Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility.

The flexibility of different regions of HIV-1 protease was examined by using a database consisting of 73 X-ray structures that differ in terms of sequence, ligands or both. The root-mean-square differences of the backbone for the set of structures were shown to have the same variation with residue number as those obtained from molecular dynamics simulations, normal mode analyses and X-ray B-factors. This supports the idea that observed structural changes provide a measure of the inherent flexibility of the protein, although specific interactions between the protease and the ligand play a secondary role. The results suggest that the potential energy surface of the HIV-1 protease is characterized by many local minima with small energetic differences, some of which are sampled by the different X-ray structures of the HIV-1 protease complexes. Interdomain correlated motions were calculated from the structural fluctuations and the results were also in agreement with molecular dynamics simulations and normal mode analyses. Implications of the results for the drug-resistance engendered by mutations are discussed briefly.

Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds.

Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=[51.4, 588.8] (for 184V) to 2.7/100-person-years;[0.7, 10.9] (for 215D). RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation.

Production costs and fruit yield profitability in the initial harvest of custard apple trees

The aim of this study was to estimate the production cost and economic indicators associated with the production and sales of fruits from 20 custard apple progenies during the initial five harvests, in order to identify the harvest season from which custard apple exploitation becomes profitable, as well as the most promising progenies from an economic point of view. The fruit yield data upon which the present work was based were obtained during the period from 2001 to 2005, in an experiment that evaluated 20 custard apple half-sibling progenies, under sprinkler irrigation. The progenies were evaluated in a random block design with five replicates and plots consisting of four plants each. The exploitation of custard apple progenies only showed to be a profitable agribusiness after the fourth year. Before that, only A3 and A4 progenies in the second year, and P3 and P11 in the third year provided profitable incomes. Considering the methodological assumptions imposed concerning the time period analysis and the prices as of July 2007, the most important profitability indicators (operating profit, return index and equilibrium price) evidenced that the A4 progeny is the most recommended, although other progenies are also highlighted, such as FJ1 and FJ2. As already discussed, the progenies showing the highest average yields of five harvests are not always the most economically recommendable ones.

GENETIC DIVERSITY AND STRUCTURE OF Oenocarpus mapora GERMPLASM CONSERVED AT EASTERN AMAZON

ABSTRACT The aim of this study was to evaluate the genetic diversity and structure in the germoplasm of Oenocarpus mapora conserved at Eastern Amazon. Thus, 88 individuals were genotyped with five microsatellite loci. These individuals belong to 24 accessions that were sampled in eight sample places of three Brazilian Amazon states conserved at the Active Germplasm Bank (AGB) of Embrapa Eastern Amazon. All loci were polymorphic and they generated 85 alleles with an average of 17 alleles per loci. Total genetic diversity (HE) was 0.48. Sample places were considered genetically distinct, with ?p = 0.354. The analysis of molecular variance (AMOVA) identified that the genetic portion among areas was of 36.14% and within 63.86%. The Nei distances varied from 0.091 between Abaetetuba and Santo Antônio do Tauá, both in the state of Pará (PA), to 4.18, between Parintins, AM and Rio Branco, AC. By means of Bayesian analysis, it was identified nine clusters that compose the accessions of the germplasm bank, with different distributions among individuals. The study showed high fixation rates per sample area, which indicates that there may have been significant inbreeding or crossing among parental individuals. It suggests that future samples should be made of different plants in natural populations. Even though, it was verified that there is considerable genetic variation in the germplasm of O. mapora.

More than Words? An Analysis on the Language and Structure of General Election Manifestos of the British Labour Party 1983-2005

The topic of this study is the language of the educational policies of the British Labour party in the General Election manifestos between the years 1983-2005. The twenty-year period studied has been a period of significant changes in world politics, and in British politics, especially for the Labour party. The emergence educational policy as a vote-winner of the manifestos of the nineties has been noteworthy. The aim of the thesis is two-fold: to look at the structure of the political manifesto as an example of genre writing and to analyze the content utilizing the approach of critical discourse analysis. Furthermore, the aim of this study is not to pinpoint policy positions but to look at what is the image that the Labour Party creates of itself through these manifestos. The analysis of the content is done by a method of close-reading. Based on the findings, the methodology for the analysis of the content was created. This study utilized methodological triangulation which means that the material is analyzed from several methodological aspects. The aspects used in this study are ones of lexical features (collocation, coordination, euphemisms, metaphors and naming), grammatical features (thematic roles, tense, aspect, voice and modal auxiliaries) and rhetoric (Burke, Toulmin and Perelman). From the analysis of the content a generic description is built. By looking at the lexical, grammatical and rhetorical features a clear change in language of the Labour Party can be detected. This change is foreshadowed already in the 1992 manifesto but culminates in the 1997 manifesto which would lead Labour to a landslide victory in the General Election. During this twenty-year period Labour has moved away from the old commitments and into the new sphere of “something for everybody”. The pervasiveness of promotional language and market inspired vocabulary into the sphere of manifesto writing is clear. The use of the metaphors seemed to be the tool for the creation of the image of the party represented through the manifestos. A limited generic description can be constructed from the findings based on the content and structure of the manifestos: especially more generic findings such as the use of the exclusive we, the lack of certain anatomical parts of argument structure, the use of the future tense and the present progressive aspect can shed light to the description of the genre of manifesto writing. While this study is only the beginning, it proves that the combination of looking at the lexical, grammatical and rhetorical features in the study of manifestos is a promising one.

A novel approach to analysing the regimes of temporary streams in relation to their controls on the composition and structure of aquatic biota

Temporary streams are those water courses that undergo the recurrent cessation of flow or the complete drying of their channel. The structure and composition of biological communities in temporary stream reaches are strongly dependent on the temporal changes of the aquatic habitats determined by the hydrological conditions. Therefore, the structural and functional characteristics of aquatic fauna to assess the ecological quality of a temporary stream reach cannot be used without taking into account the controls imposed by the hydrological regime. This paper develops methods for analysing temporary streams' aquatic regimes, based on the definition of six aquatic states that summarize the transient sets of mesohabitats occurring on a given reach at a particular moment, depending on the hydrological conditions: Hyperrheic, Eurheic, Oligorheic, Arheic, Hyporheic and Edaphic. When the hydrological conditions lead to a change in the aquatic state, the structure and composition of the aquatic community changes according to the new set of available habitats. We used the water discharge records from gauging stations or simulations with rainfall-runoff models to infer the temporal patterns of occurrence of these states in the Aquatic States Frequency Graph we developed. The visual analysis of this graph is complemented by the development of two metrics which describe the permanence of flow and the seasonal predictability of zero flow periods. Finally, a classification of temporary streams in four aquatic regimes in terms of their influence over the development of aquatic life is updated from the existing classifications, with stream aquatic regimes defined as Permanent, Temporary-pools, Temporary-dry and Episodic. While aquatic regimes describe the long-term overall variability of the hydrological conditions of the river section and have been used for many years by hydrologists and ecologists, aquatic states describe the availability of mesohabitats in given periods that determine the presence of different biotic assemblages. This novel concept links hydrological and ecological conditions in a unique way. All these methods were implemented with data from eight temporary streams around the Mediterranean within the MIRAGE project. Their application was a precondition to assessing the ecological quality of these streams.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.

Local privatization, intermunicipal cooperation, transaction costs and political interests: Evidence from Spain

Several empirical studies have analyzed the factors that influence local privatization. Variables related to fiscal stress, cost reduction, political processes and ideological attitudes are the most common explanatory variables used in these studies. In this paper, we add to this literature by examining the influence of transaction costs and political factors on local governments’ choices through new variables. In addition to this, we consider the role of additional aspects, such as intermunicipal cooperation as a potential alternative to privatization in order to exploit scale economies or scope economies. We consider two relevant services: solid waste collection and water distribution. Results from our estimates show that privatization (that is, contracting out to a private firm) is less common for water distribution than for solid waste collection. Higher transaction costs in water distribution are consistent with this finding. Furthermore, we find that municipalities with a conservative ruling party privatize more often regardless of the ideological orientation of the constituency. This shows that those political interests able to influence local elections are more important in determining the form of delivery than is the basic ideological stance of the constituency. Finally, we find that intermunicipal cooperation is an alternative to local privatization.

Change of Electricity Distribution Industry: Drivers and Opening Business Opportunities

As a result of the recent regulatory amendments and other development trends in the electricity distribution business, the sector is currently witnessing radical restructuring that will eventually impact the business logics of the sector. This report represents upcoming changes in the electricity distribution industry and concentrates on the factors that are expected to be the most fundamental ones. Electricity network companies nowadays struggle with legislative and regulatory requirements that focus on both the operational efficiency and the reliability of electricity distribution networks. The forces that have an impact on the distribution network companies can be put into three main categories that define the transformation at a general level. Those are: (1) a requirement for a more functional marketplace for energy, (2) environmental aspects (combating climate change etc.), and (3) a strongly emphasized requirement for the security of energy supply. The first point arises from the legislators’ attempt to increase competition in electricity retail markets, the second one concerns both environmental protection and human safety issues, and the third one indicates societies’ reduced willingness to accept interruptions in electricity supply. In the future, regulation of electricity distribution business may lower the threshold for building more weather-resistant networks, which in turn means increased underground cabling. This development pattern is reinforced by tightening safety and environmental regulations that ultimately make the overhead lines expensive to build and maintain. The changes will require new approaches particularly in network planning, construction, and maintenance. The concept for planning, constructing, and maintaining cable networks is necessary because the interdependencies between network operations are strong, in other words, the nature of the operation requires a linkage to other operations.

Costs and Benefits of a Shared Digital Long-Term Preservation System

Paper presented at the 40th Annual Conference of LIBER (Ligue des Bibliothèques Européennes de Recherche - Association of European Research Libraries) on July 1st, 2011; with the slides used at the presentation.

Costs and Benefits of a Shared Digital Long-Term Preservation System

This paper describes the cost-benefit analysis of digital long-term preservation (LTP) that was carried out in the context of the Finnish National Digital Library Project (NDL) in 2010. The analysis was based on the assumption that as many as 200 archives, libraries, and museums will share an LTP system. The term ‘system’ shall be understood as encompassing not only information technology, but also human resources, organizational structures, policies and funding mechanisms. The cost analysis shows that an LTP system will incur, over the first 12 years, cumulative costs of €42 million, i.e. an average of €3.5 million per annum. Human resources and investments in information technology are the major cost factors. After the initial stages, the analysis predicts annual costs of circa €4 million. The analysis compared scenarios with and without a shared LTP system. The results indicate that a shared system will have remarkable benefits. At the development and implementation stages, a shared system shows an advantage of €30 million against the alternative scenario consisting of five independent LTP solutions. During the later stages, the advantage is estimated at €10 million per annum. The cumulative cost benefit over the first 12 years would amount to circa €100 million.

Harmonization of Environmental Costs and Investments Reporting

The objective of this Master’s Thesis is to examine the current state of environmental costs and investments reporting at Stora Enso in the Business Area of Printing and Reading. Differences and the factors causing the differences in environmental costs and investments reporting are examined in order to further harmonize the reporting between the mills. Research method is a case study, which comprises 11 paper mills. Environmental costs are studied from year 2012 and environmental investments from year 2011 or from 2012 depending on the mill. The results show that there are two types of differences such as actual and harmonisable affecting to environmental costs reporting. Actual differences result from factors such as location and technical features of the mill. Harmonisable differences represent differences, which distort the actual differences. Factors that cause harmonisable differences are identification and traceability of environmental costs as well as interpretation of the instructions. Estimation of the environmental share of indirect environmental investments causes differences between the mills in environmental investments reporting, as it has to be done case-by-case judgments. A further research could consider a detailed examination of the data registering process in order to further improve traceability of environmental costs. Furthermore, identification and reporting of potential savings could be studied from environmental point of view as resource efficiency is an increasing interest.