A coiled-coil motif that sequesters ions to the hydrophobic core

Most core residues of coiled coils are hydrophobic. Occasional polar residues are thought to lower stability, but impart structural specificity. The coiled coils of trimeric autotransporter adhesins (TAAs) are conspicuous for their large number of polar residues in position d of the core, which often leads to their prediction as natively unstructured regions. The most frequent residue, asparagine (N@d), can occur in runs of up to 19 consecutive heptads, frequently in the motif [I/V]xxNTxx. In the Salmonella TAA, SadA, the core asparagines form rings of interacting residues with the following threonines, grouped around a central anion. This conformation is observed generally in N@d layers from trimeric coiled coils of known structure. Attempts to impose a different register on the motif show that the asparagines orient themselves specifically into the core, even against conflicting information from flanking domains. When engineered into the GCN4 leucine zipper, N@d layers progressively destabilized the structure, but zippers with 3 N@d layers still folded at high concentration. We propose that N@d layers maintain the coiled coils of TAAs in a soluble, export-competent state during autotransport through the outer membrane. More generally, we think that polar motifs that are both periodic and conserved may often reflect special folding requirements, rather than an unstructured state of the mature proteins.     

The parcellation of cortical areas using replicator dynamics in fMRI

In this paper, we show that replicator dynamics can be used as an exploratory analysis tool to detect subregions of cortical areas on the basis of the similarity between fMRI time series. As similarity measure, we propose to use canonical correlation, a multivariate extension to the typically employed Pearson's correlation coefficient. We applied the replicator process to data obtained from two different experimental paradigms in the search for subregions within the left lateral frontal cortex (LFC). In both cases, the replicator process resulted in a parcellation that corresponds to a recently suggested subdivision of the LFC in anterior-posterior direction. Most notably, these results were very consistent when compared across different measurements of a single subject and across a group of subjects.     

Distal molar movement with Kloehn headgear: is it stable?

The aim of this study was to evaluate intramaxillary molar movement after 8 months of cervical traction and posttreatment displacement 7 years later. The total molar displacements in relation to stable intraosseous reference points were compared with those observed in an untreated control group that also had intraosseous reference indicators inserted. During the headgear period, the type of molar displacement could be predicted by the direction of the force system acting on the teeth. It was noted, however, that the variation in the vertical development was related more to each patient's growth pattern than to the force system applied. After cessation of the headgear, intramaxillary displacement of the molars was noted, and the total displacement of the molars did not differ from that of the untreated group. The indication for intramaxillary displacement of the molars by means of extraoral traction is therefore questioned.     

Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response

Background

Recently, interferon-inducible guanylate binding protein (GBP2) has been discussed as a possible control factor in tumor development, which is controlled by p53, and inhibits NF-Kappa B and Rac protein as well as expression of matrix metalloproteinase 9. However, the potential role that GBP2 plays in tumor development and prognosis has not yet been studied.

Methods

We analyzed whether GBP2 mRNA levels are associated with metastasis-free interval in 766 patients with node negative breast carcinomas who did not receive systemic chemotherapy. Furthermore, response to anthracycline-based chemotherapy was studied in 768 breast cancer patients.

Results

High expression of GBP2 in breast carcinomas was associated with better prognosis in the univariate (P < 0.001, hazard ratio 0.763, 95 % CI 0.650–0.896) as well as in the multivariate Cox analysis (P = 0.008, hazard ratio 0.731, 95 % CI 0.580–0.920) adjusted to the established clinical factors age, pT stage, grading, hormone and ERBB2 receptor status. The association was particularly strong in subgroups with high proliferation and positive estrogen receptor status but did not reach significance in carcinomas with low expression of proliferation associated genes. Besides its prognostic capacity, GBP2 also predicted pathologically complete response to anthracycline-based chemotherapy (P = 0.0037, odds ratio 1.39, 95 % CI 1.11–1.74). Interestingly, GBP2 correlated with a recently established T cell signature, indicating tumor infiltration with T cells (R = 0.607, P < 0.001).

Conclusion

GBP2 is associated with better prognosis in fast proliferating tumors and probably represents a marker of an efficient T cell response.     

CD83 on murine APC does not function as a costimulatory receptor for T cells

The transmembrane glycoprotein CD83 is rapidly upregulated on murine and human DC upon maturation and therefore a costimulatory function for T cell activation has been suggested. Studies employing human APC indeed showed that CD83 expression was positively correlated to the stimulatory capacity of the APC. Murine APC that were CD83 deficient however, did not display a reduced capacity to activate T cells. To elucidate this contradiction, we thoroughly compared the stimulatory capacity of CD83-overexpressing and CD83-deficient APC. Here we show that CD83 expression levels on APC did not affect the capacity of the APC to activate CD8(+) T cells. CD83 expression levels did not significantly affect CD4(+) T cell activation in vivo, but a weak positive correlation of CD83 expression with CD4(+) T cell activation was observed in vitro under suboptimal stimulation conditions. As CD83 expression also positively correlated with MHC-II but not with MHC-I expression, this differential stimulation specifically of CD4(+) T cells could be explained by a higher density of MHC-II peptide complexes on the APC surface. Taken together, our results strongly suggest that CD83 does not deliver crucial costimulatory signals to murine T cells.     

CD83 regulates splenic B cell maturation and peripheral B cell homeostasis

The central function of murine CD83 that is expressed on thymic epithelial cells is to induce the progression of double-positive thymocytes to single CD4-positive T cells. Several lines of evidence suggest an additional role for CD83 in the regulation of peripheral T and B cell responses. Here we show that CD83 is expressed by immature B cells and regulates their further maturation and survival in the periphery. Employing mixed bone marrow chimeras, we compare wild-type, CD83 over-expressing and CD83-deficient B cells within the same host. CD83 over-expression on the immature B cells themselves led to an accumulation of transitional B cells and a reciprocally reduced maturation of follicular B cells that was strictly correlated to the intensity of CD83 over-expression. The absence of CD83 on B cells resulted in a decreased maturation of marginal zone B cells and conferred a mild selection advantage for B cell survival in the periphery. Consenting with these findings, the over-expression of CD83 specifically and dose dependently interfered with homeostasis of B cells while T cell survival was not affected by CD83 over-expression over a period of 30 weeks. Taken together, our data suggest that CD83 negatively regulates B cell maturation and survival.     

Seasonal pattern of Fasciola hepatica antibodies in dairy herds in Northern Germany

Fasciolosis, caused by the liver fluke Fasciola hepatica, is one of the most important parasitoses in cattle farming worldwide. In dairy cows, the trematode leads to economic losses due to decreased milk yield, a negative impact on reproduction parameters, and liver condemnations. In the present study, the seasonal patterns of F. hepatica antibodies in bulk-tank milk from dairy herds located in East Frisia, a region of the federal state Lower Saxony in the north of Germany, were investigated. This region was chosen since it is known as a high risk area for fluke infections due to its coastal location at the North Sea with the consequence of rather moist pastures. Between 669 and 868 bulk-tank milk samples were collected in January, September and November 2008 and 2010, respectively, and analysed for antibodies against F. hepatica with an in-house ELISA based on excretory-secretory antigens of the liver fluke. The overall East Frisian prevalence was 49.1%, 57.1% and 53.9% in January, September and November 2008 and 45.1%, 49.5% and 48.4% in 2010. From a number of 606 farms, which were sampled in all six investigated months, 34.5% of the farms continued to remain positive, whereas 30.9% continued to remain negative. A percentage of 69.1% (419 farms) were positive on at least one sampling occasion during the study period. The distributions of optical density ratio (ODR) values were skewed to the left but showed a second, lower peak in a high ODR range. Statistical analysis revealed a significant difference concerning the prevalence increase from January to September 2008. Furthermore, the prevalence decrease from September as well as November 2008 to these months in 2010 was significantly different, what might result from a more frequent use of anthelminthics or different climatic conditions.     

Enhanced production of low energy electrons by alpha particle impact

Radiation damage to living tissue stems not only from primary ionizing particles but to a substantial fraction from the dissociative attachment of secondary electrons with energies below the ionization threshold. We show that the emission yield of those low energy electrons increases dramatically in ion-atom collisions depending on whether or not the target atoms are isolated or embedded in an environment. Only when the atom that has been ionized and excited by the primary particle impact is in immediate proximity of another atom is a fragmentation route known as interatomic Coulombic decay (ICD) enabled. This leads to the emission of a low energy electron. Over the past decade ICD was explored in several experiments following photoionization. Most recent results show its observation even in water clusters. Here we show the quantitative role of ICD for the production of low energy electrons by ion impact, thus approaching a scenario closer to that of radiation damage by alpha particles: We choose ion energies on the maximum of the Bragg peak where energy is most efficiently deposited in tissue. We compare the electron production after colliding He(+) ions on isolated Ne atoms and on Ne dimers (Ne(2)). In the latter case the Ne atom impacted is surrounded by a most simple environment already opening ICD as a deexcitation channel. As a consequence, we find a dramatically enhanced low energy electron yield. The results suggest that ICD may have a significant influence on cell survival after exposure to ionizing radiation.