Manipulation of the Quorum Sensing Signal AI-2 Affects the Antibiotic-Treated Gut Microbiota

The mammalian gut microbiota harbors a diverse ecosystem where hundreds of bacterial species interact with each other and their host. Given that bacteria use signals to communicate and regulate group behaviors (quorum sensing), we asked whether such communication between different commensal species can influence the interactions occurring in this environment. We engineered the enteric bacterium, Escherichia coli, to manipulate the levels of the interspecies quorum sensing signal, autoinducer-2 (AI-2), in the mouse intestine and investigated the effect upon antibiotic-induced gut microbiota dysbiosis. E. coli that increased intestinal AI-2 levels altered the composition of the antibiotic-treated gut microbiota, favoring the expansion of the Firmicutes phylum. This significantly increased the Firmicutes/Bacteroidetes ratio, to oppose the strong effect of the antibiotic, which had almost cleared the Firmicutes. This demonstrates that AI-2 levels influence the abundance of the major phyla of the gut microbiota, the balance of which is known to influence human health.

Impacto dos instrumentos de fiscalidade municipal em contexto de reabilitação urbana

Dada a importância da reabilitação urbana e o peso financeiro associado às operações, identifiquei os instrumentos fiscais associados à reabilitação e a aplicabilidade de um deles à área de reabilitação urbana Coimbra Baixa. Começa-se por encontrar uma definição de cidade, como sistema social complexo em constante evolução e enunciam-se as principais modificações sofridas ao longo do tempo histórico. Dentre os acontecimentos históricos, faz-se alusão à Revolução industrial, período que alterou a economia e a sociedade até então existente e o período do pós II Guerra Mundial, época de construção nova e reconstrução. Portugal, fortemente influenciado pelas mudanças trazidas pela era industrial, como o êxodo rural e a desertificação progressiva dos centros urbanos, apresenta como característica urbanística a expansão do território, construída sem um procedimento planificado e regulamentado. As medidas politicas e legais que foram implementadas, como, o congelamento das rendas, inibitório de investimento na manutenção e conservação dos imóveis arrendados e a tradição portuguesa de comprar ou construir imoveis para habitação ao invés de arrendar, contribuíram fortemente para a degradação física do edificado. Perante o estado avançado de degradação das áreas centrais, foram implementadas políticas urbanas de reabilitação como alternativa à construção nova. Para tal, foram criados e implantados diversos programas de apoio financeiro, nacionais e europeus que se descrevem. Relativamente à regulação da reabilitação urbana, identificam-se os diversos diplomas legais existentes, que regulam as intervenções de reabilitação urbana que contemplam. Seguidamente procede-se a uma análise sucinta do sistema fiscal português e à descrição dos tributos suscetíveis de afetar a reabilitação urbana, identificando-se os benefícios fiscais criados para incentivar e promover as ações de reabilitação urbana. Finalmente, com a aplicação de um caso prático, procura-se avaliar o impacto do benefício fiscal, em sede de IMI, à área de reabilitação urbana intitulada de Coimbra Baixa, no município de Coimbra.

The influence of the rearing period on intramammary infections in Swiss dairy heifers: A cross-sectional study

Healthy replacement heifers are one of the foundations of a healthy dairy herd. Farm management andrearing systems in Switzerland provide a wide variety of factors that could potentially be associated withintramammary infections (IMI) in early lactating dairy heifers. In this study, IMI with minor mastitispathogens such as coagulase-negative staphylococci (CNS), contagious pathogens, and environmentalmajor pathogens were identified. Fifty-four dairy farms were enrolled in the study. A questionnaire wasused to collect herd level data on housing, management and welfare of young stock during farm isitsand interviews with the farmers. Cow-level data such as breed, age at first calving, udder condition andswelling, and calving ease were also recorded. Data was also collected about young stock that spent aperiod of at least 3 months on an external rearing farm or on a seasonal alpine farm. At the quarterlevel, teat conditions such as teat lesions, teat dysfunction, presence of a papilloma and teat lengthwere recorded. Within 24 h after parturition, samples of colostral milk from 1564 quarters (391 heifers)were collected aseptically for bacterial culture. Positive bacteriological culture results were found in 49%of quarter samples. Potential risk factors for IMI were identified at the quarter, animal and herd levelusing multivariable and multilevel logistic regression analysis. At the herd level tie-stalls, and at cow-level the breed category “Brown cattle” were risk factors for IMI caused by contagious major pathogenssuch as Staphylococcus aureus (S. aureus). At the quarter-level, teat swelling and teat lesions were highlyassociated with IMI caused by environmental major pathogens. At the herd level heifer rearing at externalfarms was associated with less IMI caused by major environmental pathogens. Keeping pregnant heifersin a separate group was negatively associated with IMI caused by CNS. The odds of IMI with coagulase-negative staphylococci increased if weaning age was less than 4 months and if concentrates were fed tocalves younger than 2 weeks. This study identified herd, cow- and quarter-level risk factors that may beimportant for IMI prevention in the future.

Hādhā kitāb Kashf al-qināʻ ʻan wujūh hujjīyat al-ijtimāʻ [microform] /

Caption title.

Determination of alpha-conotoxin binding modes on neuronal nicotinic acetylcholine receptors

alpha-Conotoxins, from cone snails, and alpha-neurotoxins, from snakes, are competitive inhibitors of nicotinic acetylcholine receptors (nAChRs) that have overlapping binding sites in the ACh binding pocket. These disulphide-rich peptides are used extensively as tools to localize and pharmacologically characterize specific nAChRs subtypes. Recently, a homology model based on the high-resolution structure of an ACh binding protein (AChBP) allowed the three-fingered alpha-neurotoxins to be docked onto the alpha7 nAChR. To investigate if alpha-conotoxins interact with the nAChR in a similar manner, we built homology models of human alpha7 and alpha3beta2 nAChRs, and performed docking simulations of alpha-conotoxins ImI, PnIB, PnIA and MII using the program GOLD. Docking revealed that alpha-conotoxins have a different mode of interaction compared with alpha-neurotoxins, with surprisingly few nAChR residues in common between their overlapping binding sites. These docking experiments show that Imi and PnIB bind to the ACh binding pocket via a small cavity located above the beta9/beta10 hairpin of the (+)alpha7 nAChR subunit. Interestingly, PnIB, PnIA and MII were found to bind in a similar location on alpha7 or alpha3beta2 receptors mostly through hydrophobic interactions, while ImI bound further from the ACh binding pocket, mostly through electrostatic interactions. These findings, which distinguish alpha-conotoxin and alpha-neurotoxin binding modes, have implications for the rational design of selective nAChR antagonists. Copyright (C) 2004 John Wiley Sons, Ltd.

Toxin insights into nicotinic acetylcholine receptors

Venomous species have evolved cocktails of bioactive peptides to facilitate prey capture. Given their often exquisite potency and target selectivity, venom peptides provide unique biochemical tools for probing the function of membrane proteins at the molecular level. in the field of the nicotinic acetylcholine receptors (nAChRs), the subtype specific snake alpha-neurotoxins and cone snail alpha-conotoxins have been widely used to probe receptor structure and function in native tissues and recombinant systems. However, only recently has it been possible to generate an accurate molecular view of these nAChR-toxin interactions. Crystal structures of AChBP, a homologue of the nAChR ligand binding domain, have now been solved in complex with alpha-cobratoxin, alpha-conotoxin PnIA and alpha-conotoxin Iml. The orientation of all three toxins in the ACh binding site confirms many of the predictions obtained from mutagenesis and docking simulations on homology models of mammalian nAChR. The precise understanding of the molecular determinants of these complexes is expected to contribute to the development of more selective nAChR modulators. In this commentary, we review the structural data on nAChR-toxin interactions and discuss their implications for the design of novel ligands acting at the nAChR. (c) 2006 Elsevier Inc. All rights reserved.

Alpha-selenoconotoxins, a new class of potent alpha(7) neuronal nicotinic receptor antagonists

Disulfide bonds are important structural motifs that play an essential role in maintaining the conformational stability of many bioactive peptides. Of particular importance are the conotoxins, which selectively target a wide range of ion channels that are implicated in numerous disease states. Despite the enormous potential of conotoxins as therapeutics, their multiple disulfide bond frameworks are inherently unstable under reducing conditions. Reduction or scrambling by thiol-containing molecules such as glutathione or serum albumin in intracellular or extracellular environments such as blood plasma can decrease their effectiveness as drugs. To address this issue, we describe a new class of selenoconotoxins where cysteine residues are replaced by selenocysteine to form isosteric and non-reducible diselenide bonds. Three isoforms of alpha-conotoxin ImI were synthesized by t-butoxycarbonyl chemistry with systematic replacement of one([ Sec(2,8)] ImI or [Sec(3,12)] ImI), or both([Sec(2,3,8,12)] ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the alpha(7) nicotinic acetylcholine receptor, with each seleno-analogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.

Hydrophobicity and surface electrostatic charge of conidia of the mycoparasite Coniothyrium minitans

The effect of increasing culture age on cell surface hydrophobicity (CSH) and cell surface electrostatic charge (measured as zeta potential) of conidia from five isolates of Coniothyrium minitans representing three different morphological types was examined. Conidial CSH of three isolates (A2 960/1, CH1 and CH2) decreased with culture age, whereas CSH of two others (B 1300/2 and IMI 134523) remained high for the whole 42 day experimental period. In contrast, cell surface electrostatic charge decreased uniformly in conidia of all five isolates for the first 34 d and then rose slightly at 42 d. The variation in cell surface electrostatic charge (spectrum width) of the sampled conidia decreased with age for all five isolates. In all five isolates cell surface electrostatic charge of conidia became increasingly negative as the pH of the buffer used to suspend conidia was increased from pH 3.0 to 9.0. No relationship between colony morphology of C. minitans and conidial CSH and cell surface electrostatic charge was found.

The relationship between fracture toughness and microstructure in titanium alloys

Linear Elastic Fracture Mechanics has been used to study the microstructural factors controlling the strength and toughness of two alpha-beta, titanium alloys. Fracture toughness was found to be independent of orientation for alloy Ti/6A1/4-V, but orientation dependent for IMI 700, bend and tension specimens giving similar toughness values. Increasing the solution temperature led to the usual inverse relationship between strength and toughness, with toughness becoming a minimum as the beta transus was approached. The production of a double heat treated microstructure led to a 100% increase in toughness in the high strength alloy and a 20% increase in alloy Ti/6A1/4V, with little decrease in strength. The double heat treated microstruoture was produced by cooling from the beta field into the alpha beta field, followed. by conventional solution treatment and ageing. Forging above the beta transus led to an increase in toughness over alpha beta forging in the high strength alloy, but had little effect on the toughness of Ti/6A1/4V. Light and electron microscopy showed that the increased toughness resulted from the alpha phase being changed from mainly continuous to a discontinuous platelet form in a transformed beta matrix. Void formation occurred at the alpha-beta interface and crack propagation was via the interface or across the platelet depending on which process required the least energy. Varying the solution treatment temperature produced a varying interplatelet spacing and platelet thickness. The finest interplatelet spacing was associated with the highest toughness, since a higher applied stress was required to give the necessary stress concentration to initiate void formation. The thickest alpha platelet size gave the highest toughness which could be interpreted in terms of Krafftt's "process zone size" and the critical crack tip displacement criterion by Hahn and Rosenfield from an analysis by Goodier and Field.

The Fiftieth Anniversary of the Institute of Mathematics and Informatics

In October 1997 we celebrate the fiftieth anniversary of the founding of the Institute for Mathematics and Informatics (IMI) of the Bulgarian Academy of Sciences (BAS).

Digital Libraries and Portals Saving National Cultural Heritage (IMI–BAS Experience)

The current research activities of the Institute of Mathematics and Informatics at the Bulgarian Academy of Sciences (IMI—BAS) include the study and application of knowledge-based methods for the creation, integration and development of multimedia digital libraries with applications in cultural heritage. This report presents IMI-BAS’s developments at the digital library management systems and portals, i.e. the Bulgarian Iconographical Digital Library, the Bulgarian Folklore Digital Library and the Bulgarian Folklore Artery, etc. developed during the several national and international projects: - "Digital Libraries with Multimedia Content and its Application in Bulgarian Cultural Heritage" (contract 8/21.07.2005 between the IMI–BAS, and the State Agency for Information Technologies and Communications; - FP6/IST/P-027451 PROJECT LOGOS "Knowledge-on-Demand for Ubiquitous Learning", EU FP6, IST, Priority 2.4.13 "Strengthening the Integration of the ICT research effort in an Enlarged Europe" - NSF project D-002-189 SINUS "Semantic Technologies for Web Services and Technology Enhanced Learning". - NSF project IO-03-03/2006 ―Development of Digital Libraries and Information Portal with Virtual Exposition "Bulgarian Folklore Heritage". The presented prototypes aims to provide flexible and effective access to the multimedia presentation of the cultural heritage artefacts and collections, maintaining different forms and format of the digitized information content and rich functionality for interaction. The developments are a result of long- standing interests and work in the technological developments in information systems, knowledge processing and content management systems. The current research activities aims at creating innovative solutions for assembling multimedia digital libraries for collaborative use in specific cultural heritage context, maintaining their semantic interoperability and creating new services for dynamic aggregation of their resources, access improvement, personification, intelligent curation of content, and content protection. The investigations are directed towards the development of distributed tools for aggregating heterogeneous content and ensuring semantic compatibility with the European digital library EUROPEANA, thus providing possibilities for pan- European access to rich digitalised collections of Bulgarian cultural heritage.

Digitization of Old Mathematical Periodicals Published by the Institute of Mathematics and Informatics, Bulgarian Academy of Sciences

The digitization practice for retro-converting of the mathematical periodicals, published by the Institute of Mathematics and Informatics, Bulgarian Academy of Sciences (IMI-BAS) and the followed benefits for long-term preserving and assuring open access to these materials is discussed in the article.

PREFACE

The Conference on Partial Differential Equations and Applications, Sofia, September 14–16, 2011 (In honor of 65-th Anniversary of Professor Petar Popivanov) took place in the premises of the Institute of Mathematics and Informatics (IMI) of the Bulgarian Academy of Sciences (BAS). The conference was organized by the Section “Differential Equations and Mathematical Physics” of IMI with the participation of research groups on PDE from Universit`a di Cagliari and Universit`a di Torino (Italy), with the organizing committee – N. Kutev (IMI–BAS) – chair, G. Boyadzhiev (IMI–BAS) – secretary, T. Gramchev (Univ. Cagliari) and A. Oliaro (Univ. Torino) – members, and thefollowing program/scientific committee: T. Gramchev (chair), N. Kutev (IMI–BAS), L. Rodino (Universit`a di Torino), M. Ruzhansky (Imperial College London), A. Slavova (IMI–BAS), C. Van Der Mee (Universit`a di Cagliari).

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease.

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of protective neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.