Reversal of pathological pain through specific spinal GABAA receptor subtypes

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.     

The role of site accessibility in microRNA target recognition

MicroRNAs are key regulators of gene expression, but the precise mechanisms underlying their interaction with their mRNA targets are still poorly understood. Here, we systematically investigate the role of target-site accessibility, as determined by base-pairing interactions within the mRNA, in microRNA target recognition. We experimentally show that mutations diminishing target accessibility substantially reduce microRNA-mediated translational repression, with effects comparable to those of mutations that disrupt sequence complementarity. We devise a parameter-free model for microRNA-target interaction that computes the difference between the free energy gained from the formation of the microRNA-target duplex and the energetic cost of unpairing the target to make it accessible to the microRNA. This model explains the variability in our experiments, predicts validated targets more accurately than existing algorithms, and shows that genomes accommodate site accessibility by preferentially positioning targets in highly accessible regions. Our study thus demonstrates that target accessibility is a critical factor in microRNA function.     

Churchman's “process of unfolding”—Its significance for policy analysis and evaluation

Churchman's process of unfolding is one of his lesser known concepts, yet it is essential for understanding his dialectical systems approach. This paper gives a brief introduction to the concept and presents a simple framework for applying it to policy analysis and program evaluation.     

Testament to conversations on critical systems thinking between two systems practitioners

This is a testament to conversations held in Berne and Fribourg, Switzerland, in late 1988. The main theme that we present concerns seeking to find an adequate epistemology for systems practice, to find a truly critical approach, by shifting our interests from systems science to systems rationality (i.e., by reaching out toward a systems epistemological ideal) and by dealing with sociological phenomena such as the effects of material conditions and false consciousness and inequalities associated with these. Social rationalities relating to positivism, interpretivism, and critique are considered. Limitations and legitimacies of these rationalities in social contexts are made explicit in these discussions.Conversations were held in Berne and Fribourg, Switzerland, between 30 November and 5 December 1988.     

Von Boltzmann zu Planck

Ohne Zusammenfassung Vorgelegt von S. Flügge     

A deep dynamo generating Mercury's magnetic field

Mercury has a global magnetic field of internal origin and it is thought that a dynamo operating in the fluid part of Mercury's large iron core is the most probable cause. However, the low intensity of Mercury's magnetic field--about 1% the strength of the Earth's field--cannot be reconciled with an Earth-like dynamo. With the common assumption that Coriolis and Lorentz forces balance in planetary dynamos, a field thirty times stronger is expected. Here I present a numerical model of a dynamo driven by thermo-compositional convection associated with inner core solidification. The thermal gradient at the core-mantle boundary is subadiabatic, and hence the outer region of the liquid core is stably stratified with the dynamo operating only at depth, where a strong field is generated. Because of the planet's slow rotation the resulting magnetic field is dominated by small-scale components that fluctuate rapidly with time. The dynamo field diffuses through the stable conducting region, where rapidly varying parts are strongly attenuated by the skin effect, while the slowly varying dipole and quadrupole components pass to some degree. The model explains the observed structure and strength of Mercury's surface magnetic field and makes predictions that are testable with space missions both presently flying and planned.     

Unified spatial scaling of species and their trophic interactions

Two largely independent bodies of scaling theory address the quantitative relationships between habitat area, species diversity and trophic interactions. Spatial theory within macroecology addresses how species richness scales with area in landscapes, while typically ignoring interspecific interactions. Complexity theory within community ecology addresses how trophic links scale with species richness in food webs, while typically ignoring spatial considerations. Recent studies suggest unifying these theories by demonstrating how spatial patterns influence food-web structure and vice versa. Here, we follow this suggestion by developing and empirically testing a more unified scaling theory. On the basis of power-law species-area relationships, we develop link-area and non-power-law link-species models that accurately predict how trophic links scale with area and species richness of microcosms, lakes and streams from community to metacommunity levels. In contrast to previous models that assume that species richness alone determines the number of trophic links, these models include the species' spatial distribution, and hence extend the domain of complexity theory to metacommunity scales. This generality and predictive success shows how complexity theory and spatial theory can be unified into a much more general theory addressing new domains of ecology.