Anatomically distinct activation of endothelin-3 and the L-arginine/nitric oxide pathway in the kidney with advanced aging

Aging is associated with spontaneous degenerative changes of renal function and structure. The aim of this study was to determine changes of the endothelin (ET) system and NO tissue bioactivity during the physiological aging process. Renal protein expression of ET-1 and ET-3, ETA, and ETB receptor mRNA expression, ET receptor binding and distribution, and tissue NO metabolite content were determined in adult, middle-aged, and senescent normotensive female Wistar rats. In senescent animals, medullary ET-3 content increased 3.4-fold (p<0.05 vs. adult), whereas aging did not affect ET-3 levels in the cortex. Local NO bioavailability, determined by NO metabolite tissue measurements, decreased in the cortex only. ET receptor binding capacity--predominantly due to ETB receptor binding--was lower in medulla than in cortex. Aging had no effect on ET-1 binding capacity or ET receptor distribution, whereas with advanced age gene expression of both receptors decreased. In conclusion, aging causes distinctive expressional changes of the renal endothelin system in otherwise healthy rats. The pronounced increase of endothelin-3 in the renal medulla is associated with preservation of local NO metabolite levels, changes not observed in the cortex. These findings could be important for pathologies and possibly therapy associated with renal aging.     

Structural insights into the interaction of ROCKI with the switch regions of RhoA

The Rho-ROCK pathway modulates the phosphorylation level of a variety of important signaling proteins and is thereby involved in miscellaneous cellular processes including cell migration, neurite outgrowth, and smooth muscle contraction. The observation of the involvement of the Rho-ROCK pathway in tumor invasion and in diseases such as hypertension and bronchial asthma makes it an interesting target for drug development. We herein present the crystal structure of the complex between active RhoA and the Rho-binding domain of ROCKI. The Rho-binding domain structure forms a parallel alpha-helical coiled-coil dimer and, in contrast to the published Rho-protein kinase N structure, binds exclusively to the switch I and II regions of the guanosine 5'-(beta,gamma-imido)triphosphate-bound RhoA. The switch regions of two different RhoA molecules form a predominantly hydrophobic patch, which is complementarily bound by two identical short helices of 13 residues (amino acids 998-1010). The identified ROCK-binding site of RhoA strikingly supports the assumption of a common consensus-binding site for effector recognition.     

Tumor stroma-associated antigens for anti-cancer immunotherapy

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell survival seem to be more suitable therapeutic targets. However, even such antigens may be subject to immune evasion due to impaired processing and cell surface expression. Since development and progression of tumors is not only dependent on cancer cells themselves but also on the active contribution of the stromal cells, e.g. by secreting growth supporting factors, enzymes degrading the extracellular matrix or angiogenic factors, the tumor stroma may also serve as a target for immune intervention. To this end several antigens have been identified which are induced or upregulated on the tumor stroma. Tumor stroma-associated antigens are characterized by an otherwise restricted expression pattern, particularly with respect to differentiated tissues, and they have been successfully targeted by passive and active immunotherapy in preclinical models. Moreover, some of these strategies have already been translated into clinical trials.     

Sex ratio in populations of Silene otites in relation to vegetation cover,population size and fungal infection

Abstract. In contrast to populations of most dioecious Silene species (which usually are female-biased), populations of Silene otites have been frequently reported to be male-biased. We describe sex ratio variation in 34 natural S. otites populations in Central Germany in relation to vegetation cover, population size and fungal infection. The overall sex ratio was unbiased in 1994 and only slightly male-biased in 1995. Sex ratio varied among the populations from 26.6 % to 72.6 % females. The sex ratio of small populations varied strongly due to stochastic processes. Furthermore, we found that populations in habitats with high vegetation cover contained a higher percentage of females. Hermaphroditic plants, theoretically, could increase male bias as they only produce male or hermaphroditic offspring. Their frequency in the populations, however, was far too low to affect sex ratio. In 1994 12.1 % and in 1995 17.0 % of the plants were infected by the smut fungus Ustilago major. Disease incidence in the population was not related to sex ratio, suggesting equal susceptibility of males and females. The sex ratio of partially infected plants did not deviate from the population sex ratio, both under field conditions and in a greenhouse laboratory experiment. The results suggest that the frequently reported male bias in Silene otites populations is not a general pattern, but is mainly caused by environmental conditions.     

DieTabulae Rhodologicae von Gandoger

Ohne Zusammenfassung     

Evolution of a Mitochondrial CytochromebGene Sequence in the Species-Rich GenusSebastes(Teleostei, Scorpaenidae) and Its Utility in Testing the Monophyly of the SubgenusSebastomus

The ecologically diverse and species-rich rockfishes (Sebastes) are a useful group for the study of marine speciation. The monophyly of the genus is generally accepted, as is the validity of most of the numerous species found along the West Coast of North America. However, the subgeneric groupings that would help in the proposal and interpretation of various speciation schemes are poorly supported based on widely overlapping morphological characters. The use of genetic characters provides an alternative approach. In this study, we present the first quantitative analysis supporting the monophyly of all 14 species of the subgenusSebastomusamong 54 congeners. The structural features and evolution of the 750 bp of the cytochromebgene used to test the monophyly were similar to those of other vertebrates. Low levels of intrageneric sequence divergence (<10%) and incipient levels of saturation at third-codon positions were found in the gene. The monophyly ofSebastomuswas supported in extensive phylogenetic analyses using distance, cladistic, and likelihood methods. Further corroboration was obtained from permutation- and simulation-based statistical tests.