Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally.     

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

Induced pluripotent stem cells (iPSCs) are adult somatic cells genetically reprogrammed to an embryonic stem cell‐like state. Notwithstanding their autologous origin and their potential to differentiate towards cells of all three germ layers, iPSC reprogramming is still affected by low efficiency. As dermal fibroblast is the most used human cell for reprogramming, we hypothesize that the variability in reprogramming is, at least partially, because of the skin fibroblasts used. Human dermal fibroblasts harvested from five different anatomical sites (neck, breast, arm, abdomen and thigh) were cultured and their morphology, proliferation, apoptotic rate, ability to migrate, expression of mesenchymal or epithelial markers, differentiation potential and production of growth factors were evaluated in vitro. Additionally, gene expression analysis was performed by real‐time PCR including genes typically expressed by mesenchymal cells. Finally, fibroblasts isolated from different anatomic sites were reprogrammed to iPSCs by integration‐free method. Intriguingly, while the morphology of fibroblasts derived from different anatomic sites differed only slightly, other features, known to affect cell reprogramming, varied greatly and in accordance with anatomic site of origin. Accordingly, difference also emerged in fibroblasts readiness to respond to reprogramming and ability to form colonies. Therefore, as fibroblasts derived from different anatomic sites preserve positional memory, it is of great importance to accurately evaluate and select dermal fibroblast population prior to induce reprogramming.     

Lipid mediators in marine diatoms

Aquatic Ecology - Diatoms are eukaryotic microalgae representing one of the major groups in the marine phytoplankton, accounting for up to 40% of annual productivity at sea. They are widely...     

Long bone scaling in Captorhinidae: do limb bones scale according to elastic similarity in sprawling basal amniotes?

Captorhinids are a speciose clade of sauropsids that are crucial to understand several aspects of basal amniote general biology. Members of the Captorhinidae explored different diets and, amongst basal amniotes, were one of the first groups to demonstrate high‐fibre herbivory. Several papers have been published on the cranial anatomy of captorhinids, but there are relatively few studies which focus on the post‐cranium, especially on the appendicular skeleton and long bones. This contribution presents the first quantitative long bone scaling in Captorhinidae performed through morphometric analyses. From classical biomechanical research, it is well‐established that to accommodate an increase in size, gravity will result in elastic deformation of long bones. This outcome is especially significant in terrestrial tetrapods with a sprawling limb posture such as captorhinids, where great torsional stresses are applied to long bones, both during locomotion and in the resting phase. In this paper, we test whether the consistent evolutionary size increase in captorhinids led to major re‐patterning in long bone structure as theoretically expected, based on the theory of elastic similarity. Morphometric analysis shows that, apart from a small positive allometry in the humerus, captorhinid long bones scale geometrically as body size increases. Thus, the predicted elastic similarity to maintain similar levels in peak stress with an increase in dimensions does not seem not to apply to long bone evolution in captorhinids. We propose that, as already observed experimentally in larger‐bodied varanid lizards, large captorhinids could also mitigate size‐related increases in stress by reducing femur rotation and increasing the percentage of the stride cycle during which the right hindfoot was on the ground (i.e. the duty factor). In this way, large captorhinids could avoid reaching peak stress thresholds by sacrificing speed during locomotion and without a substantial long bone re‐patterning or postural change.     

Disparity vs. diversity in Stegosauria (Dinosauria,Ornithischia): cranial and post-cranial sub-dataset provide different signals

The Stegosauria represents an iconic group of ornithischian dinosaurs, with a fossil record spanning the Middle Jurassic to the Late Cretaceous. In this contribution I present the first detailed analysis of the relationship between disparity and diversity through the evolutionary history of the group. The analysis has been performed on a recently published cladistic dataset, allowing the separate study of the signals deriving from discrete characters and from continuous morphometric characters. Whereas the disparity as sum of variance is decoupled with respect to diversity, the sum of ranges provides a signal fairly consistent with the trend in the number of taxa. Both sub-data sets show that evolution of stegosaurs can be considered essentially as symmetrical, i.e. the maximum exploration of the possible morphospace takes place about half way through the history of the group, with subsequent significant decline until extinction in the Upper Cretaceous. An interesting result is a decoupling of the tempo and mode of evolution of the cranium and postcranium in stegosaurs. Specifically, the evolutionary radiation with maximum saturation of morphospace is anticipated in the cranial skeleton, with maximum peak in the Oxfordian; in contrast, the postcranium explores the largest number of morphotypes subsequently during the Kimmeridgian.     

The identification of a selective dopamine D2 partial agonist,D3 antagonist displaying high levels of brain exposure

The identification of a highly selective D₂ partial agonist, D₃ antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.     

The ultrastructure of malpighian tubules and the chemical composition of the cocoon of Aeolothrips intermedius Bagnall (Thysanoptera)

The secretory activity of the two branched malpighian tubules (MTs) of the second‐instar larva in Aeolothrips intermedius is described. MTs of adult thrips have the typical ultrastructure of excretory epithelium with apical microvilli containing long mitochondria and a rich system of basal membrane infoldings. In the second‐instar larva just before pupation, the ultrastructure of MT epithelial cells is dramatically different, and there are numerous huge Golgi systems in the cytoplasm. These cells are involved in an intense secretory activity to produce an electron‐dense product which is released into the MTs lumen. This secretion is extruded from the hindgut and used by the second‐instar larva to build an elaborate protective cocoon for pupation. Electron‐spray‐ionization mass spectrometry analysis of the cocoon revealed the presence of a β‐N‐acetyl‐glucosamine, the main component of chitin, which is also present in the cocoons of Neuroptera and some Coleoptera. J. Morphol., 2010. © 2009 Wiley‐Liss, Inc.