Host ethnicity and virus genotype shape the hepatitis B virus-specific T-cell repertoire

Repertoire composition, quantity, and qualitative functional ability are the parameters that define virus-specific T-cell responses and are linked with their potential to control infection. We took advantage of the segregation of different hepatitis B virus (HBV) genotypes in geographically and genetically distinct host populations to directly analyze the impact that host and virus variables exert on these virus-specific T-cell parameters. T-cell responses against the entire HBV proteome were analyzed in a total of 109 HBV-infected subjects of distinct ethnicities (47 of Chinese origin and 62 of Caucasian origin). We demonstrate that HBV-specific T-cell quantity is determined by the virological and clinical profiles of the patients, which outweigh any influence of race or viral diversity. In contrast, HBV-specific T-cell repertoires are divergent in the two ethnic groups, with T-cell epitopes frequently found in Caucasian patients seldom detected in Chinese patients. In conclusion, we provide a direct biological evaluation of the impact that host and virus variables exert on virus-specific T-cell responses. The discordance between HBV-specific CD8 T-cell repertoires present in Caucasian and Chinese subjects shows the ability of HLA micropolymorphisms to diversify T-cell responses and has implications for the rational development of therapeutic and prophylactic vaccines for worldwide use.     

Bioreactors in tissue engineering—principles,applications and commercial constraints

Bioreactor technology is vital for tissue engineering. Usually, bioreactors are used to provide a tissue-specific physiological in vitro environment during tissue maturation. In addition to this most obvious application, bioreactors have the potential to improve the efficiency of the overall tissue-engineering concept. To date, a variety of bioreactor systems for tissue-specific applications have been developed. Of these, some systems are already commercially available. With bioreactor technology, various functional tissues of different types were generated and cultured in vitro. Nevertheless, these efforts and achievements alone have not yet led to many clinically successful tissue-engineered implants. We review possible applications for bioreactor systems within a tissue-engineering process and present basic principles and requirements for bioreactor development. Moreover, the use of bioreactor systems for the expansion of clinically relevant cell types is addressed. In contrast to cell expansion, for the generation of functional three-dimensional tissue equivalents, additional physical cues must be provided. Therefore, bioreactors for musculoskeletal tissue engineering are discussed. Finally, bioreactor technology is reviewed in the context of commercial constraints.     

The Involvement of Mitochondrial Amidoxime Reducing Components 1 and 2 and Mitochondrial Cytochrome b5 in N-Reductive Metabolism in Human Cells

The mitochondrial amidoxime reducing component mARC is a recently discovered molybdenum enzyme in mammals. mARC is not active as a standalone protein, but together with the electron transport proteins NADH-cytochrome b₅ reductase (CYB5R) and cytochrome b₅ (CYB5), it catalyzes the reduction of N-hydroxylated compounds such as amidoximes. The mARC-containing enzyme system is therefore considered to be responsible for the activation of amidoxime prodrugs. All hitherto analyzed mammalian genomes code for two mARC genes (also referred to as MOSC1 and MOSC2), which share high sequence similarities. By RNAi experiments in two different human cell lines, we demonstrate for the first time that both mARC proteins are capable of reducing N-hydroxylated substrates in cell metabolism. The extent of involvement is highly dependent on the expression level of the particular mARC protein. Furthermore, the mitochondrial isoform of CYB5 (CYB5B) is clearly identified as an essential component of the mARC-containing N-reductase system in human cells. The participation of the microsomal isoform (CYB5A) in N-reduction could be excluded by siRNA-mediated down-regulation in HEK-293 cells and knock-out in mice. Using heme-free apo-CYB5, the contribution of mitochondrial CYB5 to N-reductive catalysis was proven to strictly depend on heme. Finally, we created recombinant CYB5B variants corresponding to four nonsynonymous single nucleotide polymorphisms (SNPs). Investigated mutations of the heme protein seemed to have no significant impact on N-reductive activity of the reconstituted enzyme system.     

Life Cycle Impacts and Benefits of Wood along the Value Chain: The Case of Switzerland

Sustainable use of wood may contribute to coping with energy and material resource challenges. The goal of this study is to increase knowledge of the environmental effects of wood use by analyzing the complete value chain of all wooden goods produced or consumed in Switzerland. We start from a material flow analysis of current wood use in Switzerland. Environmental impacts related to the material flows are evaluated using life cycle assessment–based environmental indicators. Regarding climate change, we find an overall average benefit of 0.5 tonnes carbon dioxide equivalent per cubic meter of wood used. High environmental benefits are often achieved when replacing conventional heat production and energy‐consuming materials in construction and furniture. The environmental performance of wood is, however, highly dependent on its use and environmental indicators. To exploit the mitigation potential of wood, we recommend to (1) apply its use where there are high substitution benefits like the replacement of fossil fuels for energy or energy‐intensive building materials, (2) take appropriate measures to minimize negative effects like particulate matter emissions, and (3) keep a systems perspective to weigh effects like substitution and cascading against each other in a comprehensive manner. The results can provide guidance for further in‐depth studies and prospective analyses of wood‐use scenarios.     

TNF but not Fas ligand provides protective anti-L. major immunity in C57BL/6 mice

The pro-inflammatory cytokine TNF is essential for a protective immune response to some but not all strains of Leishmania major. TNF-deficient mice of a resistant genetic background succumbed rapidly to an infection with L. major BNI. Another member of the TNF superfamily, Fas ligand (FasL), has also been reported to be critical for the immune response to L. major. To test the relative importance of TNF versus FasL for the control of L. major BNI, we infected wildtype C57BL/6 (B6.WT), B6.TNF(-/-), B6.gld and C57BL/6.gld x TNF(-/-) (B6.gld.TNF(-/-)) double-negative mice. Visceral, fatal disease was only observed in B6.TNF(-/-) mice, but not in B6 gld mice. The course of infection and the immune response of B6.gld.TNF(-/-) mice were similar to those of B6.TNF(-/-) mice. B6.gld.TNF(-/-) mice had a high tissue parasite burden and expressed prominent amounts of inducible nitric oxide synthase (iNOS) in the skin, the lymph nodes (LN) and the spleen as previously reported for B6.TNF(-/-) mice, whereas the tissue parasite load and the iNOS expression of B6.gld mice resembled that of B6.WT controls. Neither the TNF- nor the FasL-deficiency exerted a detectable intrinsic effect on the proliferation of T cells. Thus, TNF, but not FasL is essential for the control of L. major BNI. The discrepancy between these and other published data are most likely due to the use of different strains of the pathogen.     

Orange luminescence of α-Al2O3 related to clusters consisting of F centers and divalent cations

The orange luminescence of α-Al₂O₃ under UV excitation is characterized by a 2.07-eV orange broadband emission that has not yet been elucidated. This emission is present in natural and synthetic crystals and powders, as well as in Be-treated samples. All orange-luminescent materials have low Fe concentration (mostly <1000 ppm) with traces of divalent cations, mostly Mg, or Be in Be-diffused material (dozens of ppm). Mg²⁺, Mn²⁺, and Be²⁺ cations substitute for trivalent Al. To accommodate the charge deficit, several defects are created, including oxygen vacancies also called F centers. Indeed, our excitation spectra revealed the presence of several different F centers (F, F⁺, and clustered F₂, F₂⁺, F₂²⁺) in those samples. However, the thermal stability and the measured luminescence lifetimes do not match with previously reported characteristics of isolated F centers. Based on our experiments, we suggest that a complex aggregate of two F centers (F₂²⁺) trapped at divalent cations is a major cause of this uncommon microsecond lifetime emission, even if a variety of other defects, including Cr³⁺, V³⁺, or interstitial Al³⁺, are present.     

Monogene Formen der arteriellen Hypertonie

medizinische genetik - Die Grundlage der arteriellen Hypertonie bei der überwiegenden Mehrzahl der Patienten ist multifaktorieller, zum großen Teil umweltbedingter Genese und derzeit in...