Design of antimicrobial compounds based on peptide structures

New antimicrobial compounds are of major importance because of the growing problem of bacterial resistance and antimicrobial peptides have been gaining a lot of interest. Their mechanism of action, however, is often obscure. Here a set of non-peptidic compounds with antimicrobial activity are presented that have been designed based on criteria derived from three-dimensional structures of antimicrobial peptides. Even though only a small set of compounds has been designed, the activity immediately matches that of the original peptides, supporting the proposed criteria for activity, i.e. not the peptidic nature of antimicrobial peptides is responsible for their activity but rather the proper arrangement of the relevant functional groups.     

Interphase microtubules determine the initial alignment of the mitotic spindle

In the fission yeast Schizosaccharomyces pombe, interphase microtubules (MTs) position the nucleus [1, 2], which in turn positions the cell-division plane [1, 3]. It is unclear how the spindle orients, with respect to the predetermined division plane, to ensure that the chromosomes are segregated across this plane. It has been proposed that, during prometaphase, the astral MT interaction with the cell cortex aligns the spindle with the cell axis [4] and also participates in a spindle orientation checkpoint (SOC), which delays entry into anaphase as long as the spindle is misaligned [5-7]. Here, we trace the position of the spindle throughout mitosis in a single-cell assay. We find no evidence for the SOC. We show that the spindle is remarkably well aligned with the cell longitudinal axis at the onset of mitosis, by growing along the axis of the adjacent interphase MT. Misalignment of nascent spindles can give rise to anucleate cells when spindle elongation is impaired. We propose a new role for interphase microtubules: through interaction with the spindle pole body, interphase microtubules determine the initial alignment of the spindle in the subsequent cell division.     

Gene, phenotype and function: GLABROUS1 and resistance to herbivory in natural populations of Arabidopsis lyrata

The molecular genetic basis of adaptive variation is of fundamental importance for evolutionary dynamics, but is still poorly known. Only in very few cases has the relationship between genetic variation at the molecular level, phenotype and function been established in natural populations. We examined the functional significance and genetic basis of a polymorphism in production of leaf hairs, trichomes, in the perennial herb Arabidopsis lyrata. Earlier studies suggested that trichome production is subject to divergent selection. Here we show that the production of trichomes is correlated with reduced damage from insect herbivores in natural populations, and using statistical methods developed for medical genetics we document an association between loss of trichome production and mutations in the regulatory gene GLABROUS1. Sequence data suggest that independent mutations in this regulatory gene have provided the basis for parallel evolution of reduced resistance to insect herbivores in different populations of A. lyrata and in the closely related Arabidopsis thaliana. The results show that candidate genes identified in model organisms provide a valuable starting point for analysis of the genetic basis of phenotypic variation in natural populations.     

Rates of evolution of avirulence phenotypes and DNA markers in a northwest European population of Puccinia striiformis f. sp. tritici

The effects of evolutionary processes in fungal pathogen populations may occur more rapidly and display larger effects in agricultural systems than in wild ecosystems because of human involvement by plant breeding and crop management. In this study, we analysed the rate of evolution in three lineages of a northwest European population of a biotrophic and asexual reproduced fungal pathogen, Puccinia striiformis f. sp. tritici, causing yellow rust on wheat. Pathogen samples were collected between 1975 and 2002 in the UK and Denmark, and assayed for 14 individual avirulence/virulence alleles and up to 234 amplified fragment length polymorphism (AFLP) primer pairs producing approximately 17,000 AFLP fragments. The large number of fragments and a targeted sampling of isolates allowed a reconstruction of phylogenies in great detail, i.e. no homoplasy and a representation of sequential, evolutionary steps by pathogen samples. A recent, phenotypic loss of avirulence was observed at least once for loci corresponding to P. striiformis f. sp. tritici resistance Yr2, Yr3, Yr4, Yr7, Yr9, and Yr15, whereas Avr6 and Avr17 were lost independently in all three lineages, corresponding to 16 events of loss of avirulence (emergence of virulence). The opposite process, restoration of avirulence, was observed for Yr9 and Yr32. An interpretation of phenotypic changes within lineages as independent mutation events resulted in mutation frequencies from 1.4x10(-6) to 4.1x10(-6) per AFLP fragment (locus) per generation, whereas the effective rate by which a mutation from avirulence to virulence was established in the pathogen population, when subject to selection by host resistance genes, was approximately three orders of magnitude faster.     

Evolutionary mechanisms shaping the genetic population structure of marine fishes; lessons from the European flounder (Platichthys flesus L.)

A number of evolutionary mechanisms have been suggested for generating low but significant genetic structuring among marine fish populations. We used nine microsatellite loci and recently developed methods in landscape genetics and coalescence-based estimation of historical gene flow and effective population sizes to assess temporal and spatial dynamics of the population structure in European flounder (Platichthys flesus L.). We collected 1062 flounders from 13 localities in the northeast Atlantic and Baltic Seas and found temporally stable and highly significant genetic differentiation among samples covering a large part of the species' range (global F(ST) = 0.024, P < 0.0001). In addition to historical processes, a number of contemporary acting evolutionary mechanisms were associated with genetic structuring. Physical forces, such as oceanographic and bathymetric barriers, were most likely related with the extreme isolation of the island population at the Faroe Islands. A sharp genetic break was associated with a change in life history from pelagic to benthic spawners in the Baltic Sea. Partial Mantel tests showed that geographical distance per se was not related with genetic structuring among Atlantic and western Baltic Sea samples. Alternative factors, such as dispersal potential and/or environmental gradients, could be important for generating genetic divergence in this region. The results show that the magnitude and scale of structuring generated by a specific mechanism depend critically on its interplay with other evolutionary mechanisms, highlighting the importance of investigating species with wide geographical and ecological distributions to increase our understanding of evolution in the marine environment.     

Food web dynamics affect Northeast Arctic cod recruitment

Proper management of ecosystems requires an understanding of both the species interactions as well as the effect of climate variation. However, a common problem is that the available time-series are of different lengths. Here, we present a general approach for studying the dynamic structure of such interactions. Specifically, we analyse the recruitment of the world's largest cod stock, the Northeast Arctic cod. Studies based on data starting in the 1970-1980s indicate that this stock is affected by temperature through a variety of pathways. However, the value of such studies is somewhat limited by the fact that they are based on a quite specific ecological and climatic situation. Recently, this stock has consisted of fairly young fish and the spawning stock has consisted of relatively few age groups. In this study, we develop a model for the effect of capelin (the cod's main prey) and herring on cod recruitment since 1973. Based on this model, we analyse data on cod, herring and temperature going back to 1921 and find that food-web effects explain a significant part of the cod recruitment variation back to around 1950.     

Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels

The adipocytokine leptin has recently been shown to enhance the expression of aromatase via promoter II and I.3 using an AP-1 motif. Thus, we evaluated the correlation between plasma leptin concentrations and total body aromatization (TBA) as well as plasma levels of estrone (E(1)), estradiol (E(2)) and estrone sulfate (E(1)S) in postmenopausal breast cancer patients. Twenty-two postmenopausal women with metastatic breast cancer, participating in tracer studies for the measurement of total body aromatization (TBA) in vivo, were available. In addition, blood samples for plasma estrogens and leptin measurements were available from another 22 breast cancer patients and 114 healthy postmenopausal women participating in the mammography-screening program. Values for TBA varied from 1.46 to 4.72% while plasma leptin levels ranged from 1.83 to 95.51 ng/ml in the same group of patients. All plasma estrogen levels were in the normal range expected for postmenopausal women. We found a significant correlation between pretreatment leptin levels and TBA (r(s) 0.452, P=0.01). In contrast, basal levels of TBA did not correlate to body mass index (BMI) in the same group of patients. Plasma leptin levels correlated to plasma levels of estradiol (r(s) 0.659, P=0.007), and estrone sulfate (r(s) 0.562, P=0.01) in the group of breast cancer patients (n=44) as well as in the group of healthy postmenopausal women (estradiol, r(s) 0.363, P< or =0.001, estrone sulfate r(s) 0.353, P< or =0.001). In conclusion, we found plasma leptin levels to correlate to TBA in breast cancer patients and to plasma levels of estradiol and estrone sulfate in breast cancer patients as well as in healthy postmenopausal females. These findings suggest that leptin may influence on aromatase activity in vivo, providing a possible link between body weight and plasma estrogen levels as well as breast cancer risk.     

Factors influencing conservation attitudes of local people in Western Serengeti,Tanzania

Attitudinal studies are increasingly being adopted as tools for evaluating public understanding, acceptance and the impact of conservation interventions. The findings of these studies have been useful in guiding the policy interventions. Many factors affect conservation attitudes positively or negatively. The factors inspiring positive attitudes are likely to enhance the conservation objectives while those inducing negative attitudes may detrimentally undermine these objectives. The magnitude of the resultant effects of each particular factor is determined by the historical, political, ecological, socio-cultural and economic conditions and this may call for different management interventions. In this study we examined how conservation attitudes in western Serengeti are shaped by the following factors: level of conflicts with protected areas; wildlife imposed constraints (inadequate pasture, water, diseases, loss of livestock during migration, theft and depredation); participation in the community based project; and socio-demographic factors (age, education level, wealth, immigration, gender and household size). The results indicated that the level of conflicts, participation in the community based project, inadequate pasture, lack of water, diseases, wealth and education were important in shaping peoples’ attitudes. However, in a stepwise linear regression analysis, 59% of the variation in peoples’ attitudes was explained by three variables i.e., conflict level with protected areas, lack of water and participation in the community based project. In addition to these variables, level of education also contributed in explaining 51% of the variation in people’s attitude regarding the status of the game reserves. Five variables (lack of water, level of education, inadequate pasture, participation in the community based project and diseases) explained 12% of the variation in people’s attitude towards Serengeti National Park. The paper discusses the implications for conservation of these results and recommends some measures to realise effective conservation of wildlife resources.     

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.     

Traditional Ecological Knowledge of a Riverine Forest in Turkana, Kenya: Implications for Research and Management

The present study explores traditional ecological knowledge (TEK) of Turkana pastoralists and cultivators in the context of a riverine forest in northern Kenya. The Turkwel River and its floodplain sustain a thick forest, which is used for grazing and extraction of non-timber forest products. However, sedentarisation and agricultural expansion have resulted in localised clear-felling of trees, while river damming has altered the natural flow regime. A series of structured, semi-structured, and group interviews were combined with a botanical inventory in order to assess the relevance of TEK to ecological research and forest conservation. Turkana informants gave 102 vernacular names for the 113 woody species. Of these, 85% had a domestic or pastoral use among the 105 specific uses that were described. Ethnobotanical knowledge was relatively homogenous and not related to age, gender, or source of livelihood. The informants had in-depth knowledge of some key ecological processes. The conceived threats to forest survival were primarily cultivation and permanent settlements, while the effects of river damming and livestock grazing were disputed. A claimed decline in rainfall was confirmed by official data. There is strong evidence that TEK could be used to generate hypotheses for research and to design sustainable conservation strategies. A revised version of the indigenous system of tree management should be incorporated into the official forestry policy in order to resolve future conflicts between pastoralists and cultivators.