ untranslated region. The genotype distribution and minor allele frequencies were also determined in a group of female control subjects. The genotypes of case-mother was MTHFR 677CT, MTR 2756AG, TSER 3R2R, TS D0D6 and BHMT 742AA. The BHMT 742AA genotype, in combination of genotypes of case-mother at five, four or three polymorphic loci, was either absent or present in a small number of control women. The case mother was a life-long vegetarian. Although the precise maternal risk factor(s) cannot be pin-pointed, it is possible that BHMT 742AA genotype coupled with restricted intake of those folate micronutrients present chiefly in foods of animal origin may play a role.text/html2011-09-25T15:35:15+01:00http://www.webmedcentral.com/Dr. Clyde WintersDid Haplogroup M23 Originate in Africa
http://www.webmedcentral.com/article_view/2237
Haplogroup M23 is an ancient M haplogroup found only in Madagascar and among African Americans. In this paper we discuss the genomic , archaeological, and historical evidence that indicates that M23 may have originated in Africa, and that haplogroup M probably expanded across Africa before the out of Africa exit by anatomically modern humans 60kya.text/html2012-03-10T10:59:17+01:00http://www.webmedcentral.com/Dr. Clyde WintersFirst European Farmers were not Eastern Europeans
http://www.webmedcentral.com/article_view/3150
Phylogenetic evidence indicate that the first European farmers carried haplogroup N1. The N haplogroup probably expanded across Africa from the Great Lakes region of East Africa into West Africa 80kya and into Iberia 40kya. The archaeological and genetic evidence indicate that although there were changes in the material culture of Euopean hunter-gatherer groups and European farmers there was probably continuity between the N1a hunter-gatherer population and the farming groups of Europe.