How do the different components of episodic memory develop? Role of executive functions and short-term feature-binding abilities.

This study investigated the development of all 3 components of episodic memory (EM), as defined by Tulving, namely, core factual content, spatial context, and temporal context. To this end, a novel, ecologically valid test was administered to 109 participants aged 4-16 years. Results showed that each EM component develops at a different rate. Ability to memorize factual content emerges early, whereas context retrieval abilities continue to improve until adolescence, due to persistent encoding difficulties (isolated by comparing results on free recall and recognition tasks). Exploration of links with other cognitive functions revealed that short-term feature-binding abilities contribute to all EM components, and executive functions to temporal and spatial context, although ability to memorize temporal context is predicted mainly by age.

Automatic filtering and substantiation of drug safety signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

Gelatinase expression and proteolytic activity in giant-cell arteritis

Objectives: Gelatinases (MMP2 and MMP9) are expressed in giant-cell arteritis (GCA) and are thought to play a role in vessel disruption. However, their activation status and enzymatic activity have not been evaluated. Our aim was to investigate the distribution and proteolytic activity of gelatinases in GCA lesions at different stages. Methods: Expression of MMP2, MMP9, MMP2-activator MMP14 and their natural inhibitors TIMP1 and TIMP2 was determined by real-time PCR and immunohistochemistry in temporal artery sections from 46 patients and 12 controls. MMP activation status and enzymatic activity were assessed by gelatin and film in situ zymography. Results: Vascular smooth muscle cells from normal specimens constitutively expressed pro-MMP2 and its inhibitor TIMP2 with no resulting proteolytic activity. In GCA MMP2, MMP9 and MMP14 were strongly expressed in their active form by infiltrating leucocytes. Inflamed arteries also expressed TIMP1 and TIMP2. However, the MMP9/TIMP1 and MMP2/TIMP2 ratios were higher in patients compared with controls, indicating an increased proteolytic balance in GCA which was confirmed by in situ zymography. Maximal gelatinase expression and activity occurred at the granulomatous areas surrounding the internal elastic lamina (IEL). Myointimal cells also expressed MMPs and exhibited proteolytic activity, suggesting a role for gelatinases in vascular remodelling and repair. Conclusions: GCA lesions show intense expression of gelatinases. Activators and inhibitors are regulated to yield enhanced gelatinase activation and proteolytic activity. Distribution of expression and proteolytic activity suggests that gelatinases have a major role not only in the progression of inflammatory infiltrates and vessel destruction but also in vessel repair.

Relationships between users, resources and services in learning object repositories

In this paper we describe a proposal for defining the relationships between resources, users and services in a digital repository. Nowadays, virtual learning environments are widely used but digital repositories are not fully integrated yet into the learning process. Our final goal is to provide final users with recommendation systems and reputation schemes that help them to build a true learning community around the institutional repository, taking into account their educational context (i.e. the courses they are enrolled into) and their activity (i.e. system usage by their classmates and teachers). In order to do so, we extend the basic resource concept in a traditional digital repository by adding all the educational context and other elements from end-users' profiles, thus bridging users, resources and services, and shifting from a library-centered paradigm to a learning-centered one.

Emotional and effortful control abilities in 42-month-old very preterm and full-term children.

BACKGROUND: Very preterm (VP) infants are at greater risk for cognitive difficulties that may persist during school-age, adolescence and adulthood. Behavioral assessments report either effortful control (part of executive functions) or emotional reactivity/regulation impairments. AIMS: The aim of this study is to examine whether emotional recognition, reactivity, and regulation, as well as effortful control abilities are impaired in very preterm children at 42 months of age, compared with their full-term peers, and to what extent emotional and effortful control difficulties are linked. STUDY DESIGN: Children born very preterm (VP; < 29 weeks gestational age, n=41) and full-term (FT) aged-matched children (n=47) participated in a series of specific neuropsychological tests assessing their level of emotional understanding, reactivity and regulation, as well as their attentional and effortful control abilities. RESULTS: VP children exhibited higher scores of frustration and fear, and were less accurate in naming facial expressions of emotions than their aged-matched peers. However, VP children and FT children equally performed when asked to choose emotional facial expression in social context, and when we assessed their selective attention skills. VP performed significantly lower than full terms on two tasks of inhibition when correcting for verbal skills. Moreover, significant correlations between cognitive capacities (effortful control) and emotional abilities were evidenced. CONCLUSIONS: Compared to their FT peers, 42 month-olds who were born very preterm are at higher risk of exhibiting specific emotional and effortful control difficulties. The results suggest that these difficulties are linked. Ongoing behavioral and emotional impairments starting at an early age in preterms highlight the need for early interventions based on a better understanding of the relationship between emotional and cognitive difficulties.

Evolutionary perspective on the interplay between family life, and parent and offspring personality

Consistent inter-individual variation in behaviour over time and across contexts has been reported for a wide variety of animals, a phenomenon commonly referred to as personality. As behavioural patterns develop inside families, rearing conditions could have lasting effects on the expression of adult personality. In species with parental care, conflicts among family members impose selection on parental and offspring behaviour through co-adaptation. Here, we argue that the interplay between the evolution of personality traits (i.e. boldness, exploration, activity, aggressiveness and sociability) expressed outside the family context and the specialized behaviours expressed inside families (i.e. offspring begging behaviour and parental response to offspring solicitations) can have important evolutionary consequences. Personality differences among parents may relate to the typically observed variation in the way they respond to offspring demand, and dependent offspring may already express personality differences which may relate to the way they communicate with their parents and siblings. However, there has been little research on how personality relates to parental and offspring behaviours. Future research should thus focus on how and why personality may be related to the specialized parent and offspring behaviour that evolved as adaptations to family life.

Activity patterns and foraging behaviour of Audouin's gulls at the Ebro Delta, NW Mediterranean.

Twenty Audouin´s gulls, Larus audouinii, breeding in the Ebro Delta (NW Mediterranean) were radio-tracked in 1998 to study their foraging behaviour and activity patterns. Some detrimental effects of tagging on the breeding success of the birds were detected, especially when both members of the pair were tagged. The results were actually constrained by the low number of locations due to natural breeding failure and failure in tag emission, as well as the adverse effect of tagging. However, through a combination of aircraft surveys at sea and a fixed station for automatic tracking of the presence of the birds at the colony, novel individual-based information of home ranges and activity patterns was obtained. Trawler fishing activity seemed to influence both the foraging range and habitat use: while trawlers operated, gulls overlapped their fishing grounds with vessels, probably to scavenge on discards. Very few locations were obtained during a trawling moratorium period, although they were all recorded in coastal bays and terrestrial habitats. During the trawling activity period, gulls ranged over a minimum convex polygon area of 2900 km2. Gulls were tracked up to 40 km from the colony, but some individuals were observed beyond 150 km while still breeding. Arrivals and departures from the colony were in accordance with the trawling timetable. However, most birds also showed some nocturnal foraging activity, probably linked to active fishing of clupeoids (following diel migrations) or to the exploitation of purse-seine fishing activity. Foraging trips lasted on average 15 hours: males performed significantly shorter trips than females, which spent more time outside the colony. The proportion of nocturnal time involved in the foraging trips was the same for males and females, but whilst all males initiated their trips both during the day and at night, some females only initiated their trips during the day. Hatching success was found to be related to foraging effort by males. Gulls spent on average ca. 38% of their time budget outside the nesting territory, representing the time devoted mainly to flying, foraging and other activities.

Analysis of SKI-1/S1P prodomain provides insight on maturation and activation of SKI-1/S1P zymogen

SKI-l/SlP protease is a member of the proprotein convertase family, with several functions in cellular metabolism and homeostasis. It is responsible for the processing of several cellular substrates, including ATF6, SREBPs, and GlcNAc-1- phosphotranspherase. Furthermore, SKI-1/SlP is also responsible for maturation of arenavirus surface glycoprotein into GP1 and GP2 subunits. This processing is a strict requirement in order to achieve fully mature and fusion-competent virions. Furthermore, SKI-1/SlP itself is synthesized as an inactive zymogen, requiring sequential autocatalytic processing at several sites (B'/B and C) in its prodomain in order to mature and become fully active. Our project focused on the analysis of SKI- 1/S1P prodomain in the biogenesis of the active enzyme. In this context we have additionally developed and characterized a novel cell-based sensor for assessment of cellular activity of the enzyme, with a potential application in screening for novel SKI- 1/S1P inhibitors. In a first aim we have analysed the relevance of cleavage motifs found in the enzyme prodomain. Using molecular and biochemistry tools we have identified and characterized a novel C' maturation site. Furthermore, we found that SKI-1/SlP autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. Contrasting with other proprotein convertases, incompletely matured intermediates of SKI-1/SlP exhibit full catalytic activity toward selected substrates. In a second aim, we turned our attention to the structural basis of SKI-1/SlP N- terminus assisted folding. Studying the folding and activity of prodomain-truncated forms of the enzyme we found that a minimal folding unit is contained in the AB region. Deletion of the BC sequence affected auto-maturation but not folding, and partial activity was retained. However, the BC region seemed required for complete and full activity. Phylogenetic analyses showed that the AB sequence is highly conserved, while the BC fragment is variable in sequence and length. Specifically, replacement of the human prodomain with that of Drosophila, resulted in a fully mature and active chimeric enzyme, suggesting an evolution process of SKI-1/SlP prodomain towards a more complex arrangement and steps of activation. Overall, the additional data we have produced might provide fundamental knowledge crucial for the development of novel SKI-1/SlP inhibitors while also providing new SKI- 1/S1P variants with potential use in crystallization purpose. -- SKI-l/SlP est une protéase membre de la famille des proprotéines convertases (PCs), avec plusieurs fonctions dans le métabolisme cellulaire et de l'homéostasie. Il est responsable pour la maturation de plusieurs substrats cellulaires, y compris ATF6, SREBPs et GlcNAc-1-phosphotranspherase. SKI-l/SlP est également responsable pour la maturation de la glycoprotéine des arénavirus, une exigence stricte pour atteindre des virions infectieuse. Synthétisé comme un zymogène inactif, SKI-l/SlP nécessite d'un traitement autocatalytique séquentiel sur plusieurs sites (B'/B et C) de son prodomaine afin de devenir pleinement active. Notre projet était axé sur l'analyse de SKI-l/SlP prodomaine dans la biogenèse de l'enzyme. Dans ce contexte, nous avons développé un nouveau senseur-cellulaire pour l'évaluation de l'activité de l'enzyme. Ce dernier pourrait avoir une potentielle application dans l'identification de nouveaux inhibiteurs de SKI-l/SlP. Premièrement, nous avons analysé la pertinence des motifs de clivage trouvés dans le prodomaine de l'enzyme. En utilisant des outils moléculaires et biochimiques, nous avons identifié et caractérisé un nouveau site de maturation (C'). Aussi, nous avons constaté que la maturation de SKI-l/SlP a des intermédiaires dont le domaine catalytique reste associé à des fragments du prodomaine de différentes longueurs. Contrastant avec d'autres PCs, les intermédiaires partiellement matures de SKI-1 / SIP présentent une activité catalytique complète envers des substrats spécifiques. Dans un deuxième but nous avons tourné notre attention sur la base structurelle du pliage de SKI-l/SlP assisté par son N-terminus: En étudiant l'activité et pliage des formes tronquées dans le prodomaine de l'enzyme, nous avons constaté qu'une unité de pliage minimale est contenue dans la région de l'AB. La suppression de la séquence d'auto-BC affecte la maturation mais pas le pliage, et l'activité partielle est maintenue. Cependant, la région BC semble nécessaire pour une activité complète. Les analyses phylogénétiques ont montré que la séquence AB est fortement conservée, tandis que le fragment de BC est variable en longueur et en séquence. En particulier, le remplacement du prodomaine humain avec celui de la drosophile, a donné lieu à une enzyme chimérique complètement mature et active. Suggérant un processus d'évolution du prodomaine vers un arrangement et des mesures d'activation plus complexe. Globalement, ces donnees supplémentaires augment les connaissances fondamentales cruciales pour le développement de nouveaux inhibiteurs de SKI-1/ SIP, tout en offrant de nouvelles variantes SKI-1 / SIP dans le but d'obtenir la structure cristallographique de l'enzyme.

New kernel functions and learning methods for text and data mining

Recent advances in machine learning methods enable increasingly the automatic construction of various types of computer assisted methods that have been difficult or laborious to program by human experts. The tasks for which this kind of tools are needed arise in many areas, here especially in the fields of bioinformatics and natural language processing. The machine learning methods may not work satisfactorily if they are not appropriately tailored to the task in question. However, their learning performance can often be improved by taking advantage of deeper insight of the application domain or the learning problem at hand. This thesis considers developing kernel-based learning algorithms incorporating this kind of prior knowledge of the task in question in an advantageous way. Moreover, computationally efficient algorithms for training the learning machines for specific tasks are presented. In the context of kernel-based learning methods, the incorporation of prior knowledge is often done by designing appropriate kernel functions. Another well-known way is to develop cost functions that fit to the task under consideration. For disambiguation tasks in natural language, we develop kernel functions that take account of the positional information and the mutual similarities of words. It is shown that the use of this information significantly improves the disambiguation performance of the learning machine. Further, we design a new cost function that is better suitable for the task of information retrieval and for more general ranking problems than the cost functions designed for regression and classification. We also consider other applications of the kernel-based learning algorithms such as text categorization, and pattern recognition in differential display. We develop computationally efficient algorithms for training the considered learning machines with the proposed kernel functions. We also design a fast cross-validation algorithm for regularized least-squares type of learning algorithm. Further, an efficient version of the regularized least-squares algorithm that can be used together with the new cost function for preference learning and ranking tasks is proposed. In summary, we demonstrate that the incorporation of prior knowledge is possible and beneficial, and novel advanced kernels and cost functions can be used in algorithms efficiently.

Constrained Total Energy Expenditure and Metabolic Adaptation to Physical Activity in Adult Humans.

Current obesity prevention strategies recommend increasing daily physical activity, assuming that increased activity will lead to corresponding increases in total energy expenditure and prevent or reverse energy imbalance and weight gain [1-3]. Such Additive total energy expenditure models are supported by exercise intervention and accelerometry studies reporting positive correlations between physical activity and total energy expenditure [4] but are challenged by ecological studies in humans and other species showing that more active populations do not have higher total energy expenditure [5-8]. Here we tested a Constrained total energy expenditure model, in which total energy expenditure increases with physical activity at low activity levels but plateaus at higher activity levels as the body adapts to maintain total energy expenditure within a narrow range. We compared total energy expenditure, measured using doubly labeled water, against physical activity, measured using accelerometry, for a large (n = 332) sample of adults living in five populations [9]. After adjusting for body size and composition, total energy expenditure was positively correlated with physical activity, but the relationship was markedly stronger over the lower range of physical activity. For subjects in the upper range of physical activity, total energy expenditure plateaued, supporting a Constrained total energy expenditure model. Body fat percentage and activity intensity appear to modulate the metabolic response to physical activity. Models of energy balance employed in public health [1-3] should be revised to better reflect the constrained nature of total energy expenditure and the complex effects of physical activity on metabolic physiology.

Recognition of prior learning in online postgraduate education

The recognition of prior experiential learning (RPEL) involves the assessment ofskills and knowledge acquired by an individual through previous experience, which isnot necessarily related to an academic context. RPEL practices are far from generalisedin higher education, and there is a lack of specific guidelines on how to implement RPLprograms in particular settings, such as management education or online programs. TheRPEL pilot program developed in a Spanish virtual university is used throughout thearticle as the basis for further reflection on the design and implementation of RPEL inonline postgraduate education in the business field. The role of competences as a centraltheoretical foundation for RPEL is explained, and the context and characteristics of theRPEL program described. Special attention is paid to the key elements of the program¿sdesign and to the practical aspects of its implementation. The results of the program areassessed and general conclusions and suggestions for further research are discussed.

Mobile Subscription Acquisition and Retention Costs - An Actvity-Based Model

The objective of this master’s thesis was to develop a model for mobile subscription acquisition cost, SAC, and mobile subscription retention cost, SRC, by applying activity-based cost accounting principles. The thesis was conducted as a case study for a telecommunication company operating on the Finnish telecommunication market. In addition to activity-based cost accounting there were other theories studied and applied in order to establish a theory framework for this thesis. The concepts of acquisition and retention were explored in a broader context with the concepts of customer satisfaction, loyalty and profitability and eventually customer relationship management to understand the background and meaning of the theme of this thesis. The utilization of SAC and SRC information is discussed through the theories of decision making and activity-based management. Also, the present state and future needs of SAC and SRC information usage at the case company as well as the functions of the company were examined by interviewing some members of the company personnel. With the help of these theories and methods it was aimed at finding out both the theory-based and practical factors which affect the structure of the model. During the thesis study it was confirmed that the existing SAC and SRC model of the case company should be used as the basis in developing the activity-based model. As a result the indirect costs of the old model were transformed into activities and the direct costs were continued to be allocated directly to acquisition of new subscriptions and retention of old subscriptions. The refined model will enable managing the subscription acquisition, retention and the related costs better through the activity information. During the interviews it was found out that the SAC and SRC information is also used in performance measurement and operational and strategic planning. SAC and SRC are not fully absorbed costs and it was concluded that the model serves best as a source of indicative cost information. This thesis does not include calculating costs. Instead, the refined model together with both the theory-based and interview findings concerning the utilization of the information produced by the model will serve as a framework for the possible future development aiming at completing the model.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.