Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.     

Functional ultrasound imaging of the brain

We present functional ultrasound (fUS), a method for imaging transient changes in blood volume in the whole brain at better spatiotemporal resolution than with other functional brain imaging modalities. fUS uses plane-wave illumination at high frame rate and can measure blood volumes in smaller vessels than previous ultrasound methods. fUS identifies regions of brain activation and was used to image whisker-evoked cortical and thalamic responses and the propagation of epileptiform seizures in the rat brain.     

‘Ecologically complex carbon’– linking biodiversity values,carbon storage and habitat structure in some austral temperate forests

Aim We assessed how avian biodiversity and above‐ground carbon storage were related in different forest age‐classes, including mature stands (> 100 years), in a managed, mixed‐species eucalypt forest. Location Gippsland, south‐eastern Australia. Methods In 50 2‐ha stands ranging in age from ≤ 5 years to mature stands > 100 years, we undertook repeated avian surveys, performed detailed habitat measurements and estimated amounts of above‐ground carbon. Extensive wildfire reduced the number of sites to 28 (seven in each of four age classes) upon which analyses and inferences were made. We also analysed data on carbon storage and some bird responses from previously published studies. Results Mature vegetation (> 100 years) had the greatest richness, abundance and biomass of birds. Key ecological resources, such as tree‐hollows for nesting, generally occurred mostly in stands > 60 years. Avian richness per unit of above‐ground carbon storage was relatively low for stands of 20–60 years. While above‐ground carbon storage appeared to increase in a monotonic fashion as stands age and mature, there were quantum increases in all measures of avian biodiversity in mature stands (> 100 years). Main conclusions Our results suggest that carbon is organized in a different way, with substantially greater biodiversity benefits, in very old stands. Mature vegetation simultaneously maximizes both avian biodiversity and above‐ground carbon storage. These results bolster arguments for allocating highest priorities to the preservation of old‐growth forest stands rather than alternative investments (e.g. reafforestation for carbon sequestration).     

Module-based multiscale simulation of angiogenesis in skeletal muscle

Background  

Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem.     

Zur Theorie der lateralen Inhibition

Summary Recently it was shown (Reichardt 1961) that lateral neural inhibition, such as was found in the lateral eye of Limulus polyphemus by Hartline and Ratliff, can in principle compensate for the dioptric apparatus of the eye. The model of lateral inhibition in Limulus developed there is here considered further, with emphasis on the changes in the effective structure of the nerve network (and the associated vector transformation) resulting from the forced inactivity of fibers whose inhibition exceeds their excitation. The stability of the network model as a function of the inhibition coefficients is studied and two theorems regarding the stability are proven. The dependence of the properties of the network on the pattern of receptor excitation are investigated and it is shown by examples that the network could be used for form discrimination. This model's relationship to previously known pattern recognition systems is discussed and its possible application in computer technology is mentioned.