Spatio-temporal dynamics and transition from asymptotic equilibrium to bounded oscillations in Chrysomya albiceps (Diptera, Calliphoridae)

The sensitivity of parameters that govern the stability of population size in Chrysomya albiceps and describe its spatial dynamics was evaluated in this study. The dynamics was modeled using a density-dependent model of population growth. Our simulations show that variation in fecundity and mainly in survival has marked effect on the dynamics and indicates the possibility of transitions from one-point equilibrium to bounded oscillations. C. albiceps exhibits a two-point limit cycle, but the introduction of diffusive dispersal induces an evident qualitative shift from two-point limit cycle to a one fixed-point dynamics. Population dynamics of C. albiceps is here compared to dynamics of Cochliomyia macellaria, C. megacephala and C. putoria.

Empirical approaches to inequality of opportunity: principles, measures, and evidence

We put together the different conceptual issues involved in measuring inequality of opportunity, discuss how these concepts have been translated into computable measures, and point out the problems and choices researchers face when implementing these measures. Our analysis identifies and suggests several new possibilities to measure inequality of opportunity. The approaches are illustrated with a selective survey of the empirical literature on income inequality of opportunity.

Genetic heterogeneity of the Coppock-like cataract: a mutation in CRYBB2 on chromosome 22q11.2.

PURPOSE: To identify the genetic defect for the Coppock-like cataract (CCL) affecting a Swiss family, which defect was unlinked to the chromosome 2q33-35 CCL locus. METHODS: A large family was characterized for linkage analysis by slit lamp examination or by the review of drawings made before cataract extraction. The affection status was attributed before genotyping, and the genotyping was masked to the affection status. Two-point and multipoint linkage analyses were performed using the MLINK and the LINKMAP components of the LINKAGE program package (ver. 5.1), respectively. Mutational analysis of candidate genes was performed by a combination of direct cycle sequencing and an amplification refractory mutation system assay. RESULTS: Ten individuals were affected with the CCL phenotype. The disease was autosomal dominant and appeared to be fully penetrant. A new CCL locus was identified on chromosome 22q11.2 within a 11.67-cM interval (maximum lod score [Zmax] = 4.14; theta = 0). Mutational analysis of the CRYBB2 candidate gene identified a disease-causing mutation in exon 6. This sequence change was identical with that previously described to be associated with the cerulean cataract, a clinically distinct entity. CONCLUSIONS: The CCL phenotype is genetically heterogeneous with a second gene on chromosome 22q11.2, CRYBB2. The CCL and the cerulean cataract are two distinct clinical entities associated with the same genetic defect. This work provides evidence for a modifier factor that influences cataract formation and that remains to be identified.

Uncertainty Quantification with Support Vector Regression Prediction Models

Uncertainty quantification of petroleum reservoir models is one of the present challenges, which is usually approached with a wide range of geostatistical tools linked with statistical optimisation or/and inference algorithms. The paper considers a data driven approach in modelling uncertainty in spatial predictions. Proposed semi-supervised Support Vector Regression (SVR) model has demonstrated its capability to represent realistic features and describe stochastic variability and non-uniqueness of spatial properties. It is able to capture and preserve key spatial dependencies such as connectivity, which is often difficult to achieve with two-point geostatistical models. Semi-supervised SVR is designed to integrate various kinds of conditioning data and learn dependences from them. A stochastic semi-supervised SVR model is integrated into a Bayesian framework to quantify uncertainty with multiple models fitted to dynamic observations. The developed approach is illustrated with a reservoir case study. The resulting probabilistic production forecasts are described by uncertainty envelopes.

The effectiveness of a standardised preoperative preparation in reducing child and parent anxiety: a single-blind randomised controlled trial.

AIMS: To evaluate the effect of a structured preoperative preparation on child and parent state anxiety, child behavioural change and parent satisfaction. BACKGROUND: It is estimated that around 50-70% of hospitalised children experience severe anxiety and distress prior to surgery. Children who are highly anxious and distressed preoperatively are likely to be distressed on awakening and have negative postoperative behaviour. Although education before surgery has been found to be useful mostly in North America, the effectiveness of preoperative preparation programme adapted to the Australian context remains to be tested. DESIGN: This single-blind randomised controlled study was conducted at a tertiary referral hospital for children in Western Australia. METHODS: Following ethics approval and parental consent, 73 children and one of their carers (usually a parent) were randomly assigned into two groups. The control group had standard practice with no specific preoperative education and the experimental group received a preoperative preparation, including a photo file, demonstration of equipment using a role-modelling approach and a tour. RESULTS: The preoperative preparation reduced parent state anxiety significantly (-2·32, CI -4·06 to -0·56, p = 0·009), but not child anxiety (-0·59, CI -1·23 to 0·06, p = 0·07). There was no significant difference in child postoperative behaviour or parent satisfaction between the groups. There was a significant two-point pain score reduction in the preoperative preparation group, when compared with the control group median 2 (IQR 5) and 4 (IQR 4), respectively (p = 0·001).¦CONCLUSIONS: Preoperative preparation was more efficient on parent than child. Although the preoperative preparation had limited effect on child anxiety, it permitted to decrease pain experience in the postoperative period.¦RELEVANCE TO CLINICAL PRACTICE: Parents should be actively involved in their child preoperative preparation.

Cheminformatic studies of molecular properties and their influence on bioactivity in the context of drug discovery

Molecular shape has long been known to be an important property for the process of molecular recognition. Previous studies postulated the existence of a drug-like shape space that could be used to artificially bias the composition of screening libraries, with the aim to increase the chance of success in Hit Identification. In this work, it was analysed to which extend this assumption holds true. Normalized Principal Moments of Inertia Ratios (NPRs) have been used to describe the molecular shape of small molecules. It was investigated, whether active molecules of diverse targets are located in preferred subspaces of the NPR shape space. Results illustrated a significantly stronger clustering than could be expected by chance, with parts of the space unlikely to be occupied by active compounds. Furthermore, a strong enrichment of elongated, rather flat shapes could be observed, while globular compounds were highly underrepresented. This was confirmed for a wide range of small molecule datasets from different origins. Active compounds exhibited a high overlap in their shape distributions across different targets, making a purely shape­ based discrimination very difficult. An additional perspective was provided by comparing the shapes of protein binding pockets with those of their respective ligands. Although more globular than their ligands, it was observed that binding sites shapes exhibited a similarly skewed distribution in shape space: spherical shapes were highly underrepresented. This was different for unoccupied binding pockets of smaller size. These were on the contrary identified to possess a more globular shape. The relation between shape complementarity and exhibited bioactivity was analysed; a moderate correlation between bioactivity and parameters including pocket coverage, distance in shape space, and others could be identified, which reflects the importance of shape complementarity. However, this also suggests that other aspects are of relevance for molecular recognition. A subsequent analysis assessed if and how shape and volume information retrieved from pocket or respective reference ligands could be used as a pre-filter in a virtual screening approach. ln Lead Optimization compounds need to get optimized with respect to a variety of pararneters. Here, the availability of past success stories is very valuable, as they can guide medicinal chemists during their analogue synthesis plans. However, although of tremendous interest for the public domain, so far only large corporations had the ability to mine historical knowledge in their proprietary databases. With the aim to provide such information, the SwissBioisostere database was developed and released during this thesis. This database contains information on 21,293,355 performed substructural exchanges, corresponding to 5,586,462 unique replacements that have been measured in 35,039 assays against 1,948 molecular targets representing 30 target classes, and on their impact on bioactivity . A user-friendly interface was developed that provides facile access to these data and is accessible at http//www.swissbioisostere.ch. The ChEMBL database was used as primary data source of bioactivity information. Matched molecular pairs have been identified in the extracted and cleaned data. Success-based scores were developed and integrated into the database to allow re-ranking of proposed replacements by their past outcomes. It was analysed to which degree these scores correlate with chemical similarity of the underlying fragments. An unexpectedly weak relationship was detected and further investigated. Use cases of this database were envisioned, and functionalities implemented accordingly: replacement outcomes are aggregatable at the assay level, and it was shawn that an aggregation at the target or target class level could also be performed, but should be accompanied by a careful case-by-case assessment. It was furthermore observed that replacement success depends on the activity of the starting compound A within a matched molecular pair A-B. With increasing potency the probability to lose bioactivity through any substructural exchange was significantly higher than in low affine binders. A potential existence of a publication bias could be refuted. Furthermore, often performed medicinal chemistry strategies for structure-activity-relationship exploration were analysed using the acquired data. Finally, data originating from pharmaceutical companies were compared with those reported in the literature. It could be seen that industrial medicinal chemistry can access replacement information not available in the public domain. In contrast, a large amount of often-performed replacements within companies could also be identified in literature data. Preferences for particular replacements differed between these two sources. The value of combining different endpoints in an evaluation of molecular replacements was investigated. The performed studies highlighted furthermore that there seem to exist no universal substructural replacement that always retains bioactivity irrespective of the biological environment. A generalization of bioisosteric replacements seems therefore not possible. - La forme tridimensionnelle des molécules a depuis longtemps été reconnue comme une propriété importante pour le processus de reconnaissance moléculaire. Des études antérieures ont postulé que les médicaments occupent préférentiellement un sous-ensemble de l'espace des formes des molécules. Ce sous-ensemble pourrait être utilisé pour biaiser la composition de chimiothèques à cribler, dans le but d'augmenter les chances d'identifier des Hits. L'analyse et la validation de cette assertion fait l'objet de cette première partie. Les Ratios de Moments Principaux d'Inertie Normalisés (RPN) ont été utilisés pour décrire la forme tridimensionnelle de petites molécules de type médicament. Il a été étudié si les molécules actives sur des cibles différentes se co-localisaient dans des sous-espaces privilégiés de l'espace des formes. Les résultats montrent des regroupements de molécules incompatibles avec une répartition aléatoire, avec certaines parties de l'espace peu susceptibles d'être occupées par des composés actifs. Par ailleurs, un fort enrichissement en formes allongées et plutôt plates a pu être observé, tandis que les composés globulaires étaient fortement sous-représentés. Cela a été confirmé pour un large ensemble de compilations de molécules d'origines différentes. Les distributions de forme des molécules actives sur des cibles différentes se recoupent largement, rendant une discrimination fondée uniquement sur la forme très difficile. Une perspective supplémentaire a été ajoutée par la comparaison des formes des ligands avec celles de leurs sites de liaison (poches) dans leurs protéines respectives. Bien que plus globulaires que leurs ligands, il a été observé que les formes des poches présentent une distribution dans l'espace des formes avec le même type d'asymétrie que celle observée pour les ligands: les formes sphériques sont fortement sous­ représentées. Un résultat différent a été obtenu pour les poches de plus petite taille et cristallisées sans ligand: elles possédaient une forme plus globulaire. La relation entre complémentarité de forme et bioactivité a été également analysée; une corrélation modérée entre bioactivité et des paramètres tels que remplissage de poche, distance dans l'espace des formes, ainsi que d'autres, a pu être identifiée. Ceci reflète l'importance de la complémentarité des formes, mais aussi l'implication d'autres facteurs. Une analyse ultérieure a évalué si et comment la forme et le volume d'une poche ou de ses ligands de référence pouvaient être utilisés comme un pré-filtre dans une approche de criblage virtuel. Durant l'optimisation d'un Lead, de nombreux paramètres doivent être optimisés simultanément. Dans ce contexte, la disponibilité d'exemples d'optimisations réussies est précieuse, car ils peuvent orienter les chimistes médicinaux dans leurs plans de synthèse par analogie. Cependant, bien que d'un extrême intérêt pour les chercheurs dans le domaine public, seules les grandes sociétés pharmaceutiques avaient jusqu'à présent la capacité d'exploiter de telles connaissances au sein de leurs bases de données internes. Dans le but de remédier à cette limitation, la base de données SwissBioisostere a été élaborée et publiée dans le domaine public au cours de cette thèse. Cette base de données contient des informations sur 21 293 355 échanges sous-structuraux observés, correspondant à 5 586 462 remplacements uniques mesurés dans 35 039 tests contre 1948 cibles représentant 30 familles, ainsi que sur leur impact sur la bioactivité. Une interface a été développée pour permettre un accès facile à ces données, accessible à http:/ /www.swissbioisostere.ch. La base de données ChEMBL a été utilisée comme source de données de bioactivité. Une version modifiée de l'algorithme de Hussain et Rea a été implémentée pour identifier les Matched Molecular Pairs (MMP) dans les données préparées au préalable. Des scores de succès ont été développés et intégrés dans la base de données pour permettre un reclassement des remplacements proposés selon leurs résultats précédemment observés. La corrélation entre ces scores et la similarité chimique des fragments correspondants a été étudiée. Une corrélation plus faible qu'attendue a été détectée et analysée. Différents cas d'utilisation de cette base de données ont été envisagés, et les fonctionnalités correspondantes implémentées: l'agrégation des résultats de remplacement est effectuée au niveau de chaque test, et il a été montré qu'elle pourrait également être effectuée au niveau de la cible ou de la classe de cible, sous réserve d'une analyse au cas par cas. Il a en outre été constaté que le succès d'un remplacement dépend de l'activité du composé A au sein d'une paire A-B. Il a été montré que la probabilité de perdre la bioactivité à la suite d'un remplacement moléculaire quelconque est plus importante au sein des molécules les plus actives que chez les molécules de plus faible activité. L'existence potentielle d'un biais lié au processus de publication par articles a pu être réfutée. En outre, les stratégies fréquentes de chimie médicinale pour l'exploration des relations structure-activité ont été analysées à l'aide des données acquises. Enfin, les données provenant des compagnies pharmaceutiques ont été comparées à celles reportées dans la littérature. Il a pu être constaté que les chimistes médicinaux dans l'industrie peuvent accéder à des remplacements qui ne sont pas disponibles dans le domaine public. Par contre, un grand nombre de remplacements fréquemment observés dans les données de l'industrie ont également pu être identifiés dans les données de la littérature. Les préférences pour certains remplacements particuliers diffèrent entre ces deux sources. L'intérêt d'évaluer les remplacements moléculaires simultanément selon plusieurs paramètres (bioactivité et stabilité métabolique par ex.) a aussi été étudié. Les études réalisées ont souligné qu'il semble n'exister aucun remplacement sous-structural universel qui conserve toujours la bioactivité quel que soit le contexte biologique. Une généralisation des remplacements bioisostériques ne semble donc pas possible.

Quantum metric spaces as a model for pregeometry

A new arena for the dynamics of spacetime is proposed, in which the basic quantum variable is the two-point distance on a metric space. The scaling dimension (that is, the Kolmogorov capacity) in the neighborhood of each point then defines in a natural way a local concept of dimension. We study our model in the region of parameter space in which the resulting spacetime is not too different from a smooth manifold.

Topologies for poin distributions

The concepts of void and cluster for an arbitrary point distribution in a domain D are defined and characterized by some parameters such as volume, density, number of points belonging to them, shape, etc. After assigning a weight to each void and clusterwhich is a function of its characteristicsthe concept of distance between two point configurations S1 and S2 in D is introduced, both with and without the help of a lattice in the domain D. This defines a topology for the point distributions in D, which is different for the different characterizations of the voids and clusters.

Quantum metric spaces as a model for pregeometry

A new arena for the dynamics of spacetime is proposed, in which the basic quantum variable is the two-point distance on a metric space. The scaling dimension (that is, the Kolmogorov capacity) in the neighborhood of each point then defines in a natural way a local concept of dimension. We study our model in the region of parameter space in which the resulting spacetime is not too different from a smooth manifold.

Generalized percolation in random directed networks

We develop a general theory for percolation in directed random networks with arbitrary two-point correlations and bidirectional edgesthat is, edges pointing in both directions simultaneously. These two ingredients alter the previously known scenario and open new views and perspectives on percolation phenomena. Equations for the percolation threshold and the sizes of the giant components are derived in the most general case. We also present simulation results for a particular example of uncorrelated network with bidirectional edges confirming the theoretical predictions.

Analysis of linear networks with inconsistent initial conditions

This paper presents a new method to analyze timeinvariant linear networks allowing the existence of inconsistent initial conditions. This method is based on the use of distributions and state equations. Any time-invariant linear network can be analyzed. The network can involve any kind of pure or controlled sources. Also, the transferences of energy that occur at t=O are determined, and the concept of connection energy is introduced. The algorithms are easily implemented in a computer program.

Etude clinique et analyse de liaison au locus 3q28 de deux familles suisses avec atrophie optique dominante de Kjer (OPA1) [Clinical study and genetic 3q28 locus linkage in 2 Swiss families with Kjer dominant optic atrophy (OPA1)]

METHODS: We examined 20 patients from 2 unrelated Swiss families to describe their clinical phenotype. In addition, a linkage analysis was performed in an attempt to confirm the reported genetic homogeneity of this condition as well as to refine its genomic localization. RESULTS: Two point analysis provided a cumulative LOD-score of 3.03 with marker D3S 2305. The absence of recombination precluded further refinement of the disease interval. CONCLUSIONS: Our data confirm the genetic homogeneity and the extreme variability of expression, occasionally mimicking low tension glaucoma.

Outcome evaluation of ankle osteoarthritis treatments using spatio-temporal gait parameters and plantar pressure during unconstrained long distance walking : P25

Introduction: Ankle arthrodesis (AD) and total ankle replacement (TAR) are typical treatments for ankle osteoarthritis (AO). Despite clinical interest, there is a lack of their outcome evaluation using objective criteria. Gait analysis and plantar pressure assessment are appropriate to detect pathologies in orthopaedics but they are mostly used in lab with few gait cycles. In this study, we propose an ambulatory device based on inertial and plantar pressure sensors to compare the gait during long-distance trials between healthy subjects (H) and patients with AO or treated by AD and TAR. Methods: Our study included four groups: 11 patients with AO, 9 treated by TAR, 7 treated by AD and 6 control subjects. An ambulatory system (Physilog®, CH) was used for gait analysis; plantar pressure measurements were done using a portable insole (Pedar®-X, DE). The subjects were asked to walk 50 meters in two trials. Mean value and coefficient of variation of spatio-temporal gait parameters were calculated for each trial. Pressure distribution was analyzed in ten subregions of foot. All parameters were compared among the four groups using multi-level model-based statistical analysis. Results: Significant difference (p <0.05) with control was noticed for AO patients in maximum force in medial hindfoot and forefoot and in central forefoot. These differences were no longer significant in TAR and AD groups. Cadence and speed of all pathologic groups showed significant difference with control. Both treatments showed a significant improvement in double support and stance. TAR decreased variability in speed, stride length and knee ROM. Conclusions: In spite of a small sample size, this study showed that ankle function after AO treatments can be evaluated objectively based on plantar pressure and spatio-temporal gait parameters measured during unconstrained walking outside the lab. The combination of these two ambulatory techniques provides a promising way to evaluate foot function in clinics.

1017-011 Tuttle Lake Watershed Final Report

The Tuttle Lake Watershed is approximately 125,000 acres and Tuttle Lake itself is 2,270 acres; 5,609 acres of the watershed lies in Iowa territory within Emmet County. It is a sub-watershed of the larger East Fork Des Moines River Watershed, also referred to as Hydrologic Unit Code 07100003. For the purpose of this document, grant money is only being applied for the project implementation in the Iowa portion of the Tuttle Lake Watershed. Tuttle Lake was placed on the 2002 EPA 303(d) Impaired Waters List due to a “very large population of suspended algae and very high levels of inorganic turbidity.” In 2004, the Iowa Department of Natural Resources (IDNR) completed a Total Maximum Daily Load (TMDL) study on Tuttle Lake and found excess sediment and phosphorus levels being the primary pollutants causing the algae and turbidity impairment. Although two point sources were located in Minnesota, IDNR determined that the influx of nutrients is likely from agricultural runoff and re-suspension of lake sediment. The condition of Tuttle Lake is such that the reduction of sediment, nutrients [phosphorus and nitrogen] and pathogens is the primary objective. To achieve that objective, wetlands will be constructed in this first phase to reduce the delivery of nitrogen, phosphorus, and sediment to Tuttle Lake.

Holographic collisions in confining theories

We study the gravitational dual of a high-energy collision in a confining gauge theory. We consider a linearized approach in which two point particles traveling in an AdS-soliton background suddenly collide to form an object at rest (presumably a black hole for large enough center-of-mass energies). The resulting radiation exhibits the features expected in a theory with a mass gap: late-time power law tails of the form t −3/2, the failure of Huygens" principle and distortion of the wave pattern as it propagates. The energy spectrum is exponentially suppressed for frequencies smaller than the gauge theory mass gap. Consequently, we observe no memory effect in the gravitational waveforms. At larger frequencies the spectrum has an upward-stairway structure, which corresponds to the excitation of the tower of massive states in the confining gauge theory. We discuss the importance of phenomenological cutoffs to regularize the divergent spectrum, and the aspects of the full non-linear collision that are expected to be captured by our approach.