Melampomagnolide B: a new antileukemic sesquiterpene

Melampomagnolide B has been identified as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was designed and synthesized in order to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types.     

The genome sequence of the leaf-cutter ant Atta cephalotes reveals insights into its obligate symbiotic lifestyle

Leaf-cutter ants are one of the most important herbivorous insects in the Neotropics, harvesting vast quantities of fresh leaf material. The ants use leaves to cultivate a fungus that serves as the colony's primary food source. This obligate ant-fungus mutualism is one of the few occurrences of farming by non-humans and likely facilitated the formation of their massive colonies. Mature leaf-cutter ant colonies contain millions of workers ranging in size from small garden tenders to large soldiers, resulting in one of the most complex polymorphic caste systems within ants. To begin uncovering the genomic underpinnings of this system, we sequenced the genome of Atta cephalotes using 454 pyrosequencing. One prediction from this ant's lifestyle is that it has undergone genetic modifications that reflect its obligate dependence on the fungus for nutrients. Analysis of this genome sequence is consistent with this hypothesis, as we find evidence for reductions in genes related to nutrient acquisition. These include extensive reductions in serine proteases (which are likely unnecessary because proteolysis is not a primary mechanism used to process nutrients obtained from the fungus), a loss of genes involved in arginine biosynthesis (suggesting that this amino acid is obtained from the fungus), and the absence of a hexamerin (which sequesters amino acids during larval development in other insects). Following recent reports of genome sequences from other insects that engage in symbioses with beneficial microbes, the A. cephalotes genome provides new insights into the symbiotic lifestyle of this ant and advances our understanding of host-microbe symbioses.     

Regulation of cullin RING E3 ubiquitin ligases by CAND1 in vivo

Cullin RING ligases are multi-subunit complexes consisting of a cullin protein which forms a scaffold onto which the RING protein Rbx1/2 and substrate receptor subunits assemble. CAND1, which binds to cullins that are not conjugated with Nedd8 and not associated with substrate receptors, has been shown to function as a positive regulator of Cullin ligases in vivo. Two models have been proposed to explain this requirement: (i) CAND1 sequesters cullin proteins and thus prevents autoubiquitination of substrate receptors, and (ii) CAND1 is required to promote the exchange of bound substrate receptors. Using mammalian cells, we show that CAND1 is predominantly cytoplasmically localized and that cullins are the major CAND1 interacting proteins. However, only small amounts of CAND1 bind to Cul1 in cells, despite low basal levels of Cul1 neddylation and approximately equal cytoplasmic endogenous protein concentrations of CAND1 and Cul1. Compared to F-box protein substrate receptors, binding of CAND1 to Cul1 in vivo is weak. Furthermore, preventing binding of F-box substrate receptors to Cul1 does not increase CAND1 binding. In conclusion, our study suggests that CAND1 does not function by sequestering cullins in vivo to prevent substrate receptor autoubiquitination and is likely to regulate cullin RING ligase activity via alternative mechanisms.     

The strategy concept and John Maynard Smith’s influence on theoretical biology

Here we argue that the concept of strategies, as it was introduced into biology by John Maynard Smith, is a prime illustration of the four dimensions of theoretical biology in the post-genomic era. These four dimensions are: data analysis and management, mathematical and computational model building and simulation, concept formation and analysis, and theory integration. We argue that all four dimensions of theoretical biology are crucial to future interactions between theoretical and empirical biologists as well as with philosophers of biology.     

Electronic structures of highly symmetrical compounds of f elements: XXXIX. Do more covalent europium(III) compounds exhibit an anti-nephelauxetic behavior?

By comparing the nephelauxetic ratios β of a number of molecular Pr^III compounds, and the Slater parameters F² (or Racah parameters E¹) of molecular Nd^III and selected Sm^III compounds, presumably more covalent types of Eu^III compounds could be identified. Powdered [Eu{N(SiMe₃)₂}₃] (1), “[Eu{OC(tBu)₃}₃]” (“3”) and [Eu(η⁵-C₅H₅)₃(CNC₆H₁₁)] (5) were resynthesized following usual procedures. The absorption transitions ⁷F₀ → ⁵D₀ of an oriented single crystal of 1, a glassy frozen solution of 1 dissolved in a mixture of 2-MeTHF/THF (ratio 3:1) ([Eu{N(SiMe₃)₂}₃(THF)], (2)), of “3” dissolved in 2-MeTHF ([Eu{OC(tBu)₃}₃(MeTHF)], (4)), and of 5 dissolved in a mixture of the inert solvents methylcyclohexane/toluene (ratio 1:1), were measured at room and low temperatures (90 K). The energy differences of this transition for compounds 1, 2, 4 and 5 are larger than those of [Eu(H₂O)₉]³⁺ or even gaseous Eu³⁺, indicating quasi “anti-nephelauxetic” effects. Crystal field calculations, however, reveal that lower Slater parameters F² (or Racah parameters E¹) have to be used than those of [Eu(H₂O)₉]³⁺ in order to reproduce the experimental energy differences between ⁷F₀ and ⁵D₀, thus indicating the expected nephelauxetic effects of more covalent Eu^III compounds.     

Plasticity and acclimation to light reflected in temporal and spatial changes of small-scale macroalgal distribution in a stream

The small-scale distribution pattern of macroalgae in the river Ilm, in Germany was monitored. These patterns were then related to abiotic factors and tested to discover whether the distribution of the common macroalgae, Cladophora glomerata (L.) Kütz. and Vaucheria sp., was linked to differences in their photosynthetic plasticity. Cladophora glomerata revealed higher maximum photosynthetic electron transport rates after acclimation to high light (HL) compared with low light (LL) acclimated samples. By contrast, Vaucheria sp. did not acclimate to different growth light conditions. The photosynthetic performance of both algae also varied according to diurnal conditions. High light caused a reversible decrease of the dark-adapted quantum yield (F(v)/F(m)) in C. glomerata and a concomitant reversible decrease of the light-adapted quantum yield (DeltaF/F'(m)). In Vaucheria sp., F(v)/F(m) remained mostly unchanged over the day, whereas DeltaF/F'(m) decreased during the morning at low light. Photosynthetic pigments confirmed acclimational differences between the species. HL C. glomerata showed increased chlorophyll a:chlorophyll b ratios, and higher amounts of xanthophyll-cycle pigments compared with LL samples, whereas Vaucheria sp. did not reveal differences between the light treatments. While preferences for substrate size, water velocity, and depth are similar for C. glomerata and Vaucheria sp., the physiological responses to light conditions are different. It is concluded that light conditions significantly affect the small-scale spatial distribution of macroalgae and that fitness is enhanced in species with a higher plasticity in photosynthetic acclimation in unstable environments.     

Insulin-like growth factor-1 contributes to neovascularization in age-related macular degeneration

Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. IGF-1 is produced in neurons and retinal pigment epithelium (RPE) but its targets and impact in CNV are not understood. IGF-1 immunoreactivity was abundant throughout surgically isolated human CNV tissues and RPE cells were immunopositive for IGF-1R. Cultured RPE cells obtained from CNV tissues expressed IGF-1R. IGF-1 stimulation of cultured cells from CNV tissues induced monophasic sustained rises in intracellular free Ca(2+). VEGF concentration in the medium of unstimulated RPE cell cultures from CNV tissues increased with time to a steady-state (8h) which was increased twofold by IGF-1 stimulation. Thus, in RPE cells IGF-1 stimulates the second messenger Ca(2+) and increases VEGF secretion which, in turn, induces neovascularization.     

An inhibitor of O-glycosylation induces apoptosis in NIH3T3 cells and developing mouse embryonic mandibular tissues

The family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (ppGaNTases) is responsible for initiating mucin-type O-linked glycosylation in higher eukaryotes. To begin to examine the biological role of O-linked glycosylation, mammalian cells were treated with a small molecule inhibitor (designated 1-68A, Ref. 15) of ppGaNTase activity. NIH3T3 cells exposed to the inhibitor were shown to undergo a significant reduction in cell surface O-glycosylation as detected by staining with jacalin and peanut agglutinin lectins after 30 min of treatment; no reduction in staining using antibodies to O-linked N-acetylglucosamine or the lectin concanavalin A was detected. Apoptosis was also observed in treated cells after 45 min of exposure, ostensibly following the O-glycosylation reduction. Overexpression of several different ppGaNTase isoforms restored cell surface O-glycosylation and rescued inhibitor-induced apoptosis. Additionally, mouse embryonic mandibular organ cultures exposed to 1-68A developed abnormally, presumably because of epithelial and mesenchymal apoptosis that followed a reduction in jacalin and peanut agglutinin staining. Our studies suggest that mucin-type O-linked glycosylation may be required for normal development and that ppGaNTases may play a role in the regulation of apoptosis.