Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species

Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been –and still are– considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC) or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl) tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA) and their genetically matched wild-type vhl (RCC4 VHL) counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770^T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066) with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with apoptosis induction in VHL deficient cell line as demonstrated with PARP activation and Annexin V staining. Our study demonstrated the feasibility of selectively targeting the loss of the vhl tumor suppressor gene for potential clinical benefit. Our results may have great impact on the development of new targeted therapies from natural products for the treatment of cancer and other genetic diseases.     

Expanding the MiniAp‐4 BBB‐shuttle family: Evaluation of proline cis‐trans ratio as tool to fine‐tune transport

Venoms have recently emerged as a promising field in drug discovery due to their good selectivity and affinity for a wide range of biological targets. Among their multiple potential applications, venoms are a rich source of blood‐brain barrier (BBB) peptide shuttles. We previously described a short nontoxic derivative of apamin, MiniAp‐4, which can transport a wide range of cargoes across the BBB. Here, we have studied the conformation of the proline residue of a range of MiniAp‐4 analogues by high‐field NMR techniques, with the aim to identify whether there is a direct relation between the cis/trans population and a range of features, such as the capacity to transport molecules across a human‐based cellular model and stability in various media. The most promising candidate showed improved transport properties for a relevant small fluorophore.     

The impact of the American mink (Neovison vison) on native vertebrates in mountainous streams in Central Spain

The American mink (Neovison vison) is responsible for the widespread decline of its prey species in the regions where it is an invasive species. The current expansion of the mink in the Iberian Peninsula has aroused concern among conservationists about its negative impact on the rich native fauna. However, evidence for this is still scarce, although there are several studies establishing a direct causal relationship between declining native species and the presence of the American mink. Thus, it is important to further investigate the responses of native species to the American mink in several habitats and locations to enhance our knowledge about the patterns of the effect of the mink in Spain, as well as to inform conservation actions. A field study of the impact of the American mink on a mountainous vertebrate community in central Spain is presented. We studied six species: two fish, one amphibian, one bird, and two mammals. The general results showed a species-specific sensitivity to mink presence, with the Mediterranean water shrew (Neomys anomalus) and the southern water vole (Arvicola sapidus) being the most affected because their ranges were significantly decreased after the introduction of the mink. Regarding the other species, neither their abundance nor range was apparently affected by the American mink. The predatory behavior of the mink and interactions with other carnivores could account for these results. These data aid in shedding light about the current impact of the mink on invaded areas of the Iberian Peninsula and highlight the variability of its effects, as well as the urgent need to establish a general program of control of the mink to avoid negative effects upon native prey communities. Furthermore, given the different responses of native species, we propose that measures to protect native species should be based on species-specific goals and attributes.     

Productivity in Physical and Chemical Science Predicts the Future Economic Growth of Developing Countries Better than Other Popular Indices

Scientific productivity of middle income countries correlates stronger with present and future wealth than indices reflecting its financial, social, economic or technological sophistication. We identify the contribution of the relative productivity of different scientific disciplines in predicting the future economic growth of a nation. Results show that rich and poor countries differ in the relative proportion of their scientific output in the different disciplines: countries with higher relative productivity in basic sciences such as physics and chemistry had the highest economic growth in the following five years compared to countries with a higher relative productivity in applied sciences such as medicine and pharmacy. Results suggest that the economies of middle income countries that focus their academic efforts in selected areas of applied knowledge grow slower than countries which invest in general basic sciences.     

Role of Escherichia coli FtsN protein in the assembly and stability of the cell division ring

Deprivation of FtsN, the last protein in the hierarchy of divisome assembly, causes the disassembly of other elements from the division ring, even extending to already assembled proto‐ring proteins. Therefore the stability and function of the divisome to produce rings active in septation is not guaranteed until FtsN is recruited. Disassembly follows an inverse sequential pathway relative to assembly. In the absence of FtsN, the frequencies of FtsN and FtsQ rings are affected similarly. Among the proto‐ring components, ZipA are more sensitive than FtsZ or FtsA rings. In contrast, removal of FtsZ leads to an almost simultaneous disappearance of the other elements from rings. Although restoration of FtsN allows for a quick reincorporation of ZipA into proto‐rings, the de novo joint assembly of the three components when FtsZ levels are restored to FtsZ‐deprived filaments is even faster. This suggests that the recruitment of ZipA into FtsZ‐FtsA incomplete proto‐rings may require first a period for the reversal of these partial assemblies.     

Does the Type of Event Influence How User Interactions Evolve on Twitter?

The number of people using on-line social networks as a new way of communication is continually increasing. The messages that a user writes in these networks and his/her interactions with other users leave a digital trace that is recorded. Thanks to this fact and the use of network theory, the analysis of messages, user interactions, and the complex structures that emerge is greatly facilitated. In addition, information generated in on-line social networks is labeled temporarily, which makes it possible to go a step further analyzing the dynamics of the interaction patterns. In this article, we present an analysis of the evolution of user interactions that take place in television, socio-political, conference, and keynote events on Twitter. Interactions have been modeled as networks that are annotated with the time markers. We study changes in the structural properties at both the network level and the node level. As a result of this analysis, we have detected patterns of network evolution and common structural features as well as differences among the events.