A note on the theory SID<ω of stratified induction

We introduce and analyse a theory of finitely stratified general inductive definitions over the natural numbers, inline image, and establish its proof theoretic ordinal, inline image. The definition of inline image bears some similarities with Leivant's ramified theories for finitary inductive definitions.

Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macro-lactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.

Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A-induced hepatitis

Concanavalin A (Con A)-induced injury is an established natural killer T (NKT) cell-mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A-stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses. Levels of extracellular nucleotides are in turn closely regulated by ectonucleotidases, such as CD39/NTPDase1. Effects of extracellular nucleotides and CD39 on NKT cell activation and upon hepatic inflammation have been largely unexplored to date. Here, we show that NKT cells express both CD39 and CD73/ecto-5'-nucleotidase and can therefore generate adenosine from extracellular nucleotides, whereas natural killer cells do not express CD73. In vivo, mice null for CD39 are protected from Con A-induced liver injury and show substantively lower serum levels of interleukin-4 and interferon-gamma when compared with matched wild-type mice. Numbers of hepatic NKT cells are significantly decreased in CD39 null mice after Con A administration. Hepatic NKT cells express most P2X and P2Y receptors; exceptions include P2X3 and P2Y11. Heightened levels of apoptosis of CD39 null NKT cells in vivo and in vitro appear to be driven by unimpeded activation of the P2X7 receptor. CONCLUSION: CD39 and CD73 are novel phenotypic markers of NKT cells. Deletion of CD39 modulates nucleotide-mediated cytokine production by, and limits apoptosis of, hepatic NKT cells providing protection against Con A-induced hepatitis. This study illustrates a further role for purinergic signaling in NKT-mediated mechanisms that result in liver immune injury.

Timing of extreme drought modifies reproductive output in semi-natural grassland

Questions Do extreme dry spells in late summer or in spring affect abundance and species composition of the reproductive shoots and the seed rain in the next annual crop? Are drought effects on reproductive shoots related to the rooting depths of species? Location Species-rich semi-natural grassland at Negrentino, Switzerland. Methods In plots under automated rain-out shelters, rainwater was added to simulate normal conditions and compare them with two experimentally effected long dry spells, in late summer (2004) and in the following spring (2005). For 28 plots, numbers of reproductive shoots per species were counted in 1-m2 areas and seed rain was estimated using nine sticky traps of 102 cm2 after dry spells. Results The two extreme dry spells in late summer and spring were similar in length and their probability of recurrence. They independently reduced the subsequent reproductive output of the community, while their seasonal timing modified its species composition. Compared to drought in spring, drought in late summer reduced soil moisture more and reduced the number of reproductive shoots of more species. The negative effects of summer drought decreased with species’ rooting depth. The shallow-rooted graminoids showed a consistent susceptibility to summer drought, while legumes and other forbs showed more varied responses to both droughts. Spring drought strongly reduced density (–53%) and species richness (–43%) of the community seed rain, while summer drought had only a marginally significant impact on seed density of graminoids (–44%). Reductions in seed number per shoot vs reproductive shoot density distinguished the impacts of drought with respect to its seasonal timing. Conclusion The essentially negative impact of drought in different seasons on reproductive output suggests that more frequent dry spells could contribute to local plant diversity loss by aggravating seed deficiency in species-rich grassland.