Modeling of antigenomic therapy of mitochondrial diseases by mitochondrially addressed RNA targeting a pathogenic point mutation in mitochondrial DNA

Defects in mitochondrial genome can cause a wide range of clinical disorders, mainly neuromuscular diseases. Presently, no efficient therapeutic treatment has been developed against this class of pathologies. Because most of deleterious mitochondrial mutations are heteroplasmic, meaning that wild type and mutated forms of mitochondrial DNA (mtDNA) coexist in the same cell, the shift in proportion between mutant and wild type molecules could restore mitochondrial functions. Recently, we developed mitochondrial RNA vectors that can be used to address anti-replicative oligoribonucleotides into human mitochondria and thus impact heteroplasmy level in cells bearing a large deletion in mtDNA. Here, we show that this strategy can be also applied to point mutations in mtDNA. We demonstrate that specifically designed RNA molecules containing structural determinants for mitochondrial import and 20-nucleotide sequence corresponding to the mutated region of mtDNA, are able to anneal selectively to the mutated mitochondrial genomes. After being imported into mitochondria of living human cells in culture, these RNA induced a decrease of the proportion of mtDNA molecules bearing a pathogenic point mutation in the mtDNA ND5 gene

Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria

Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNALeu(UUR). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNALeu(UUR) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders

Top quark production in the reaction e"+e"-#->#e#nu#tb at linear collider energies

The complete tree-level cross sections for the reaction e"+e"- #-># e#nu#tb are computed for top masses of 160 to 200 GeV at center-of-mass energies between 0.2 and 2.0 TeV using the packages CompHEP and GRACE. It is demonstrated that t anti t-pair production dominates around #sq root#s = 0.5 TeV, whereas soft photon t-channel exchange contributions grow with increasing energy such that above 1.5 TeV it dominates. Detailed cross section considerations close to the t anti t threshold reveals some peculiar properties. It is shown that a precise top quark mass determination is not significantly hampered by the existence of non-t anti t diagrams. With desirable assumptions on linear collider luminosities the CKM matrix element vertical stroke V_t_b vertical stroke might be measured best at or close to #sq root#s = 2 TeV. (orig.)23 refs.Available from TIB Hannover: RA 2999(95-151) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Structure of the baryonic flux tube in N_f=2 lattice QCD at finite temperature

We study the flux tube profile in the baryonic system in full QCD at finite temperature of N_t=8 lattice. We fix the maximally Abelian gauge and measure the monopole and the photon parts of the Abelian action density, the color electric field and the monopole current on both sides of the finite temperature transition. We demonstrate the disappearance of the flux tube in the high temperature phase. (orig.)Available from TIB Hannover: RA 2999(03-144) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

A guide to experimental elementary particle physics literature, 1985--1989

We present an indexed guide to experimental high energy physics literature for the years 1985--1989. No actual data are given, but approximately 3500 papers are indexed by Beam/Target/Momentum, Reaction/Momentum (including the final stare), Final State Particle, and Accelerator/Experiment/ Detector