A Time-Calibrated Road Map of Brassicaceae Species Radiation and Evolutionary History

The Brassicaceae include several major crop plants and numerous important model species in comparative evolutionary research such as Arabidopsis, Brassica, Boechera, Thellungiella, and Arabis species. As any evolutionary hypothesis needs to be placed in a temporal context, reliably dated major splits within the evolution of Brassicaceae are essential. We present a comprehensive time-calibrated framework with important divergence time estimates based on whole-chloroplast sequence data for 29 Brassicaceae species. Diversification of the Brassicaceae crown group started at the Eocene-to-Oligocene transition. Subsequent major evolutionary splits are dated to ∼20 million years ago, coinciding with the Oligocene-to-Miocene transition, with increasing drought and aridity and transient glaciation events. The age of the Arabidopsis thaliana crown group is 6 million years ago, at the Miocene and Pliocene border. The overall species richness of the family is well explained by high levels of neopolyploidy (43% in total), but this trend is neither directly associated with an increase in genome size nor is there a general lineage-specific constraint. Our results highlight polyploidization as an important source for generating new evolutionary lineages adapted to changing environments. We conclude that species radiation, paralleled by high levels of neopolyploidization, follows genome size decrease, stabilization, and genetic diploidization.     

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections, and inflammation. Although its contribution in translational regulation of proline repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with haploinsufficiency. Network-based bioinformatic analysis of proline repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine-modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide the first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer.     

Neutral Sphingomyelinase in Physiological and Measles Virus Induced T Cell Suppression

T cell paralysis is a main feature of measles virus (MV) induced immunosuppression. MV contact mediated activation of sphingomyelinases was found to contribute to MV interference with T cell actin reorganization. The role of these enzymes in MV-induced inhibition of T cell activation remained equally undefined as their general role in regulating immune synapse (IS) activity which relies on spatiotemporal membrane patterning. Our study for the first time reveals that transient activation of the neutral sphingomyelinase 2 (NSM2) occurs in physiological co-stimulation of primary T cells where ceramide accumulation is confined to the lamellum (where also NSM2 can be detected) and excluded from IS areas of high actin turnover. Genetic ablation of the enzyme is associated with T cell hyper-responsiveness as revealed by actin dynamics, tyrosine phosphorylation, Ca²⁺-mobilization and expansion indicating that NSM2 acts to suppress overshooting T cell responses. In line with its suppressive activity, exaggerated, prolonged NSM2 activation as occurring in co-stimulated T cells following MV exposure was associated with aberrant compartmentalization of ceramides, loss of spreading responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression.     

Importance of flagella in acute and chronic Pseudomonas aeruginosa infections

Pseudomonas aeruginosa is an environmental microorganism and a causative agent of diverse acute and chronic, biofilm-associated infections. Advancing research-based knowledge on its adaptation to conditions within the human host is bound to reveal novel strategies and targets for therapeutic intervention. Here, we investigated the traits that P. aeruginosa PA14 as well as a virulence attenuated ΔlasR mutant need to survive in selected murine infection models. Experimentally, the genetic programs that the bacteria use to adapt to biofilm-associated versus acute infections were dissected by passaging transposon mutant libraries through mouse lungs (acute) or mouse tumours (biofilm-infection). Adaptive metabolic changes of P. aeruginosa were generally required during both infection processes. Counter-selection against flagella expression was observed during acute lung infections. Obviously, avoidance of flagella-mediated activation of host immunity is advantageous for the wildtype bacteria. For the ΔlasR mutant, loss of flagella did not confer a selective advantage. Apparently, other pathogenesis mechanisms are active in this virulence attenuated strain. In contrast, the infective process of P. aeruginosa in the chronic biofilm model apparently required expression of flagellin. Together, our findings imply that the host immune reactions against the infectious agent are very decisive for acuteness and duration of the infectious disease. They direct disease outcome.     

Ferroxidases and xanthine oxidase in plasma of healthy newborn infants

In the neonatal period, there is a high iron load, while both the level and molar oxidase activity of ceruloplasmin are low. On the other hand, the neonatal xanthine oxidase (XO) activity is higher than later in life and XO has a significant iron-oxidizing capacity. We therefore studied the physiological contribution of XO to the ferroxidase activity of the plasma in 20 full-term newborn infants. Ferroxidase activity was measured spectrophotometrically, with Fe⁺⁺ as substrate. The uric acid formed by XO was assayed by means of HPLC, with electrochemical detection.

The total ferroxidase activity in the plasma was about one-fourth of the adult level and rapidly increased doubling within 3 days after birth. About 90% of the plasma ferroxidase activity was due to ceruloplasmin, the remainder being accounted for by ferroxidase II. The XO activity underwent a 30% (statistically non-significant) elevation at 24 h, though ferroxidase activity attributable to XO was not detected at any time.

Accordingly, XO does not seem to add substantially to the total iron-oxidizing capacity of the plasma in the neonatal period. The high molar ferroxidase activity is probably of importance at the endothelial cell surface.     

Structural and Functional Alterations in Right Dorsomedial Prefrontal and Left Insular Cortex Co-Localize in Adolescents with Aggressive Behaviour: An ALE Meta-Analysis

Recent neuroimaging work has suggested that aggressive behaviour (AB) is associated with structural and functional brain abnormalities in processes subserving emotion processing and regulation. However, most neuroimaging studies on AB to date only contain relatively small sample sizes. To objectively investigate the consistency of previous structural and functional research in adolescent AB, we performed a systematic literature review and two coordinate-based activation likelihood estimation meta-analyses on eight VBM and nine functional neuroimaging studies in a total of 783 participants (408 [224AB/184 controls] and 375 [215 AB/160 controls] for structural and functional analysis respectively). We found 19 structural and eight functional foci of significant alterations in adolescents with AB, mainly located within the emotion processing and regulation network (including orbitofrontal, dorsomedial prefrontal and limbic cortex). A subsequent conjunction analysis revealed that functional and structural alterations co-localize in right dorsomedial prefrontal cortex and left insula. Our results are in line with meta-analytic work as well as structural, functional and connectivity findings to date, all of which make a strong point for the involvement of a network of brain areas responsible for emotion processing and regulation, which is disrupted in AB. Increased knowledge about the behavioural and neuronal underpinnings of AB is crucial for the development of novel and implementation of existing treatment strategies. Longitudinal research studies will have to show whether the observed alterations are a result or primary cause of the phenotypic characteristics in AB.     

Search for seasonality in occurrence of parasites of cod,Gadus morhua L. in a fjord at 70°N

Samples of cod from the subarctic fjord, Balsfjord, in Norway, were collected in spring, summer and autumn from spring 1986 to spring 1987. The macroparasite fauna was investigated for seasonality in prevalence, mean intensity and abundance. Anisakis simplex had maximum mean intensity and abundance in the autumn. Echinorhynchus gadi had minimum prevalence, mean intensity and abundance in the autumn, but this was not statistically significant. None of the remaining 11 species of parasites demonstrated seasonality according to our definition.