Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis.

OBJECTIVES: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. METHODS: A series of 20 dipeptides of general structure NH(2) -L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1) , pK(2) and pK(3) ) and lipophilicity parameters (log P(N) and log D(7.4) ) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP) , meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). RESULTS: Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. CONCLUSION: This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression. Chirality 24:566-576, 2012. © 2012 Wiley Periodicals, Inc.

Sex allocation conflict in ants: when the queen rules.

Insect societies are paramount examples of cooperation, yet they also harbor internal conflicts whose resolution depends on the power of the opponents. The male-haploid, female-diploid sex-determining system of ants causes workers to be more related to sisters than to brothers, whereas queens are equally related to daughters and sons. Workers should thus allocate more resources to females than to males, while queens should favor an equal investment in each sex. Female-biased sex allocation and manipulation of the sex ratio during brood development suggest that workers prevail in many ant species. Here, we show that queens of Formica selysi strongly influenced colony sex allocation by biasing the sex ratio of their eggs. Most colonies specialized in the production of a single sex. Queens in female-specialist colonies laid a high proportion of diploid eggs, whereas queens in male-specialist colonies laid almost exclusively haploid eggs, which constrains worker manipulation. However, the change in sex ratio between the egg and pupae stages suggests that workers eliminated some male brood, and the population sex-investment ratio was between the queens' and workers' equilibria. Altogether, these data provide evidence for an ongoing conflict between queens and workers, with a prominent influence of queens as a result of their control of egg sex ratio.

Dynamic Modelling of Material Flows and Sustainable Resource Use: Case Studies in Regional Metabolism and Space Life Support Systems

Sustainable resource use is one of the most important environmental issues of our times. It is closely related to discussions on the 'peaking' of various natural resources serving as energy sources, agricultural nutrients, or metals indispensable in high-technology applications. Although the peaking theory remains controversial, it is commonly recognized that a more sustainable use of resources would alleviate negative environmental impacts related to resource use. In this thesis, sustainable resource use is analysed from a practical standpoint, through several different case studies. Four of these case studies relate to resource metabolism in the Canton of Geneva in Switzerland: the aim was to model the evolution of chosen resource stocks and flows in the coming decades. The studied resources were copper (a bulk metal), phosphorus (a vital agricultural nutrient), and wood (a renewable resource). In addition, the case of lithium (a critical metal) was analysed briefly in a qualitative manner and in an electric mobility perspective. In addition to the Geneva case studies, this thesis includes a case study on the sustainability of space life support systems. Space life support systems are systems whose aim is to provide the crew of a spacecraft with the necessary metabolic consumables over the course of a mission. Sustainability was again analysed from a resource use perspective. In this case study, the functioning of two different types of life support systems, ARES and BIORAT, were evaluated and compared; these systems represent, respectively, physico-chemical and biological life support systems. Space life support systems could in fact be used as a kind of 'laboratory of sustainability' given that they represent closed and relatively simple systems compared to complex and open terrestrial systems such as the Canton of Geneva. The chosen analysis method used in the Geneva case studies was dynamic material flow analysis: dynamic material flow models were constructed for the resources copper, phosphorus, and wood. Besides a baseline scenario, various alternative scenarios (notably involving increased recycling) were also examined. In the case of space life support systems, the methodology of material flow analysis was also employed, but as the data available on the dynamic behaviour of the systems was insufficient, only static simulations could be performed. The results of the case studies in the Canton of Geneva show the following: were resource use to follow population growth, resource consumption would be multiplied by nearly 1.2 by 2030 and by 1.5 by 2080. A complete transition to electric mobility would be expected to only slightly (+5%) increase the copper consumption per capita while the lithium demand in cars would increase 350 fold. For example, phosphorus imports could be decreased by recycling sewage sludge or human urine; however, the health and environmental impacts of these options have yet to be studied. Increasing the wood production in the Canton would not significantly decrease the dependence on wood imports as the Canton's production represents only 5% of total consumption. In the comparison of space life support systems ARES and BIORAT, BIORAT outperforms ARES in resource use but not in energy use. However, as the systems are dimensioned very differently, it remains questionable whether they can be compared outright. In conclusion, the use of dynamic material flow analysis can provide useful information for policy makers and strategic decision-making; however, uncertainty in reference data greatly influences the precision of the results. Space life support systems constitute an extreme case of resource-using systems; nevertheless, it is not clear how their example could be of immediate use to terrestrial systems.

Efficacité allocative des budgets publics et méthode de l'allocation contingente

Cette contribution s'intéresse à la convergence qui devrait exister entre la demande populaire en matière de prestations publiques et les décisions budgétaires des autorités afin que le secteur public soit efficace du point de vue allocatif. Elle cherche à appliquer la méthode de l'allocation contingente dans une volonté d'impliquer la population dans la répartition des ressources budgétaires. Schématiquement, il s'agit d'interroger les administré-e-s dans le cadre d'une enquête et de leur demander d'allouer un budget donné entre les différentes catégories de prestations publiques que l'administration doit offrir. Cette méthode est appliquée ici de façon expérimentale en utilisant comme périmètre d'analyse les budgets des collectivités locales suisses. Les tests effectués sur les résultats montrent que les préférences révélées ne le sont pas sur une base aléatoire. Si des différences apparaissent entre les allocations contingentes et la manière dont les ressources sont effectivement réparties entre les prestations communales, ces différences semblent découler d'une divergence de vues réelle et non d'un biais lié à la méthode.

Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins.

Gliotransmitters Travel in Time and Space.

The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.

Genetic components to caste allocation in a multiple-queen ant species.

Reproductive division of labor and the coexistence of distinct castes are hallmarks of insect societies. In social insect species with multiple queens per colony, the fitness of nestmate queens directly depends on the process of caste allocation (i.e., the relative investment in queen, sterile worker and male production). The aim of this study is to investigate the genetic components to the process of caste allocation in a multiple-queen ant species. We conducted controlled crosses in the Argentine ant Linepithema humile and established single-queen colonies to identify maternal and paternal family effects on the relative production of new queens, workers, and males. There were significant effects of parental genetic backgrounds on various aspects of caste allocation: the paternal lineage affected the proportion of queens and workers produced whereas the proportions of queens and males, and females and males were influenced by the interaction between parental lineages. In addition to revealing nonadditive genetic effects on female caste determination in a multiple-queen ant species, this study reveals strong genetic compatibility effects between parental genomes on caste allocation components.

Palaeotectonic and palaeogeographic evolution of the western Tethys and PeriTethyan domain (IGCP Project 369)

Project No. 369 (''Comparative Evolution of PeriTethyan Rift Basins'') of the International Geological Correlation Program produced a new palaeotectonic-palaeo-geographic atlas of the western PeriTethyan domain. The atlas contains more than two hundred new maps and documents grouped in nine regional sets (Iberia, Polish Trough, Eastern European and Scythian Platforms, Moesian Platform, Levant, Arabian Platform,, Northern Africa, NE Africa-NW Arabia, Libya-Pelagian Shelf plus a set of reconstructions for the whole western Tethys. The area, considered in the atlas stretches. from west to east, from the eastern Atlantic shores to the Urals and, from north to south, from the Baltic shield to equatorial Africa; the time span covered extends from the Late. Carboniferous to the Present. The dataset, resulting from an extensive cooperation between industrial and academic sources, is accessible interactively on a CD-ROM (Stampfli et al., 2001a) and includes legend, timetable, short explanatory notes, full references and additional supporting data. This dataset provides information on the development of the Tethyan realm in space and time. In particular, the relation between the Variscan and Cimmerian cycles in the Mediterranean realm is illustrated by numerous palaeogeographic and palaeotectonic maps.

Evaluation of a novel biomaterial in the suprachoroidal space of the rabbit eye.

PURPOSE: Drug delivery to treat diseases of the posterior segment of the eye, such as choroidal neovascularization and its complications, is hampered by poor intraocular penetration and rapid elimination of the drug from the eye. The purpose of this study was to investigate the feasibility and tolerance of suprachoroidal injections of poly(ortho ester) (POE), a bioerodible and biocompatible polymer, as a biomaterial potentially useful for development of sustained drug delivery systems. METHODS: After tunnelization of the sclera, different formulations based on POE were injected (100 microL) into the suprachoroidal space of pigmented rabbits and compared with 1% sodium hyaluronate. Follow-up consisted of fundus observations, echography, fluorescein angiography, and histologic analysis over 3 weeks. RESULTS: After injection, POE spread in the suprachoroidal space at the posterior pole. It was well tolerated and progressively disappeared from the site of injection without sequelae. No bleeding or retinal detachment occurred. Echographic pictures showed that the material was present in the suprachoroidal space for 3 weeks. Angiography revealed minor pigment irregularities at the site of injection, but no retinal edema or necrosis. Histology showed that POE was well tolerated in the choroid. CONCLUSIONS: POE suprachoroidal injections, an easy, controllable, and reproducible procedure, were well tolerated in the rabbit eye. POE appears to be a promising biomaterial to deliver drugs focally to the choroid and the retina.