Expression of RAGE and HMGB1 in Thymic Epithelial Tumors,Thymic Hyperplasia and Regular Thymic Morphology

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall''s corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.     

Wedged between bottom-up and top-down processes: aphids on tansy

Abstract. 1. Many species of aphids exploit a single host‐plant species and have to cope with changing environmental conditions. They often vary greatly in abundance even when feeding on the same host. In a field experiment, the bottom‐up (plant quality/patch type frequency) and top‐down (ant attendance/predation) effects on the abundance of four species of aphids feeding on tansy (Tanacetum vulgare) were tested using a full factorial design. In addition, a model was used to examine these patch characteristics for their relative effects on the population dynamics and abundance of different aphid species. 2. Aphid numbers changed significantly depending on the quality of the host plant and the presence/absence of attending ants. The obligate myrmecophile, Metopeurum fuscoviride, was abundant on high‐quality plants, while on poor quality plants or on plants without attending ants these aphids did not survive until the end of the experiment. The facultative myrmecophiles, Aphis fabae and Brachycaudus cardui, and the unattended aphid species, Macrosiphoniella tanacetaria, all reached similar peak population densities, but M. tanacetaria did best in poor quality patches. 3. Natural enemies reduced aphid numbers, but those species feeding on high‐quality plants survived longer than those on poor‐quality plants, which existed only for a short period of time, especially when associated with ants. Losses due to migration of winged morphs and mortality caused by parasitoids were insignificant. 4. Varying the frequency of different patch types in a model indicates that different degrees of associations with ants are favoured in different environments. If the proportion of high‐quality patches in a habitat is large, obligate myrmecophiles do best. On increasing the number of poor‐quality patches, unattended species become more abundant. 5. The results suggest that, in spite of large species specific differences in growth rates, degree of myrmecophily or life cycle features, the temporal and spatial variability in top‐down and bottom‐up forces differentially affects aphid species and allows the simultaneous exploitation of a shared host‐plant species.     

Biological Markers of Auditory Gap Detection in Young,Middle-Aged,and Older Adults

The capability of processing rapid fluctuations in the temporal envelope of sound declines with age and this contributes to older adults'' difficulties in understanding speech. Although, changes in central auditory processing during aging have been proposed as cause for communication deficits, an open question remains which stage of processing is mostly affected by age related changes. We investigated auditory temporal resolution in young, middle-aged, and older listeners with neuromagnetic evoked responses to gap stimuli with different leading marker and gap durations. Signal components specific for processing the physical details of sound stimuli as well as the auditory objects as a whole were derived from the evoked activity and served as biological markers for temporal processing at different cortical levels. Early oscillatory 40-Hz responses were elicited by the onsets of leading and lagging markers and indicated central registration of the gap with similar amplitude in all three age groups. High-gamma responses were predominantly related to the duration of no-gap stimuli or to the duration of gaps when present, and decreased in amplitude and phase locking with increasing age. Correspondingly, low-frequency activity around 200 ms and later was reduced in middle aged and older participants. High-gamma band, and long-latency low-frequency responses were interpreted as reflecting higher order processes related to the grouping of sound items into auditory objects and updating of memory for these objects. The observed effects indicate that age-related changes in auditory acuity have more to do with higher-order brain functions than previously thought.     

Oryctes rhinoceros populations and behavior influenced by a baculovirus

Oryctes rhinoceros adults stopped feeding and flew less frequently, and the males mated less often after they became infected with the baculovirus of Oryctes. Monitoring the larval and adult population in Western Samoa over several years gave evidence that the incidence of the virus is dependent on the density of the O. rhinoceros population. Male beetles were more frequently infected than female bettles. Adding more virus-infected beetles to the O. rhinoceros populations of Nukunonu Atoll, where the virus had become established 5 years earlier, reduced the population significantly. The data indicated that the reduction was caused mainly by a decrease in the number of eggs deposited.     

Metabolic systems biology

The first full genome sequences were established in the mid-1990s. Shortly thereafter, genome-scale metabolic network reconstructions appeared. Since that time, we have witnessed an exponential growth in their number and uses. Here I discuss, from a personal point of view, four topics: (1) the placement of metabolic systems biology in the context of broader scientific developments, (2) its foundational concepts, (3) some of its current uses, and (4) some of the expected future developments in the field.     

Tamoxifen and raloxifene modulate gap junction coupling during early phases of retinoic acid-dependent neuronal differentiation of NTera2/D1 cells

Gap junctions (GJ) represent a cellular communication system known to influence neuronal differentiation and survival. To assess a putative role of this system for neural effects of tamoxifen (TAM) and raloxifene (RAL), we used the human teratocarcinoma cell line NTera2/D1, retinoic acid (RA)-dependent neuronal differentiation of which is regulated by gap junctions formed of connexin43 (Cx43). As demonstrated by Western blot analysis, concentrations above 1 μmol/l for TAM, and 0.1 μmol/l for RAL lead to a temporary time- and concentration-dependent increase in Cx43 immunoreactivity, which reached a peak for TAM after 1 day and for RAL after 2 days. Immunocytochemical stainings revealed the increase in Cx43 immunoreactivity to result from an accumulation in intracellular compartments such as the Golgi apparatus or lysosomes. In addition, TAM and RAL were able to prevent the RA-dependent decrease of Cx43 immunoreactivity in NTera2/D1 cells, normally observed during neuronal differentiation. This suggested a suppression of neuronal differentiation to result from these substances. According to this, treatment of NTera2/D1 cells with 10 μmol/l TAM or RAL during weeks 1 and 2 of a 6 weeks RA-driven differentiation schedule impaired, whereas treatment during weeks 5 and 6 did not impair, neuronal differentiation of these cells. Modulation of GJ coupling between NTera2/D1 cells by TAM and RAL seems therefore to perturb early neuronal differentiation, whereas differentiated neurons in the mature brain seem to be not affected. These effects could be of importance for actions of TAM and RAL on early embryonic steps of nervous system formation.     

PhysioSpace: Relating Gene Expression Experiments from Heterogeneous Sources Using Shared Physiological Processes

Relating expression signatures from different sources such as cell lines, in vitro cultures from primary cells and biopsy material is an important task in drug development and translational medicine as well as for tracking of cell fate and disease progression. Especially the comparison of large scale gene expression changes to tissue or cell type specific signatures is of high interest for the tracking of cell fate in (trans-) differentiation experiments and for cancer research, which increasingly focuses on shared processes and the involvement of the microenvironment. These signature relation approaches require robust statistical methods to account for the high biological heterogeneity in clinical data and must cope with small sample sizes in lab experiments and common patterns of co-expression in ubiquitous cellular processes. We describe a novel method, called PhysioSpace, to position dynamics of time series data derived from cellular differentiation and disease progression in a genome-wide expression space. The PhysioSpace is defined by a compendium of publicly available gene expression signatures representing a large set of biological phenotypes. The mapping of gene expression changes onto the PhysioSpace leads to a robust ranking of physiologically relevant signatures, as rigorously evaluated via sample-label permutations. A spherical transformation of the data improves the performance, leading to stable results even in case of small sample sizes. Using PhysioSpace with clinical cancer datasets reveals that such data exhibits large heterogeneity in the number of significant signature associations. This behavior was closely associated with the classification endpoint and cancer type under consideration, indicating shared biological functionalities in disease associated processes. Even though the time series data of cell line differentiation exhibited responses in larger clusters covering several biologically related patterns, top scoring patterns were highly consistent with a priory known biological information and separated from the rest of response patterns.