Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

'Family' ownership, tunnelling and earnings management:a review of the literature

In this review paper, we bring together a number of aspects of family firms that are ubiquitous in a number of institutional contexts, often as part of larger business groups. We pay particular attention to the mechanisms by which families retain control over firms, and the incentives of the families in control to expropriate other stakeholders by way of tunnelling. We examine the role of earnings management in facilitating tunnelling, and evidence about the incidence of earnings management in family firms. Our review suggests that while the literature on these aspects of family control is rich, the contexts in which the empirical exercises are undertaken are relatively few, and hence there is considerable opportunity to expand it to other contexts, in particular in the form of cross-country comparisons of the relative impact of agency conflicts and institutions on these issues.

The Effect of Family Ownership on Firm Performance: Empirical Evidence from Norway

Tutkimuksen tavoitteena on selvittää, onko perheomistajuus, eli yksityisomistus, kannattavampi omistusmuoto kuin institutionaalinen omistajuus ja, onko yrityksen iällä ja koolla vaikutusta perheyritysten menestymiseen. Aikaisempaan tutkimustietoon tukeutuen, tutkimuksen aluksi käydään myös läpi perheomistajuuteen yleisesti liitettyjä ominaispiirteitä sekä perheyritysten menestymistä verrattuna ei-perheyrityksiin. Empiirinen analyysi perheomistajuuden vaikutuksista yrityksen kannattavuuteen sekä yrityksen iän ja koon vaikutuksista perheyritysten menestymiseen toteutetaan kahden otoksen avulla, jotka koostuvat listaamattomista norjalaisista pienistä ja keskisuurista yrityksistä (pk-yrityksistä). Näin ollen satunnaisotos ja päätoimialaotos, johon listaamattomat pk-yritykset on valittu satunnaisesti Norjan tärkeimmiltä toimialoilta, analysoidaan erikseen. Analyysi toteutetaan käyttäen lineaarista regressioanalyysia. Vaikka satunnaisotoksen perusteella perheyritykset eivät näytä olevan ei-perheyrityksiä kannattavampia, päätoimialaotos osoittaa, että listaamattomissa pk-yrityksissä perhe- eli yksityisomistajuus on merkittävästi institutionaalista omistajuutta kannattavampi omistusmuoto. Eritoten nuoret ja pienet yritykset vastaavat perheyritysten paremmasta kannattavuudesta.

Family ownership – a source of sustainable success in listed companies

Extant research on exchange-listed firms has acknowledged that the concentration of ownership and the identity of owners make a difference. In addition, studies indicate that firms with a dominant owner outperform firms with dispersed ownership. During the last few years, scholars have identified one group of owners, in particular, whose ownership stake in publicly listed firm is positively related to performance: the business family. While acknowledging that family firms represent a unique organizational form, scholars have identified various concepts and theories in order to understand how the family influences organizational processes and firm performance. Despite multitude of research, scholars have not been able to present clear results on how firm performance is actually impacted by the family. In other words, studies comparing the performance of listed family and other types of firms have remained descriptive in nature since they lack empirical data and confirmation from the family business representatives. What seems to be missing is a convincing theory that links the involvement and behavioral consequences. Accordingly, scholars have not yet come to a mutual understanding of what precisely constitutes a family business. The variety of different definitions and theories has made comparability of different results difficult for instance. These two issues have hampered the development of a rigorous theory of family business. The overall objective of this study is to describe and understand how the family as a dominant owner can enhance firm performance, and can act a source of sustainable success in listed companies. In more detail, in order to develop understanding of the unique factors that can act as competitive advantages for listed family firms, this study is based on a qualitative approach and aims at theory development, not theory verification. The data in this study consist of 16 thematic interviews with CEOs, members of the board, supervisory board chairs, and founders of Finnish listed-family firms. The study consists of two parts. The first part introduces the research topic, research paradigm, methods, and publications, and also discusses the overall outcomes and contributions of the publications. The second part consists of four publications that address the research questions from different viewpoints. The analyses of this study indicate that family ownership in listed companies represents a structure that differs from the traditional views of agency and stewardship, as well as from resource-based and stakeholder views. As opposed to these theories and shareholder capitalism which consider humans as individualistic, opportunistic, and self-serving, and assume that the behaviors of an investor are based on the incentives and motivations to maximize private profits, the family owners form a collective social unit that is motivated to act together toward their mutual purpose or benefit. In addition, socio-emotional and psychological elements of ownership define the family members as owners, rather than the legal and financial dimensions of ownership. That is, collective psychological ownership of family over the business (F-CPO) can be seen as a construct that comprehensively captures the fusion between the family and the business. Moreover, it captures the realized, rather than merely potential, family influence on and interaction with the business, and thereby brings more theoretical clarity of the nature of the fusion between the family and the business, and offers a solution to the problem of family business definition. This doctoral dissertation provides academics, policy-makers, family business practitioners, and the society at large with many implications considering family and business relationships.

Santini ice creams: Co-Owning a tradition

The case studies the potential partnership between a small family business, rich in tradition, that sells ice cream in the Lisbon area and a recognized Portuguese family who runs a multinational business. The aim of this study is to address students to analyze the evolution of the small company by using the Agency and Resource-Based Theories and to outline a potentially successful co-ownership structure if the agreement were to take place. The particularity of the case regards considering and identifying the main Family Business issues to keep in mind when dealing with these types of firms.

Trust and Social Networks in a Changing Europe.

This project set out to investigate the effects of the recent massive social transitions in Eastern Europe on the everyday social lives of the inhabitants of three very different nations: Georgia, Russia and Hungary. It focused in particular on the availability and nature of the support networks available to three different segments of each of the societies (manual workers, students and entrepreneurs) and the impact of network participation on psychological and physical well-being. The group set four specific questions to investigate: the part played by individual psychological beliefs in the formation and maintenance of social networks and the consequent formation of trusting relations; the implication of the size and quality of these networks for mental health; the nature of the social groups inhabited by the respondents and the implication of their work schedule and daily routines on the maintenance of a social and family life; and an analysis of how cultures vary in their social networks and intimacy. Three different methods were used to examine social support and its implications: structured questionnaires, semi-structured short interviews and a media analysis of newspaper materials. The questionnaires were administered to 150 participants in each country, equally divided between students studying full time, manual workers employed in factories, and business people (small kiosk owners, whose work and life style differs considerably from that of the manual workers). The questionnaires investigated various predictors of social support including the locus of control, relationship beliefs, individualism-collectivism and egalitarianism, demographic variables (age, gender and occupation), social support, both in general and in relation to significant events that have occurred since the transition from communism. Those with an internal locus of control were more likely to report a higher level of social support, as were collectivists, while age too was a significant predictor, with younger respondents enjoying higher levels of support, regardless of the measures of support employed. Respondents across the cultures referred to a decline of social support and the group also found a direct correlation between social support and mental health outcomes. All 450 respondents were interviewed on their general responses to changes in their lives since the fall of communism and the effects of their work lives on their social lives and the home environment. The interviews revealed considerable variations in the way in which work-life offered opportunities for a broader social life and also provided a hindrance to the development of fulfilling relationships. Many of the work experiences discussed were culture specific, with work having a particularly negative impact on the social life of Russian entrepreneurs but being seen much more positively in Georgia. This may reflect the nature of support offered in a society as overall support levels were lowest in Russia, meaning that social support may be of particular importance there. The way in cultural values and norms about personal relationships are transmitted in a culture is a critical issue for social psychologists and the group examined newspaper articles in those newspapers read by the respondents in each of the three countries. These revealed a number of different themes. The concept of a divided society and its implications for personal relationships was clearest in Russian and Hungary, where widely-read newspapers dwelt on the contrast between "new Russians/Hungarians" and the older, poorer ones and extended considerable sympathy to those suffering from neglect in institutions. Magyar Nemzet, a paper widely read by Hungarian students reflects the generally more pessimistic tone about personal relationships in Russia and Hungary and gave a particularly detailed analysis of the implications this holds for human relations in a modern society. In Georgia, however, the tone of the newspapers is more positive, stressing greater social cohesion. Part of this cohesion is framed in the context of religion, with the church appealing to a broader egalitarianism, whereas in less egalitarian Hungary appeals by the Church are centred more on the nuclear family and its need for expansion in both size and influence. The division between the sexes was another prominent issue in Hungary and Russia, while the theme of generational conflict also emerged in Hungarian and Georgian papers, although with some understanding of "young people today". The team's original expectation that the different newspapers read by the different groups of respondents would present differing images of personal relationships was not fulfilled, as despite variations in style, they found little clear "ideological targeting" of any particular readership. They conclude that the vast majority of respondents recognised that the social transition from communism has had a significant impact on the well-being of social relationships and that this is a pertinent issue for all segments of society. While the group see the data collected as a source to be worked on for some time in the future, their initial impressions include the following. Social support is clearly an important concern across all three countries. All respondents (including the students) lament the time taken up by their heavy work schedules and value their social networks and family ties in particular. The level of social support differs across the countries investigated, with Georgian apparently enjoying significantly higher levels of social support. The analysis produced an image of a relatively cohesive and egalitarian society in which even the group most often seen as distant from the general population, business people, is supported by a strong social network. In contrast, the support networks available to the Russian respondents seem particularly weak and reflect a general sense of division and alienation within the culture as a whole. The implications of low levels of social support may vary across countries. While Russians reported the lowest level of mental health problems, the link between social support and mental health may be strongest in that country. In contrast, in Hungary it is the link between fatalism and mental health problems which is particularly strong, while in Georgia the strongest correlation was between mental health and marital quality, emphasising the significance of the marital relationship in that country.

Three essays on the concept of trust and its foundations

The present dissertation focuses on trust and comprises three empirical essays on the concept itself and its foundations. All three essays investigate trust as an expectation and rely on selfreport measures of trust. Whereas the first two chapters investigate social trust, the third chapter investigates political trust. Essentially, there are three related important debates to which the following chapters contribute. A first debate discusses problems with current selfreport measures. Scholars recently started to question whether standard trust questions really measure the same across countries and languages. Chapter 1 engages in this debate. Using data from Switzerland it studies whether different trust questions measure the same latent trust constructs across individuals belonging to three different culturallinguistic regions. The second debate concerns the socalled forms or dimensions of trust. Recently, scholars started investigating whether trust is a onedimensional construct, i.e. whether an individual's trust judgment differs for categories of trustees such as strangers, neighbors, family members and friends or not. Relying on confirmatory factor analysis Chapter 2 investigates whether individuals really do make a difference between different trustee categories and to what extent these judgments can be summarized into higherorder latent trust constructs. The third debate is concerned with causes of differences in trust across humans. Chapter 3 focuses on the role of laterlife experiences, more precisely victimization experiences and investigates their causal relationship with generalized social trust. Chapter 4 focuses on the impact of direct democratic institutions on the trust relationship between citizens and political authorities.

Is Trading Behavior Stable Across Contexts? Evidence from Style and Multi-Style Investors

In this paper we study priming of identity within the context of inherent vs. contextual financial decision making. We use a sample of individual trading accounts in equity-style funds taken from one fund family to test the hypothesis that trading styles are inherent vs. contextual. Our sample contains investors who invest either in a growth fund, a value fund, or both. We document behavioral differences between growth fund investors and value fund investors. We find that their trades depend on past returns in different ways: growth fund investors tend towards momentum trading and value fund investors tend towards contrarian trading. These differences may be due to inherent clientele characteristics, including beliefs about market prices, specific personality traits and cognitive strategies that cause them to self-select into one or the other style. We use a sample of investors that trade in both types of funds to test this proposition. Consistent with the contextual hypothesis, we find that investors who hold both types of funds trade growth fund shares differently than value fund shares.

Interviewing children and young people with learning disabilities: guidelines for researchers and multi-professional practice

We argue that it is important for researchers and service providers to not only recognize the rights of children and young people with learning disabilities to have a ‘voice’, but also to work actively towards eliciting views from all. A set of guidelines for critical self-evaluation by those engaged in systematically collecting the views of children and young people with learning disabilities is proposed. The guidelines are based on a series of questions concerning: research aims and ethics (encompassing access/gatekeepers; consent/assent; confidentiality/anonymity/secrecy, recognition, feedback and ownership; and social responsibility) sampling, design and communication

Proposal of a trust and reputation model to provide recommendation in open quality oriented environments

El auge y penetración de las nuevas tecnologías junto con la llamada Web Social están cambiando la forma en la que accedemos a la medicina. Cada vez más pacientes y profesionales de la medicina están creando y consumiendo recursos digitales de contenido clínico a través de Internet, surgiendo el problema de cómo asegurar la fiabilidad de estos recursos. Además, un nuevo concepto está apareciendo, el de pervasive healthcare o sanidad ubicua, motivado por pacientes que demandan un acceso a los servicios sanitarios en todo momento y en todo lugar. Este nuevo escenario lleva aparejado un problema de confianza en los proveedores de servicios sanitarios. Las plataformas de eLearning se están erigiendo como paradigma de esta nueva Medicina 2.0 ya que proveen un servicio abierto a la vez que controlado/supervisado a recursos digitales, y facilitan las interacciones y consultas entre usuarios, suponiendo una buena aproximación para esta sanidad ubicua. En estos entornos los problemas de fiabilidad y confianza pueden ser solventados mediante la implementación de mecanismos de recomendación de recursos y personas de manera confiable. Tradicionalmente las plataformas de eLearning ya cuentan con mecanismos de recomendación, si bien están más enfocados a la recomendación de recursos. Para la recomendación de usuarios es necesario acudir a mecanismos más elaborados como son los sistemas de confianza y reputación (trust and reputation) En ambos casos, tanto la recomendación de recursos como el cálculo de la reputación de los usuarios se realiza teniendo en cuenta criterios principalmente subjetivos como son las opiniones de los usuarios. En esta tesis doctoral proponemos un nuevo modelo de confianza y reputación que combina evaluaciones automáticas de los recursos digitales en una plataforma de eLearning, con las opiniones vertidas por los usuarios como resultado de las interacciones con otros usuarios o después de consumir un recurso. El enfoque seguido presenta la novedad de la combinación de una parte objetiva con otra subjetiva, persiguiendo mitigar el efecto de posibles castigos subjetivos por parte de usuarios malintencionados, a la vez que enriquecer las evaluaciones objetivas con información adicional acerca de la capacidad pedagógica del recurso o de la persona. El resultado son recomendaciones siempre adaptadas a los requisitos de los usuarios, y de la máxima calidad tanto técnica como educativa. Esta nueva aproximación requiere una nueva herramienta para su validación in-silico, al no existir ninguna aplicación que permita la simulación de plataformas de eLearning con mecanismos de recomendación de recursos y personas, donde además los recursos sean evaluados objetivamente. Este trabajo de investigación propone pues una nueva herramienta, basada en el paradigma de programación orientada a agentes inteligentes para el modelado de comportamientos complejos de usuarios en plataformas de eLearning. Además, la herramienta permite también la simulación del funcionamiento de este tipo de entornos dedicados al intercambio de conocimiento. La evaluación del trabajo propuesto en este documento de tesis se ha realizado de manera iterativa a lo largo de diferentes escenarios en los que se ha situado al sistema frente a una amplia gama de comportamientos de usuarios. Se ha comparado el rendimiento del modelo de confianza y reputación propuesto frente a dos modos de recomendación tradicionales: a) utilizando sólo las opiniones subjetivas de los usuarios para el cálculo de la reputación y por extensión la recomendación; y b) teniendo en cuenta sólo la calidad objetiva del recurso sin hacer ningún cálculo de reputación. Los resultados obtenidos nos permiten afirmar que el modelo desarrollado mejora la recomendación ofrecida por las aproximaciones tradicionales, mostrando una mayor flexibilidad y capacidad de adaptación a diferentes situaciones. Además, el modelo propuesto es capaz de asegurar la recomendación de nuevos usuarios entrando al sistema frente a la nula recomendación para estos usuarios presentada por el modo de recomendación predominante en otras plataformas que basan la recomendación sólo en las opiniones de otros usuarios. Por último, el paradigma de agentes inteligentes ha probado su valía a la hora de modelar plataformas virtuales complejas orientadas al intercambio de conocimiento, especialmente a la hora de modelar y simular el comportamiento de los usuarios de estos entornos. La herramienta de simulación desarrollada ha permitido la evaluación del modelo de confianza y reputación propuesto en esta tesis en una amplia gama de situaciones diferentes. ABSTRACT Internet is changing everything, and this revolution is especially present in traditionally offline spaces such as medicine. In recent years health consumers and health service providers are actively creating and consuming Web contents stimulated by the emergence of the Social Web. Reliability stands out as the main concern when accessing the overwhelming amount of information available online. Along with this new way of accessing the medicine, new concepts like ubiquitous or pervasive healthcare are appearing. Trustworthiness assessment is gaining relevance: open health provisioning systems require mechanisms that help evaluating individuals’ reputation in pursuit of introducing safety to these open and dynamic environments. Technical Enhanced Learning (TEL) -commonly known as eLearning- platforms arise as a paradigm of this Medicine 2.0. They provide an open while controlled/supervised access to resources generated and shared by users, enhancing what it is being called informal learning. TEL systems also facilitate direct interactions amongst users for consultation, resulting in a good approach to ubiquitous healthcare. The aforementioned reliability and trustworthiness problems can be faced by the implementation of mechanisms for the trusted recommendation of both resources and healthcare services providers. Traditionally, eLearning platforms already integrate recommendation mechanisms, although this recommendations are basically focused on providing an ordered classifications of resources. For users’ recommendation, the implementation of trust and reputation systems appears as the best solution. Nevertheless, both approaches base the recommendation on the information from the subjective opinions of other users of the platform regarding the resources or the users. In this PhD work a novel approach is presented for the recommendation of both resources and users within open environments focused on knowledge exchange, as it is the case of TEL systems for ubiquitous healthcare. The proposed solution adds the objective evaluation of the resources to the traditional subjective personal opinions to estimate the reputation of the resources and of the users of the system. This combined measure, along with the reliability of that calculation, is used to provide trusted recommendations. The integration of opinions and evaluations, subjective and objective, allows the model to defend itself against misbehaviours. Furthermore, it also allows ‘colouring’ cold evaluation values by providing additional quality information such as the educational capacities of a digital resource in an eLearning system. As a result, the recommendations are always adapted to user requirements, and of the maximum technical and educational quality. To our knowledge, the combination of objective assessments and subjective opinions to provide recommendation has not been considered before in the literature. Therefore, for the evaluation of the trust and reputation model defined in this PhD thesis, a new simulation tool will be developed following the agent-oriented programming paradigm. The multi-agent approach allows an easy modelling of independent and proactive behaviours for the simulation of users of the system, conforming a faithful resemblance of real users of TEL platforms. For the evaluation of the proposed work, an iterative approach have been followed, testing the performance of the trust and reputation model while providing recommendation in a varied range of scenarios. A comparison with two traditional recommendation mechanisms was performed: a) using only users’ past opinions about a resource and/or other users; and b) not using any reputation assessment and providing the recommendation considering directly the objective quality of the resources. The results show that the developed model improves traditional approaches at providing recommendations in Technology Enhanced Learning (TEL) platforms, presenting a higher adaptability to different situations, whereas traditional approaches only have good results under favourable conditions. Furthermore the promotion period mechanism implemented successfully helps new users in the system to be recommended for direct interactions as well as the resources created by them. On the contrary OnlyOpinions fails completely and new users are never recommended, while traditional approaches only work partially. Finally, the agent-oriented programming (AOP) paradigm has proven its validity at modelling users’ behaviours in TEL platforms. Intelligent software agents’ characteristics matched the main requirements of the simulation tool. The proactivity, sociability and adaptability of the developed agents allowed reproducing real users’ actions and attitudes through the diverse situations defined in the evaluation framework. The result were independent users, accessing to different resources and communicating amongst them to fulfil their needs, basing these interactions on the recommendations provided by the reputation engine.