Accumulation of nuclear DNA damage or neuron loss: molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.     

From virgin education to real education

The now famous virgin headspace experiment from late Braja D. Mookherjee and Subha Patel, and its use in the creation of scent 'Virgin No 1' by Christophe Laudamiel and Christoph Hornetz for the novel by Patrick Süskind, and the movie by Tom Tykwer 'Perfume--The Story of a Murderer' (Constantin Film-Thierry Mugler Parfums-IFF, 2006) is discussed. Another fragrance from the luxury coffret, 'Salon Rouge', is described as well, illustrating how molecules and natural ingredients can be utilized, not only to create innovative or artistic fragrance compositions, but also to provide fundamental consumer education, improving the public image both of Chemistry and Perfumery.     

High-impact sulfur compounds: constitutional and configurational assignment of sulfur-containing heterocycles

To unambiguously identify their structures and to evaluate their organoleptic properties, several constitutional und configurational isomers of dialkyl-tetrathianes and dialkyl-pentathiepanes were synthesized by two different synthetic protocols, and separated by preparative gas chromatography. Raman and NMR spectroscopy were used to differentiate between the constitutional 3,6-dialkyl-1,2,4,5-tetrathiane and the 4,6-dialkyl-1,2,3,5-tetrathiane isomers. Furthermore, cis- and trans-isomers of 3,6-dialkyl-1,2,4,5-tetrathianes were distinguished by temperature-dependent NMR experiments. Static, quantum-chemical simulations of the NMR spectra for these cis- and trans-isomers were calculated in the gas layer in order to confirm our experimental assignments. In addition, the assignment of 4,7-alkyl-1,2,3,5,6-pentathiepanes were deducted from their Raman spectra. Dialkyl-tetrathianes and dialkyl-pentathiepanes are interesting components to be used in flavor applications due to their unique olfactory impact and facets.     

Effect of emulsified feeding of oily substrate via submerged ceramic membranes on surfactant production in <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> fermentation

Aqueous two-phase systems often face mass transfer limitations due to very poor miscibility of the fluids, and to enhance the homogeneity (or emulsification) in the reaction volume, high energy inputs are required which result in high shear forces in the culture medium. For the purposes of emulsification, microporous systems have advantages over other conventional methods due to mild operating conditions and narrow droplet-size distribution. In this study, emulsification within the culture volume was achieved by feeding the oily substrate (dispersed phase) into the aqueous medium (dispersion phase) via ceramic membranes integrated in the bioreactor. The method was investigated for bioprocesses aimed at producing rhamnolipids and polyhydroxyalkanoates (PHA). Better homogenization of the mixed volume and hence improved consumption of oily substrate was successful. Surfactants are produced by various bacterial cultures, especially Pseudomonas aeruginosa species, when oil is present as the only carbon source. Are surfactants produced only as a result of bacteria feeding on the oily substrate, or as a requirement to feed on the oily substrate, owing to their surface-active characteristics? This paper also intends to draw some conclusions in this respect.     

2-D DIGE analyses of enriched secretory lysosomes reveal heterogeneous profiles of functionally relevant proteins in leukemic and activated human NK cells

As part of the innate immune system, natural killer (NK) cells detect and lyse tumor and virus-infected cells without prior antigen-dependent recognition and expansion. To this end, they utilize dual-function organelles that combine properties of conventional lysosomes and exocytotic vesicles. Upon stimulation, these secretory lysosomes (SLs) release their cytotoxic molecules into the immunological synapse. In addition, several molecules associated with secretory vesicles become exposed on the plasma membrane. Recent studies often took advantage of the few established NK cell lines, for instance to analyze the exocytotic machinery associated with NK cell vesicles. NK cell lines and primary NK cells differ, however, substantially in the expression of "typical" surface receptors and their requirements to induce target cell lysis. Here, we directly compared the lysosomal compartments of different NK cell populations. We enriched SLs of two leukemic cell lines (YTS and NKL) and IL-2-expanded NK cells by subcellular fractionation and characterized their proteome by 2-D difference gel electrophoresis and MS. Although the overall protein composition of the lysosomal preparations was very similar and more than 90% of the proteins were present at comparable levels, we define a cell line-specific setup of functionally relevant proteins involved in antigen presentation and cytotoxic effector function.     

Arginine-induced conformational change in the c-ring/a-subunit interface of ATP synthase

The rotational mechanism of ATP synthases requires a unique interface between the stator a subunit and the rotating c-ring to accommodate stability and smooth rotation simultaneously. The recently published c-ring crystal structure of the ATP synthase of Ilyobacter tartaricus represents the conformation in the absence of subunit a. However, in order to understand the dynamic structural processes during ion translocation, studies in the presence of subunit a are required. Here, by intersubunit Cys-Cys cross-linking, the relative topography of the interacting helical faces of subunits a and c from the I. tartaricus ATP synthase has been mapped. According to these data, the essential stator arginine (aR226) is located between the c-ring binding pocket and the cytoplasm. Furthermore, the spatially vicinal residues cT67C and cG68C in the isolated c-ring structure yielded largely asymmetric cross-linking products with aN230C of subunit a, suggesting a small, but significant conformational change of binding-site residues upon contact with subunit a. The conformational change was dependent on the positive charge of the stator arginine or the aR226H substitution. Energy-minimization calculations revealed possible modes for the interaction between the stator arginine and the c-ring. These biochemical results and structural restraints support a model in which the stator arginine operates as a pendulum, moving in and out of the binding pocket as the c-ring rotates along the interface with subunit a. This mechanism allows efficient interaction between subunit a and the c-ring and simultaneously allows almost frictionless movement against each other.     

Genetic covariation between effectiveness and cost of defence in aphids

Ecological immunology distinguishes between the long-term evolutionary costs of possessing defences against parasites and the short-term costs of using them. Evolutionary biologists have typically focused on the former in the search for constraints on the evolution of resistance. Here, we show in the peach-potato aphid, Myzus persicae, that short-term costs may be of equal evolutionary importance. Survivors of more resistant aphid clones suffered a higher reduction of fecundity upon parasitoid attack than survivors of more susceptible clones. This genetically based trade-off between benefits and costs of defence may limit the evolution of increased resistance and explain the maintenance of genetic variation for resistance under environmental variation in parasitism risk.     

Severe thrombocytosis and anemia associated with celiac disease in a young female patient: a case report

Introduction

Platelet counts exceeding 1.000 × 10³/μl are usually considered secondary to another cause, particularly to chronic myeloproliferative disease (CMPD). Reactive thrombocytosis due to iron deficiency rarely exceeds platelet counts of 700 × 10³/μl.

Case presentation

Here we report the case of a young woman presenting with clinical signs of severe anemia. Laboratory findings confirmed an iron-deficiency anemia associated with severe thrombocytosis of 1703 × 10³/μl. Macroscopic gastrointestinal and genitourinary tract bleeding was excluded. The excessive elevation of platelets, slightly elevated lactate dehydrogenase and slightly elevated leukocytes along with the absence of other inflammation parameters raised the suspicion of an underlying hematological disease. However, bone marrow evaluation could not prove the suspected diagnosis of a CMPD, especially essential thrombocythemia (ET). In the further clinical course the platelet count returned to normal after raising the hemoglobin to a level close to normal range with erythrocyte transfusion, and normalization of serum iron and decline of erythropoietin. Finally, following small bowel biopsy, despite the absence of typical clinical signs, celiac disease was diagnosed. After discharge from hospital the patient was commenced on a gluten-free diet and her hemoglobin almost completely normalized in the further follow-up period.

Conclusion

This case illustrates the rare constellation of an extreme thrombocytosis most likely secondary to iron deficiency due to celiac disease. This represents, to the best of the authors' knowledge, the highest reported platelet count coincident with iron deficiency. A potential mechanism for the association of iron-deficiency anemia and thrombocytosis is discussed. Even in the presence of 'atypically' high platelets one should consider the possibility of reactive thrombocytosis. Extreme thrombocytosis could emerge in the case of iron deficiency secondary to celiac disease.