The impact on microtubule network of a bracovirus IκB-like protein

Polydnavirus-encoded IκB-like proteins are similar to insect and mammalian IκB, and an immunosuppressive function in the host cells has been inferred to these proteins. Here we show that the expression of one of these IκB-like viral genes, the TnBVank1, in the Drosophila germline affects the localization of gurken, bicoid, and oskar mRNAs whose gene products are relevant for proper embryonic patterning. The altered localization of these mRNAs is suggestive of general defects in the intracellular, microtubule-based, trafficking routes. Analysis of microtubule motor proteins components such as the dynein heavy chain and the kinesin heavy chain revealed defects in the polarized microtubule network. Interestingly, the TnBVANK1 viral protein is uniformly distributed over the entire oocyte cortex, and appears to be anchored to the microtubule ends. Our data open up a very interesting issue on novel function(s) played by the ank gene family by interfering with cytoskeleton organization.     

Design of a System Dynamics Model to Analyze the Styrene Demand in the Brazilian Market

The growth of the petrochemical industry is based on end-user applications such as the automotive and construction sectors, which are the main drivers of the styrene market. However, the use of substitutes for petrochemicals is a reality and creates a competition in the applications of petroleum products. In this sense, this research aimed to design a system dynamics model to evaluate different scenarios, observing the behavior of the styrene demand over time. In the first phase of the project, a greater understanding of the issue was created and a closed loops diagram was elaborated. It was used during the second phase to design an explanatory regression validation model for the styrene demand. In phase three, a visualizing model and scenarios were designed. The scenarios themselves and the results of each scenario were evaluated. The designed and simulated scenarios aimed to evaluate the impact that the use of substitute materials and the variations in gross domestic product cause to the styrene market. The use of system dynamics together with scenario planning was efficient as different strategies for the market could be evaluated based on the simulated scenarios. A critical analysis of the model’s contribution to the decision-making within organizations concludes the study.     

GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction

The effects of three tricyclic antidepressants (TCAs) and two serotonin selective reuptake inhibitors (SSRIs) have been studied with an electrophysiological approach on Xenopus laevis oocytes expressing the rat GABA (γ-Aminobutyric-acid) transporter rGAT1. All tested TCAs and SSRIs inhibit the GABA-associated current in a dose-dependent way with low but comparable efficacy. The pre-steady-state and uncoupled currents appear substantially unaffected. The efficacy of desipramine, but not of the other drugs, is strongly increased in the lysine-glutamate or -aspartate mutants K448E and K448D. Comparison of I _max and K _0.5GABA in the absence and presence of desipramine showed that both parameters are reduced by the drug in the wild-type and in the K448E mutant. This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data.     

From carrot to clinic: an overview of the retinoic acid signaling pathway

Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.     

Anandamide extends platelets survival through CB1-dependent Akt signaling

Platelets are stored at 22°C, since incubation at 37°C results in loss of viability. Nonetheless, in our body (37°C), platelets survive for 8–10 days. This discrepancy has been explained in terms of deprivation of viability factors or accumulation of apoptotic factors during storage. We report that the endocannabinoid anandamide (AEA) may be one of the agents allowing platelet survival. In fact, at 37°C, human platelets enhance the expression of pro-apoptotic proteins (caspases, Bax, Bak) and decrease the expression of Bcl-xL, thus changing the Bcl-xL/Bak ratio, a key platelet biological clock. AEA or its non-hydrolyzable analogue, methanandamide, extend platelet life span, without reversing the changes in Bcl-xL/Bak ratio induced by heat stress. Instead, AEA binding to type-1 cannabinoid receptor activates Akt, which regulates, through phosphorylation of Bad, the interactions among different Bcl-2 family members. These findings could have implications for platelet collection and, potentially, for their clinical use.     

Esculentin(1-21), an amphibian skin membrane-active peptide with potent activity on both planktonic and biofilm cells of the bacterial pathogen Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that forms sessile communities, named biofilms. The non-motile forms are very difficult to eradicate and are often associated with the establishment of persistent infections, especially in patients with cystic fibrosis. The resistance of P. aeruginosa to conventional antibiotics has become a growing health concern worldwide and has prompted the search for new anti-infective agents with new modes of action. Naturally occurring antimicrobial peptides (AMPs) represent promising future template candidates. Here we report on the potent activity and membrane-perturbing effects of the amphibian AMP esculentin(1-21), on both the free-living and sessile forms of P. aeruginosa, as a possible mechanism for biofilm disruption. Furthermore, the findings that esculentin(1-21) is able to prolong survival of animals in models of sepsis and pulmonary infection indicate that this peptide can be a promising template for the generation of new antibiotic formulations to advance care of infections caused by P. aeruginosa.     

Unravelling the dynamics of RNA degradation by ribonuclease II and its RNA-bound complex

RNA degradation is a determining factor in the control of gene expression. The maturation, turnover and quality control of RNA is performed by many different classes of ribonucleases. Ribonuclease II (RNase II) is a major exoribonuclease that intervenes in all of these fundamental processes; it can act independently or as a component of the exosome, an essential RNA-degrading multiprotein complex. RNase II-like enzymes are found in all three kingdoms of life, but there are no structural data for any of the proteins of this family. Here we report the X-ray crystallographic structures of both the ligand-free (at 2.44 A resolution) and RNA-bound (at 2.74 A resolution) forms of Escherichia coli RNase II. In contrast to sequence predictions, the structures show that RNase II is organized into four domains: two cold-shock domains, one RNB catalytic domain, which has an unprecedented alphabeta-fold, and one S1 domain. The enzyme establishes contacts with RNA in two distinct regions, the 'anchor' and the 'catalytic' regions, which act synergistically to provide catalysis. The active site is buried within the RNB catalytic domain, in a pocket formed by four conserved sequence motifs. The structure shows that the catalytic pocket is only accessible to single-stranded RNA, and explains the specificity for RNA versus DNA cleavage. It also explains the dynamic mechanism of RNA degradation by providing the structural basis for RNA translocation and enzyme processivity. We propose a reaction mechanism for exonucleolytic RNA degradation involving key conserved residues. Our three-dimensional model corroborates all existing biochemical data for RNase II, and elucidates the general basis for RNA degradation. Moreover, it reveals important structural features that can be extrapolated to other members of this family.