The Present and the Future of Degradable Dendrimers and Derivatives in Theranostics

Interest in dendrimer-based nanomedicines has been growing recently, as it is possible to precisely manipulate the molecular weight, chemical composition, and surface functionality of dendrimers, tuning their properties according to the desired biomedical application. However, one important concern about dendrimer-based therapeutics remains-the nondegradability under physiological conditions of the most commonly used dendrimers. Therefore, biodegradable dendrimers represent an attractive class of nanomaterials, since they present advantages over conventional nondegradable dendrimers regarding the release of the loaded molecules and the prevention of bioaccumulation of synthetic materials and subsequent cytotoxicity. Here, we present an overview of the state-of-the-art of the design of biodegradable dendritic structures, with particular focus on the hurdles regarding the use of these as vectors of drugs and nucleic acids, as well as macromolecular contrast agents.The authors would like to acknowledge the FEDER funds through the Programa Operacional Factores de Competitividade − COMPETE and the Portuguese funds through FCT − Fundação para a Ciência e a Tecnologia (PTDC/CTM-NAN/112428/2009, PEst/SAU/LA0002/2013 and PEst-OE/QUI/UI0674/2013-2014) that supported this work. V. Leiro is supported by FCT (SFRH/BPD/69110/2010)

Engineering Art Galleries

The Art Gallery Problem is one of the most well-known problems in Computational Geometry, with a rich history in the study of algorithms, complexity, and variants. Recently there has been a surge in experimental work on the problem. In this survey, we describe this work, show the chronology of developments, and compare current algorithms, including two unpublished versions, in an exhaustive experiment. Furthermore, we show what core algorithmic ingredients have led to recent successes

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Boundary Conditions and Unitarity: the Maxwell-Chern-Simons System in AdS_3/CFT_2

We consider the holography of the Abelian Maxwell-Chern-Simons (MCS) system in Lorentzian three-dimensional asymptotically-AdS spacetimes, and discuss a broad class of boundary conditions consistent with conservation of the symplectic structure. As is well-known, the MCS theory contains a massive sector dual to a vector operator in the boundary theory, and a topological sector consisting of flat connections dual to U(1) chiral currents; the boundary conditions we examine include double-trace deformations in these two sectors, as well as a class of boundary conditions that mix the vector operators with the chiral currents. We carefully study the symplectic product of bulk modes and show that almost all such boundary conditions induce instabilities and/or ghost excitations, consistent with violations of unitarity bounds in the dual theory.Comment: 50+1 pages, 6 figures, PDFLaTeX; v2: added references, corrected typo

Ectoparasite activity during incubation increases microbial growth on avian eggs

We thank Estefanía López for lab work, and Tomás Pérez-Contreras and Emilio Pagani-Núñez for facilitating collection of some of the flies used in manipulations. We also thank Ángela Martínez-García for help with management of ARISA data and Natalia Juárez and Deseada Parejo for the pictures of owls and roller clutches, respectively. We appreciate the comments provided by Dr. Adèle Mennerat and five anonymous referees on earlier versions of the manuscript.All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.While direct detrimental effects of parasites on hosts are relatively well documented, other more subtle but potentially important effects of parasitism are yet unexplored. Biological activity of ectoparasites, apart from skin injuries and blood-feeding, often results in blood remains, or parasite faeces that accumulate and modify the host environment. In this way, ectoparasite activities and remains may increase nutrient availability that may favour colonization and growth of microorganisms including potential pathogens. Here, by the experimental addition of hematophagous flies (Carnus hemapterus, a common ectoparasite of birds) to nests of spotless starlings Sturnus unicolor during incubation, we explore this possible side effect of parasitism which has rarely, if ever, been investigated. Results show that faeces and blood remains from parasitic flies on spotless starling eggshells at the end of incubation were more abundant in experimental than in control nests. Moreover, eggshell bacterial loads of different groups of cultivable bacteria including potential pathogens, as well as species richness of bacteria in terms of Operational Taxonomic Units (OTUs), were also higher in experimental nests. Finally, we also found evidence of a link between eggshell bacterial loads and increased embryo mortality, which provides indirect support for a bacterial-mediated negative effect of ectoparasitism on host offspring. Trans-shell bacterial infection might be one of the main causes of embryo death and, consequently, this hitherto unnoticed indirect effect of ectoparasitism might be widespread in nature and could affect our understanding of ecology and evolution of host-parasite interactionsFinancial support was provided by Spanish Ministerio de Economía y Competitividad and FEDER (CGL2013-48193-C3-1-P, CGL2013-48193-C3-2-P), by JAE programme to DMG and MRR, and by Juan de la Cierva and Ramón y Cajal programmes to GT. All procedures were conducted under licence from the Environmental Department of the Regional Government of Andalucía, Spain (reference SGYB/FOA/AFR)

Efficacy of a 7-day course of furazolidone, levofloxacin, and lansoprazole after failed Helicobacter pylori eradication

<p>Abstract</p> <p>Background</p> <p>Increasing resistance to clarithromycin and nitroimidazole is the main cause of failure in the <it>Helicobacter pylori </it>eradication. The ideal retreatment regimen remains unclear, especially in developing countries, where the infection presents high prevalence and resistance to antibiotics. The study aimed at determining the efficacy, compliance and adverse effects of a regimen that included furazolidone, levofloxacin and lansoprazole in patients with persistent <it>Helicobacter pylori </it>infection, who had failed to respond to at least one prior eradication treatment regimen.</p> <p>Methods</p> <p>This study included 48 patients with peptic ulcer disease. <it>Helicobacter pylori </it>infection was confirmed by a rapid urease test and histological examination of samples obtained from the antrum and corpus during endoscopy. The eradication therapy consisted of a 7-day twice daily oral administration of lansoprazole 30 mg, furazolidone 200 mg and levofloxacin 250 mg. Therapeutic success was confirmed by a negative rapid urease test, histological examination and 14C- urea breath test, performed 12 weeks after treatment completion. The Chi-square method was used for comparisons among eradication rates, previous treatments and previous furazolidone use.</p> <p>Results</p> <p>Only one of the 48 patients failed to take all medications, which was due to adverse effects (vomiting). Per-protocol and intention-to-treat eradication rates were 89% (95% CI- 89%–99%) and 88% (88–92%), respectively. Mild and moderate adverse effects were reported by 41 patients (85%). For patients with one previous treatment failure, the eradication rate was 100%. Compared to furazolidone-naïve patients, eradication rates were lower in those who had failed prior furazolidone-containing regimen(s) (74% vs. 100%, p = 0.002).</p> <p>Conclusion</p> <p>An empiric salvage-regimen including levofloxacin, furazolidone and lansoprazole is very effective in the eradication of <it>Helicobacter pylori</it>, particularly in patients that have failed one prior eradication therapy.</p

Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members

Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.Spanish government and the European Union (FIS-PI10/00338) and from the ERC-2009-Adg 25027-PELE European project

Comparative genomics of the type VI secretion systems of Pantoea and Erwinia species reveals the presence of putative effector islands that may be translocated by the VgrG and Hcp proteins

<p>Abstract</p> <p>Background</p> <p>The Type VI secretion apparatus is assembled by a conserved set of proteins encoded within a distinct locus. The putative effector proteins Hcp and VgrG are also encoded within these loci. We have identified numerous distinct Type VI secretion system (T6SS) loci in the genomes of several ecologically diverse <it>Pantoea </it>and <it>Erwinia </it>species and detected the presence of putative effector islands associated with the <it>hcp </it>and <it>vgrG </it>genes.</p> <p>Results</p> <p>Between two and four T6SS loci occur among the <it>Pantoea </it>and <it>Erwinia </it>species. While two of the loci (T6SS-1 and T6SS-2) are well conserved among the various strains, the third (T6SS-3) locus is not universally distributed. Additional orthologous loci are present in <it>Pantoea </it>sp. aB-valens and <it>Erwinia billingiae </it>Eb661. Comparative analysis of the T6SS-1 and T6SS-3 loci showed non-conserved islands associated with the <it>vgrG </it>and <it>hcp</it>, and <it>vgrG </it>genes, respectively. These regions had a G+C content far lower than the conserved portions of the loci. Many of the proteins encoded within the <it>hcp </it>and <it>vgrG </it>islands carry conserved domains, which suggests they may serve as effector proteins for the T6SS. A number of the proteins also show homology to the C-terminal extensions of evolved VgrG proteins.</p> <p>Conclusions</p> <p>Extensive diversity was observed in the number and content of the T6SS loci among the <it>Pantoea </it>and <it>Erwinia </it>species. Genomic islands could be observed within some of T6SS loci, which are associated with the <it>hcp </it>and <it>vgrG </it>proteins and carry putative effector domain proteins. We propose new hypotheses concerning a role for these islands in the acquisition of T6SS effectors and the development of novel evolved VgrG and Hcp proteins.</p

Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza

<p>Abstract</p> <p>Background</p> <p>Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients.</p> <p>Methods</p> <p>Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient.</p> <p>Results</p> <p>Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1β, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus.</p> <p>Conclusions</p> <p>Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.</p