Intracellular positioning of isoforms explains an unusually large adenylate kinase gene family in the parasite Trypanosoma brucei

Adenylate kinases occur classically as cytoplasmic and mitochondrial enzymes, but the expression of seven adenylate kinases in the flagellated protozoan parasite Trypanosoma brucei (order, Kinetoplastida; family, Trypanosomatidae) easily exceeds the number of isoforms previously observed within a single cell and raises questions as to their location and function. We show that a requirement to target adenylate kinase into glycosomes, which are unique kinetoplastid-specific microbodies of the peroxisome class in which many reactions of carbohydrate metabolism are compartmentalized, and two different flagellar structures as well as cytoplasm and mitochondrion explains the expansion of this gene family in trypanosomes. The three isoforms that are selectively built into either the flagellar axoneme or the extra-axonemal paraflagellar rod, which is essential for motility, all contain long N-terminal extensions. Biochemical analysis of the only short form trypanosome adenylate kinase revealed that this enzyme catalyzes phosphotransfer of gamma-phosphate from ATP to AMP, CMP, and UMP acceptors; its high activity and specificity toward CMP is likely to reflect an adaptation to very low intracellular cytidine nucleotide pools. Analysis of some of the phosphotransfer network using RNA interference suggests considerable complexity within the homeostasis of cellular energetics. The anchoring of specific adenylate kinases within two distinct flagellar structures provides a paradigm for metabolic organization and efficiency in other flagellates.     

Potential mechanisms of avian sex manipulation

The aim of this review is to consider the potential mechanisms birds may use to manipulate the sex of their progeny, and the possible role played by maternal hormones. Over the past few years there has been a surge of reports documenting the ability of birds to overcome the rigid process of chromosomal sex determination. However, while many of these studies leave us in little doubt that mechanisms allowing birds to achieve this feat do exist, we are only left with tantalizing suggestions as to what the precise mechanism or mechanisms may be. The quest to elucidate them is made no easier by the fact that a variety of environmental conditions have been invoked in relation to sex manipulation, and there is no reason to assume that any particular mechanism is conserved among the vast diversity of species that can achieve it. In fact, a number of intriguing proposals have been put forward. We begin by briefly reviewing some of the most recent examples of this phenomenon before highlighting some of the more plausible mechanisms, drawing on recent work from a variety of taxa. In birds, females are the heterogametic sex and so non-Mendelian segregation of the sex chromosomes could conceivably be under maternal control. Another suggestion is that follicles that ultimately give rise to males and females grow at different rates. Alternatively, the female might selectively abort embryos or 'dump lay' eggs of a particular sex, deny certain ova a chance of ovulation, fertilization or zygote formation, or selectively provision eggs so that there is sex-specific embryonic mortality. The ideas outlined in this review provide good starting points for testing the hypotheses both experimentally (behaviourally and physiologically) and theoretically.     

IncP-1 R plasmids decrease the serum resistance and the virulence of Pseudomonas aeruginosa

Pseudomonas aeruginosa strain PAO1 was compared to PAO1 strains containing an IncP-1 R plasmid (RP1, R68, or R68.45) in an experimental mouse burn infection model. All R plasmids tested caused a 10- to 400-fold increase in mean lethal dose (LD50). The decrease in virulence produced by plasmids R68 and R68.45 was significantly greater than the decrease caused by the closely related plasmid RP1. All plasmids also led to an increased sensitivity of strain PAO1 to human serum bactericidal activity. Virulence and serum resistance of strain PAO1 were restored by curing of the entire plasmid R68.45 but not by deletions in the plasmid's transfer gene regions.     

Comparison of proteomic and genomic analyses of the human breast cancer cell line T47D and the antiestrogen-resistant derivative T47D-r

In search of novel mechanisms leading to the development of antiestrogen-resistance in human breast tumors, we analyzed differences in the gene and protein expression pattern of the human breast carcinoma cell line T47D and its derivative T47D-r, which is resistant toward the pure antiestrogen ZM 182780 (Faslodex trade mark, fulvestrant). Affymetrix DNA chip hybridizations on the commercially available HuGeneFL and Hu95A arrays were carried out in parallel to the proteomics analysis where the total cellular protein content of T47D or T47D-r was separated on two-dimensional gels. Thirty-eight proteins were found to be reproducibly up- or down-regulated more than 2-fold in T47D-r versus T47D in the proteomics analysis. Comparison with differential mRNA analysis revealed that 19 of these were up- or down-regulated in parallel with the corresponding mRNA molecules, among which are the protease cathepsin D, the GTPases Rab11a and MxA, and the secreted protein hAG-2. For 11 proteins, the corresponding mRNA was not found to be differentially expressed, and for eight proteins an inverse regulation was found at the mRNA level. In summary, mRNA expression data, when combined with proteomic information, provide a more detailed picture of how breast cancer cells are altered in their antiestrogen-resistant compared with the antiestrogen-sensitive state.     

Plant functional traits capture species richness variations along a flooding gradient

Local species coexistence is the outcome of abiotic and biotic filtering processes which sort species according to their trait values. However, the capacity of trait‐based approaches to predict the variation in realized species richness remains to be investigated. In this study, we asked whether a limited number of plant functional traits, related to the leaf‐height‐seed strategy scheme and averaged at the community level, is able to predict the variation in species richness over a flooding disturbance gradient. We further investigated how these mean community traits are able to quantify the strength of abiotic and biotic processes involved in the disturbance–productivity–diversity relationship. We thus tested the proposal that the deviation between the fundamental species richness, assessed from ecological niche‐based models, and realized species richness, i.e. field‐observed richness, is controlled by species interactions. Flooding regime was determined using a detailed hydrological model. A precise vegetation sampling was performed across 222 quadrats located throughout the flooding gradient. Three core functional traits were considered: specific leaf area (SLA), plant height and seed mass. Species richness showed a hump‐shaped response to disturbance and productivity, but was better predicted by only two mean community traits: SLA and height. On the one hand, community SLA that increased with flooding, controlled the disturbance‐diversity relationship through habitat filtering. On the other hand, species interactions, the strength of which was captured by community height values, played a strong consistent role throughout the disturbance gradient by reducing the local species richness. Our study highlights that a limited number of simple, quantitative, easily measurable functional traits can capture the variation in plant species richness at a local scale and provides a promising quantification of key community assembly mechanisms.     

Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma

A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.