Selenoprotein P Status Correlates to Cancer-Specific Mortality in Renal Cancer Patients

Selenium (Se) is an essential trace element for selenoprotein biosynthesis. Selenoproteins have been implicated in cancer risk and tumor development. Selenoprotein P (SePP) serves as the major Se transport protein in blood and as reliable biomarker of Se status in marginally supplied individuals. Among the different malignancies, renal cancer is characterized by a high mortality rate. In this study, we aimed to analyze the Se status in renal cell cancer (RCC) patients and whether it correlates to cancer-specific mortality. To this end, serum samples of RCC patients (n = 41) and controls (n = 21) were retrospectively analyzed. Serum Se and SePP concentrations were measured by X-ray fluorescence and an immunoassay, respectively. Clinical and survival data were compared to serum Se and SePP concentrations as markers of Se status by receiver operating characteristic (ROC) curve and Kaplan-Meier and Cox regression analyses. In our patients, higher tumor grade and tumor stage at diagnosis correlated to lower SePP and Se concentrations. Kaplan-Meier analyses indicated that low Se status at diagnosis (SePP<2.4 mg/l, bottom tertile of patient group) was associated with a poor 5-year survival rate of 20% only. We conclude that SePP and Se concentrations are of prognostic value in RCC and may serve as additional diagnostic biomarkers identifying a Se deficit in kidney cancer patients potentially affecting therapy regimen. As poor Se status was indicative of high mortality odds, we speculate that an adjuvant Se supplementation of Se-deficient RCC patients might be beneficial in order to stabilize their selenoprotein expression hopefully prolonging their survival. However, this assumption needs to be rigorously tested in prospective clinical trials.     

Pleiotropic effects of juvenile hormone in ant queens and the escape from the reproduction–immunocompetence trade-off

The ubiquitous trade-off between survival and costly reproduction is one of the most fundamental constraints governing life-history evolution. In numerous animals, gonadotropic hormones antagonistically suppressing immunocompetence cause this trade-off. The queens of many social insects defy the reproduction–survival trade-off, achieving both an extraordinarily long life and high reproductive output, but how they achieve this is unknown. Here we show experimentally, by integrating quantification of gene expression, physiology and behaviour, that the long-lived queens of the ant Lasius niger have escaped the reproduction–immunocompetence trade-off by decoupling the effects of a key endocrine regulator of fertility and immunocompetence in solitary insects, juvenile hormone (JH). This modification of the regulatory architecture enables queens to sustain a high reproductive output without elevated JH titres and suppressed immunocompetence, providing an escape from the reproduction–immunocompetence trade-off that may contribute to the extraordinary lifespan of many social insect queens.     

Metabolomic database annotations via query of elemental compositions: Mass accuracy is insufficient even at less than 1 ppm

Background  

Metabolomic studies are targeted at identifying and quantifying all metabolites in a given biological context. Among the tools used for metabolomic research, mass spectrometry is one of the most powerful tools. However, metabolomics by mass spectrometry always reveals a high number of unknown compounds which complicate in depth mechanistic or biochemical understanding. In principle, mass spectrometry can be utilized within strategies of de novo structure elucidation of small molecules, starting with the computation of the elemental composition of an unknown metabolite using accurate masses with errors <5 ppm (parts per million). However even with very high mass accuracy (<1 ppm) many chemically possible formulae are obtained in higher mass regions. In automatic routines an additional orthogonal filter therefore needs to be applied in order to reduce the number of potential elemental compositions. This report demonstrates the necessity of isotope abundance information by mathematical confirmation of the concept.     

Recombinant hTRBP and hPACT Modulate hAgo2-Catalyzed siRNA-Mediated Target RNA Cleavage In Vitro

The human TAR RNA-binding protein (hTRBP) and protein activator of protein kinase R (hPACT) are important players in RNA interference (RNAi). Together with hArgonaute2 (hAgo2) and hDicer they have been reported to form the RISC-loading complex (RLC). Among other functions, hTRBP was suggested to assist the loading of hAgo2 with small interfering RNAs (siRNAs) within the RLC. Although several studies have been conducted to evaluate the specific functions of hTRBP and hPACT in RNAi, exact mechanisms and modes of action are still unknown. Here, we present a biochemical study further evaluating the role of hTRBP and hPACT in hAgo2-loading. We found that both proteins enhance hAgo2-mediated RNA cleavage significantly; even a hAgo2 mutant impaired in siRNA binding shows full cleavage activity in the presence of hTRBP or hPACT. Pre-steady state binding studies reveal that the assembly of wildtype-hAgo2 (wt-hAgo2) and siRNAs remains largely unaffected, whereas the binding of mutant hAgo2-PAZ9 to siRNA is restored by adding either hTRBP or hPACT. We conclude that both proteins assist in positioning the siRNA within hAgo2 to ensure optimal binding and cleavage. Overall, our data indicate that hTRBP and hPACT are part of a regulative system of RNAi that is important for efficient target RNA cleavage.     

Population dynamics of intertidal oribatid mites (Acari: Cryptostigmata) from the subtropical archipelago of Bermuda

The population dynamics of the three intertidal oribatid species, Alismobates inexpectatus, Fortuynia atlantica and Carinozetes bermudensis, have been studied on the archipelago of Bermuda over the course of a year. All three species are univoltine, showing a clear seasonal demographic pattern, with reproduction from spring to late autumn and a complete standstill of egg production in winter. A seasonal shift in sex ratio could also be observed in all three species and is supposed to be based on sex-dependent mortality. The subtropical climate of Bermuda allows longer reproductive periods than shown in other intertidal or edaphic temperate species and temperature is supposed to be the main factor influencing the demography of these intertidal dwelling mites. Although all three Bermudian species exhibit the same basic seasonal demographic pattern, there are slight temporal shifts in population dynamics, presumably caused by local microclimatic differences among the populations. Larviparity, shown in other littoral oribatid mites, is clearly absent in the present species.     

Suppression of Electron Transfer to Dioxygen by Charge Transfer and Electron Transfer Complexes in the FAD-dependent Reductase Component of Toluene Dioxygenase

The three-component toluene dioxygenase system consists of an FAD-containing reductase, a Rieske-type [2Fe-2S] ferredoxin, and a Rieske-type dioxygenase. The task of the FAD-containing reductase is to shuttle electrons from NADH to the ferredoxin, a reaction the enzyme has to catalyze in the presence of dioxygen. We investigated the kinetics of the reductase in the reductive and oxidative half-reaction and detected a stable charge transfer complex between the reduced reductase and NAD⁺ at the end of the reductive half-reaction, which is substantially less reactive toward dioxygen than the reduced reductase in the absence of NAD⁺. A plausible reason for the low reactivity toward dioxygen is revealed by the crystal structure of the complex between NAD⁺ and reduced reductase, which shows that the nicotinamide ring and the protein matrix shield the reactive C4a position of the isoalloxazine ring and force the tricycle into an atypical planar conformation, both factors disfavoring the reaction of the reduced flavin with dioxygen. A rapid electron transfer from the charge transfer complex to electron acceptors further reduces the risk of unwanted side reactions, and the crystal structure of a complex between the reductase and its cognate ferredoxin shows a short distance between the electron-donating and -accepting cofactors. Attraction between the two proteins is likely mediated by opposite charges at one large patch of the complex interface. The stability, specificity, and reactivity of the observed charge transfer and electron transfer complexes are thought to prevent the reaction of reductase_TOL with dioxygen and thus present a solution toward conflicting requirements.