From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs

In Vivo Methods for the Assessment of Topical Drug Bioavailability

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described

ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress

The endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome. ER size and content in molecular chaperones increase upon physiologic and pathologic stresses on activation of unfolded protein responses (UPR). On stress resolution, the mammalian ER is remodeled to pre-stress, physiologic size and function on activation of the LC3-binding activity of the translocon component SEC62. This elicits recov-ER- phagy, i.e., the delivery of the excess ER generated during the phase of stress to endolysosomes (EL) for clearance. Here, ultrastructural and genetic analyses reveal that recov-ER-phagy entails the LC3 lipidation machinery and proceeds via piecemeal micro- ER-phagy, where RAB7/LAMP1-positive EL directly engulf excess ER in processes that rely on the Endosomal Sorting Complex Required for Transport (ESCRT)-III component CHMP4B and the accessory AAA+ ATPase VPS4A. Thus, ESCRT-III-driven micro-ER- phagy emerges as a key catabolic pathway activated to remodel the mammalian ER on recovery from ER stress

Feeding exploitation of Camargue wetlands by five species of wintering or in transit surface ducks: spatio-temporal modelization

Inventaire des proies ingérées et des proies disponibles. Méthodologie. Variabilité intraspécifique. Modélisation de l'habitat alimentair

Diet and feeding habitats of camargue dabbling ducks: What has changed since the 1960s?

In the Camargue (southern France), drastic changes in wetlands have occurred (notably extension of agriculture and salt extraction) since the 1960s, which affect the resources available to migratory waterbirds. Winter diets of Mallard (Anas platyrhynchos) and Teal (A. crecca) in 2006-2008 were assessed by analyses of gullet contents. Using PCA-based methods, duck diets were described and the main feeding habitats used by each duck species were then determined with a typology analysis. The same four food items were most important (in terms of occurrence and average dry weight) in the diet of Mallard and Teal: Oryza sativa (rice), Echinochloa sp., Scirpus maritimus and Potamogeton pusillus seeds. However, Teal diet was more diversified, with eleven feeding habitat types, compared to only five in Mallard. Both species were found to be dependent on ricefields and ricefield-like habitats. Compared to previous studies in the same area between 1964 and 1981, permanent freshwater habitats now appear to be used more intensively by Mallard and Teal, while temporary marshes are used to a lesser extent. Since the 1960s, temporary marshes have been partially replaced by permanent freshwater in order to attract more ducks, mostly for hunting. The flexibility of duck diet in response to changing food availability may explain why duck populations have not decreased in the Camargue or in Europe despite changes in land use.Peer Reviewe

Waterbird seed‐dispersal networks are similarly nested but less modular than those of frugivorous birds, and not driven by functional traits

Frugivory is widely recognized as vital for the dispersal of many plants. Moreover, plant species and their frugivorous dispersers form seed‐dispersal assemblages whose structure has important implications for the persistence and stability of the community. However, dispersal interactions between plants and non‐frugivorous animal groups such as waterbirds remain largely understudied. We aimed to characterize the structure of waterbird seed‐dispersal networks, assess if this structure is similar to that of networks formed between frugivorous birds and fleshy‐fruited plants, and identify bird or plant functional traits important for the maintenance of network structure. We used network analyses and data from four community‐level studies on waterbird gut contents, including 12 bird and 88 plant species. We compared the network structure of waterbirds to those from previous studies of frugivorous birds. We also related the contribution of each species to the network structure with functional traits (e.g. size, habitat requirements, diet). Waterbird seed‐dispersal networks are similarly nested (i.e. specialists interact with a subset of those species that interact with generalists) but less modular (i.e. fewer semi‐independent groups of highly interacting species) than those of frugivores. Dabbling ducks, diving ducks and rallids did not separate into modules. The contribution of bird or plant species to network structure was not related to any functional trait. Seed‐dispersal networks of waterbirds share some organizational patterns with those of frugivores, but the underlying processes are not related to functional traits. This is probably related to fundamental differences between waterbirds and frugivores in how seeds are ingested. Differences in the functional role of waterbirds for seed dispersal are likely driven by other processes such as differences in population size, movement, ecology or gut processing of seeds.Peer reviewe