Virale und nichtvirale Gentherapieansätze zur Behandlung von Netzhauterkrankungen

Zusammenfassung: Für die Behandlung von Netzhauterkrankungen eröffnet der Einsatz der Gentherapie neue Perspektiven. Die Verwendung von verschiedenartigen Oligonukleotiden oder viralen Expressionsvektoren erlaubt die Entwicklung von neuen Heilungsstrategien für Neovaskularisierungskrankheiten und retinale Degeneration. Therapeutische Oligonukleotide ("Antisense"-Oligonukleotide, Aptamere und siRNA) können den gezielten Abbau von Transkripten und damit die Konzentrationsabnahme eines an der Pathogenese beteiligten Proteins induzieren. Dagegen wird mit viralen Vektoren (rAAV und Lentivirus) häufig die Funktion eines defekten Gens durch die eines gesunden ersetzt und so die Ursache der Krankheit bekämpft. Die an Tiermodellen erfolgreich angewandten Gentherapien führten bereits zur Entwicklung von Medikamenten, und weitere werden zurzeit klinisch erprob

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function

Profit enhancing competitive pressure in vertically related industries

Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing

Virale und nichtvirale Gentherapieansätze zur Behandlung von Netzhauterkrankungen

Für die Behandlung von Netzhauterkrankungen eröffnet der Einsatz der Gentherapie neue Perspektiven. Die Verwendung von verschiedenartigen Oligonukleotiden oder viralen Expressionsvektoren erlaubt die Entwicklung von neuen Heilungsstrategien für Neovaskularisierungskrankheiten und retinale Degeneration. Therapeutische Oligonukleotide ("Antisense"-Oligonukleotide, Aptamere und siRNA) können den gezielten Abbau von Transkripten und damit die Konzentrationsabnahme eines an der Pathogenese beteiligten Proteins induzieren. Dagegen wird mit viralen Vektoren (rAAV und Lentivirus) häufig die Funktion eines defekten Gens durch die eines gesunden ersetzt und so die Ursache der Krankheit bekämpft. Die an Tiermodellen erfolgreich angewandten Gentherapien führten bereits zur Entwicklung von Medikamenten, und weitere werden zurzeit klinisch erprob

Mixer for solid fuels

Przedstawiono konstrukcję mieszałnika do sporządzania mieszanek pałiw stałych z miałów, mułów węgłowych i biomasy. Dobre wymieszanie użytych komponentów pozwała otrzymać pałiwo dobrej jakości, o wysokim stopniu jednorodności. Potwierdzone to zostało badaniami sprawności mieszania w mieszałniku w różnych wariantach technicznych i warunkach eksploatacyjnych.A construction of mixer for preparation of sohd fuels mixtures from fine and slime coa!s and from biomass is presented. Good mixing of components permits to receive good quality fuel with a high degree of homogeneity. This was confirmed during investigations on mixing ef-ficiency in different technical and working conditions

Enhancing the first enzymatic step in the histidine biosynthesis pathway increases the free histidine pool and nickel tolerance in Arabidopsis thaliana

Naturally selected nickel (Ni) tolerance in Alyssum lesbiacum has been proposed to involve constitutively high levels of endogenous free histidine. Transgenic Arabidopsis thaliana expressing a Salmonella typhimurium ATP phosphoribosyl transferase enzyme (StHisG) resistant to feedback inhibition by histidine contained approximately 2-fold higher histidine concentrations than wild type plants. Under exposure to a toxic Ni concentration, biomass production in StHisG expressing lines was between 14- and 40-fold higher than in wild-type plants. This suggested that enhancing the first step in the histidine biosynthesis pathway is sufficient to increase the endogenous free histidine pool and Ni tolerance in A. thaliana. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. [References: 47] 4

SAFIRA. Teilprojekt E 1.1: Entwicklung modellhafter Bewertungsansaetze zur Raumauswirkung von Sanierungsvorhaben. Textband und Anlagenband Schlussbericht

Published in 2 volumesAvailable from TIB Hannover: F04B86+a: F04B87+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung, Berlin (Germany)DEGerman

Epstein-Barr viral BNLF2a protein hijacks the tail-anchored protein insertion machinery to block antigen processing by the transport complex TAP

Virus-infected cells are eliminated by cytotoxic T lymphocytes, which recognize viral epitopes displayed on major histocompatibility complex class I molecules at the cell surface. Herpesviruses have evolved sophisticated strategies to escape this immune surveillance. During the lytic phase of EBV infection, the viral factor BNLF2a interferes with antigen processing by preventing peptide loading of major histocompatibility complex class I molecules. Here we reveal details of the inhibition mechanism of this EBV protein. We demonstrate that BNLF2a acts as a tail-anchored protein, exploiting the mammalian Asna-1/WRB (Get3/Get1) machinery for posttranslational insertion into the endoplasmic reticulum membrane, where it subsequently blocks antigen translocation by the transporter associated with antigen processing (TAP). BNLF2a binds directly to the core TAP complex arresting the ATP-binding cassette transporter in a transport-incompetent conformation. The inhibition mechanism of EBV BNLF2a is distinct and mutually exclusive of other viral TAP inhibitors

Epstein-Barr viral BNLF2a protein hijacks the tail-anchored protein insertion machinery to block antigen processing by the transport complex TAP

Virus-infected cells are eliminated by cytotoxic T lymphocytes, which recognize viral epitopes displayed on major histocompatibility complex class I molecules at the cell surface. Herpesviruses have evolved sophisticated strategies to escape this immune surveillance. During the lytic phase of EBV infection, the viral factor BNLF2a interferes with antigen processing by preventing peptide loading of major histocompatibility complex class I molecules. Here we reveal details of the inhibition mechanism of this EBV protein. We demonstrate that BNLF2a acts as a tail-anchored protein, exploiting the mammalian Asna-1/WRB (Get3/Get1) machinery for posttranslational insertion into the endoplasmic reticulum membrane, where it subsequently blocks antigen translocation by the transporter associated with antigen processing (TAP). BNLF2a binds directly to the core TAP complex arresting the ATP-binding cassette transporter in a transport-incompetent conformation. The inhibition mechanism of EBV BNLF2a is distinct and mutually exclusive of other viral TAP inhibitors