Crumbs Affects Protein Dynamics In Anterior Regions Of The Developing Drosophila Embryo

Maintenance of apico-basal polarity is essential for epithelial integrity and requires particular reinforcement during tissue morphogenesis, when cells are reorganised, undergo shape changes and remodel their junctions. It is well established that epithelial integrity during morphogenetic processes depends on the dynamic exchange of adherens junction components, but our knowledge on the dynamics of other proteins and their dynamics during these processes is still limited. The early Drosophila embryo is an ideal system to study membrane dynamics during morphogenesis. Here, morphogenetic activities differ along the anterior-posterior axis, with the extending germband showing a high degree of epithelial remodelling. We developed a Fluorescence Recovery After Photobleaching (FRAP) assay with a higher temporal resolution, which allowed the distinction between a fast and a slow component of recovery of membrane proteins during the germband extension stage. We show for the first time that the recovery kinetics of a general membrane marker, SpiderGFP, differs in the anterior and posterior parts of the embryo, which correlates well with the different morphogenetic activities of the respective embryonic regions. Interestingly, absence of crumbs, a polarity regulator essential for epithelial integrity in the Drosophila embryo, decreases the fast component of SpiderGFP and of the apical marker Stranded at Second-Venus specifically in the anterior region. We suggest that the defects in kinetics observed in crumbs mutant embryos are the first signs of tissue instability in this region, explaining the earlier breakdown of the head epidermis in comparison to that of the trunk, and that diffusion in the plasma membrane is affected by the absence of Crumbs.     

New encounters in Arctic waters: a comparison of metabolism and performance of polar cod (<Emphasis Type="Italic">Boreogadus saida</Emphasis>) and Atlantic cod (<Emphasis Type="Italic">Gadus morhua</Emphasis>) under ocean acidification and warming

Oceans are experiencing increasing acidification in parallel to a distinct warming trend in consequence of ongoing climate change. Rising seawater temperatures are mediating a northward shift in distribution of Atlantic cod (Gadus morhua), into the habitat of polar cod (Boreogadus saida), that is associated with retreating cold water masses. This study investigates the competitive strength of the co-occurring gadoids under ocean acidification and warming (OAW) scenarios. Therefore, we incubated specimens of both species in individual tanks for 4 months, under different control and projected temperatures (polar cod: 0, 3, 6, 8 °C, Atlantic cod: 3, 8, 12, 16 °C) and PCO₂ conditions (390 and 1170 µatm) and monitored growth, feed consumption and standard metabolic rate. Our results revealed distinct temperature effects on both species. While hypercapnia by itself had no effect, combined drivers caused nonsignificant trends. The feed conversion efficiency of normocapnic polar cod was highest at 0 °C, while optimum growth performance was attained at 6 °C; the long-term upper thermal tolerance limit was reached at 8 °C. OAW caused only slight impairments in growth performance. Under normocapnic conditions, Atlantic cod consumed progressively increasing amounts of feed than individuals under hypercapnia despite maintaining similar growth rates during warming. The low feed conversion efficiency at 3 °C may relate to the lower thermal limit of Atlantic cod. In conclusion, Atlantic cod displayed increased performance in the warming Arctic such that the competitive strength of polar cod is expected to decrease under future OAW conditions.     

Lunzia austriaca – a bennettitalean microsporangiate structure with Cycadopites-like in situ pollen from the Carnian (Upper Triassic) of Lunz,Austria

Based on new evidence obtained from freshly collected fossils, we here provide an emendation of Lunzia and Lunzia austriaca with an updated interpretation of the organ architecture, function and affiliation. The specimens reveal that Lunzia austriaca is a pollen organ resembling structures assigned to Weltrichia. Lunzia austriaca comprises cup-shaped pollen organs that develop up to about ten, basally fused lobes carrying appendices. The appendices are arranged pairwise and inserted laterally to a rachis-like structure, in a pinnate architecture on their adaxial side and are interpreted as prominent segments or fertile pinnae that bear numerous synangia identifying them as microsporophylls. The nature of the rachis-like structure is not straightforward. The rachis-like structure could either be fused with a bract – this fused structure then constituting the lobes – or itself been modified depicting a foliate appearance. The microsporophylls are narrow at the base and involute apically or with a sterile apical cowl. Numerous synangia with contracted bases are arranged on the inner (adaxial) side of the microsporophylls in long rows. The synangia consist of presumably four pollen sacs (microsporangia), are oblong and dehisce longitudinally. The pollen is monosulcate, elliptical and with a smooth exine (psilate). It is identified as Monocolpopollenites (=Cycadopites); from the size range, it fits best into Cycadopites accerimus. The architecture and the epidermal anatomy of Lunzia austriaca is discussed and its structure is compared with several contemporary bennettitaleans; sterile foliage and ovulate structures most likely associated with Lunzia austriaca are Pterophyllum filicoides and Westersheimia pramelreuthensis, respectively.     

Response of Antarctic benthic communities to disturbance: first results from the artificial Benthic Disturbance Experiment on the eastern Weddell Sea Shelf, Antarctica

The long-term benthic disturbance experiment (BENDEX) was started on the eastern Weddell Sea shelf off Austasen (Antarctica) during ‘Polarstern’ cruise ANT XXI/2 in December 2003 to simulate the impact of grounding icebergs on the seabed and follow the steps and timescales of recovery of disturbed benthos and demersal fish communities. Here, we report the basic approach and first results for this experimental field study. By means of 11 densely-placed hauls with a modified bottom trawl, a seabed area of approximately 100 × 1000 m was artificially scoured to inflict a similar damage to the benthic habitats as a grounding iceberg. Before the disturbance event and 11 days after it, the seafloor communities were sampled (invertebrate assemblages by multibox corers, the fish fauna by trawl hauls) and comparatively analyzed. Sediment texture and chemistry was not significantly altered by the heavy disturbance inflicted by repeated trawling, whereas the fauna was negatively affected. Invertebrate benthic biomass was drastically reduced by a factor of 10, while mean abundances were only slightly reduced. Demersal fish biomass and abundance were slightly but not significantly smaller after the disturbance. Effects of disturbance became more evident in the composition of the fish fauna, with Trematomus pennelli and T. hansoni being dominant at disturbed sites, whereas Chionodraco myersi was the dominant species in trawl catches from undisturbed stations.     

Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel,potent and selective GABAA α5 inverse agonist series

Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABA_A α5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine.     

The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and sepsis. Pneumococci can be divided into >90 serotypes that show differences in the pathogenicity and invasiveness. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia and that some invasive pneumococcal types are not recognized by this pathway. We show that human and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1β. This IL-1β production depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Some serotype 1, serotype 8, and serotype 7F bacteria, which have previously been associated with increased invasiveness and with production of toxins with reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1β production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease. The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.     

Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy

Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.