Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.

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.

Sensor Fusion of Proprioception, Force and Vision in Estimation and Robot

Sensor-based robot control allows manipulation in dynamic environments with uncertainties. Vision is a versatile low-cost sensory modality, but low sample rate, high sensor delay and uncertain measurements limit its usability, especially in strongly dynamic environments. Force is a complementary sensory modality allowing accurate measurements of local object shape when a tooltip is in contact with the object. In multimodal sensor fusion, several sensors measuring different modalities are combined to give a more accurate estimate of the environment. As force and vision are fundamentally different sensory modalities not sharing a common representation, combining the information from these sensors is not straightforward. In this thesis, methods for fusing proprioception, force and vision together are proposed. Making assumptions of object shape and modeling the uncertainties of the sensors, the measurements can be fused together in an extended Kalman filter. The fusion of force and visual measurements makes it possible to estimate the pose of a moving target with an end-effector mounted moving camera at high rate and accuracy. The proposed approach takes the latency of the vision system into account explicitly, to provide high sample rate estimates. The estimates also allow a smooth transition from vision-based motion control to force control. The velocity of the end-effector can be controlled by estimating the distance to the target by vision and determining the velocity profile giving rapid approach and minimal force overshoot. Experiments with a 5-degree-of-freedom parallel hydraulic manipulator and a 6-degree-of-freedom serial manipulator show that integration of several sensor modalities can increase the accuracy of the measurements significantly.

Multi-Eruption Solar Energetic Particle Events Observed by SOHO/ERNE

In the last two decades of studying the Solar Energetic Particle (SEP) phenomenon, intensive emphasis has been put on how and when and where these SEPs are injected into interplanetary space. It is well known that SEPs are related to solar flares and CMEs. However, the role of each in the acceleration of SEPs has been under debate since the major role was taken from flares ascribed to CMEs step by step after the skylab mission, which started the era of CME spaceborn observations. Since then, the shock wave generated by powerful CMEs in between 2-5 solar radii is considered the major accelerator. The current paradigm interprets the prolonged proton intensity-time profile in gradual SEP events as a direct effect of accelerated SEPs by shock wave propagating in the interplanetary medium. Thus the powerful CME is thought of as a starter for the acceleration and its shock wave as a continuing accelerator to result in such an intensity-time profile. Generally it is believed that a single powerful CME which might or might not be associated with a flare is always the reason behind such gradual events.

In this work we use the Energetic and Relativistic Nucleus and Electrons ERNE instrument on board Solar and Heliospheric Observatory SOHO to present an empirical study to show the possibility of multiple accelerations in SEP events. In the beginning we found 18 double-peaked SEP events by examining 88 SEP events. The peaks in the intensity-time profile were separated by 3-24 hours. We divided the SEP events according to possible multiple acceleration into four groups and in one of these groups we find evidence for multiple acceleration in velocity dispersion and change in the abundance ratio associated at transition to the second peak. Then we explored the intensity-time profiles of all SEP events during solar cycle 23 and found that most of the SEP events are associated with multiple eruptions at the Sun and we call those events as Multi-Eruption Solar Energetic Particles (MESEP) events. We use the data available by Large Angle and Spectrometric Coronograph LASCO on board SOHO to determine the CME associated with such events and YOHKOH and GOES satellites data to determine the flare associated with such events. We found four types of MESEP according to the appearance of the peaks in the intensity-time profile in large variation of energy levels. We found that it is not possible to determine whether the peaks are related to an eruption at the Sun or not, only by examining the anisotropy flux, He/p ratio and velocity dispersion. Then we chose a rare event in which there is evidence of SEP acceleration from behind previous CME. This work resulted in a conclusion which is inconsistent with the current SEP paradigm. Then we discovered through examining another MESEP event, that energetic particles accelerated by a second CME can penetrate a previous CME-driven decelerating shock. Finally, we report the previous two MESEP events with new two events and find a common basis for second CME SEPs penetrating previous decelerating shocks. This phenomenon is reported for the first time and expected to have significant impact on modification of the current paradigm of the solar energetic particle events.

A multi-screening approach for marine-derived fungal metabolites and the isolation of cyclodepsipeptides from Beauveria felina

Extracts obtained from 57 marine-derived fungal strains were analyzed by HPLC-PDA, TLC and ¹H NMR. The analyses showed that the growth conditions affected the chemical profile of crude extracts. Furthermore, the majority of fungal strains which produced either bioactive of chemically distinctive crude extracts have been isolated from sediments or marine algae. The chemical investigation of the antimycobacterial and cytotoxic crude extract obtained from two strains of the fungus Beauveria felina have yielded cyclodepsipeptides related to destruxins. The present approach constitutes a valuable tool for the selection of fungal strains that produce chemically interesting or biologically active secondary metabolites.

Espectrometria de absorção atômica: o caminho para determinações multi-elementares

This paper present an overview of way covered for the spectrometry of atomic absorption (AAS), tracing a line of the historical events in its development and its establishment as a multielement technique. Additionally, the efforts carried by through several researchers in the search for the instrumental evolution, the advances, advantages, limitations, and trends of this approach are related. Several works focusing its analytical applications are cited employing simultaneous multielement determination by flame (FAAS) and/or graphite furnace (GF AAS), and fast sequential multielement determination using FAAS are reported in the present review.

Social Presence Approach Within the Question and Answering eLearning Model: An Experiment with a Multi-Agent System

The model of Questions Answering (Q&A) for eLearning is based on collaborative learning through questions that are posed by students and their answers to that questions which are given by peers, in contrast with the classical model in which students ask questions to the teacher only. In this proposal we extend the Q&A model including the social presence concept and a quantitative measure of it is proposed; besides it is considered the evolution of the resulting Q&A social network after the inclusion of the social presence and taking into account the feedback on questions posed by students and answered by peers. The social network behaviorwas simulated using a Multi-Agent System to compare the proposed social presence model with the classical and the Q&A models

Multi-component quantitation of loratadine, pseudoephedrine and paracetamol in plasma and pharmaceutical formulations with liquid chromatography-tandem mass spectrometry utilizing a monolithic column

The purpose of this study was to develop a rapid, simple and sensitive quantitation method for pseudoephedrine (PSE), paracetamol (PAR) and loratadine (LOR) in plasma and pharmaceuticals using liquid chromatography-tandem mass spectrometry with a monolithic column. Separation was achieved using a gradient composition of methanol-0.1% formic acid at a flow rate of 1.0 mL min-1. Mass spectral transitions were recorded in SRM mode. System validation was evaluated for precision, specificity and linearity. Limit of detection for pseudoephedrine, paracetamol, and loratadine were determined to be 3.14, 1.86 and 1.44 ng mL-1, respectively, allowing easy determination in plasma with % recovery of 93.12 to 101.56%.

Síntese de cristais líquidos derivados do nitroazobenzeno: uma proposta de síntese multi-etapas aplicada às aulas de química orgânica experimental

We describe a synthetic route consisting of five steps from aniline to obtain liquid crystal compounds derived from nitroazobenzene. Syntheses were performed during the second half of the semester in organic chemistry laboratory classes. Students characterized the liquid crystal phase by the standard melting point techniques, differential scanning calorimetry and polarized optical microscopy. These experiments allow undergraduate students to explore fundamentally important reactions in Organic Chemistry, as well as modern concepts in Chemistry such as self-assembly and self-organization, nanostructured materials and molecular electronics.

Cultural aspects of globalizing university-industry knowledge interaction in China

Previous studies of the local involvement of multinational corporation (MNC) subsidiaries focus on host-country firms and local business partners such as suppliers and customers. The role of host-country universities in the same context of innovation networks is neglected. Furthermore, there are many organizational culture- and knowledge-related differences between universities and companies, and this is likely to pose additional challenges for successful collaboration. Early university-industry (U-I) studies have primarily been limited within a national boundary, being concerned with a single level of culture (i.e., at an organizational level) and one-way knowledge transfer from university to industry. Research on more dynamic knowledge interaction in multinational settings is lacking. This is particularly true in the business context of China. In today’s globalizing and rapidly changing organizations, addressing cultural differences and clashes is an everyday reality, and inter-cultural U-I collaboration is becoming a key asset for gaining global competitiveness. This study deals with Finnish MNC subsidiaries’ research collaboration with Chinese universities. It aims to explore the essence of such U-I collaboration and knowledge interaction, uncovering the deep functioning mechanisms of culture underlying effective collaborative knowledge creation and innovation. The study reviews critically different bodies of literature including knowledge management theories and studies, U-I collaboration and knowledge interaction, and cross-cultural research in terms of organizational knowledge generation and utilization. It adopts a case study strategy with qualitative research methods, and data is collected through in-depth interviews and participant observation. The study presents the following major findings: 1. In the light of a comprehensive analysis of U-I collaboration, an effective matching strategy is proposed, in the assumption that good alignment of knowledge interaction strategies and approaches with their corresponding knowledge type, capability development and research task may greatly enhance the effectiveness of cross-cultural U-I collaboration and knowledge interaction. 2. It is proposed that in the Chinese MNC context more dynamic types of knowledge interaction like knowledge co-creation should be of key concern particularly when dealing simultaneously with multi-disciplinary applied research of human factors and technologies. U-I knowledge interaction, otherwise, pays attention only to the study of one-way technology and knowledge transfer. 3. It is posited that the influence of culture on collaborative knowledge interaction can be studied in a valuable way when knowledge-related variables are simultaneously taken into account. A systematic analysis of the role of knowledge in cross-cultural knowledge interaction could best be approached from multi-aspects of knowledge including not only nature, characteristics and types of knowledge but also the process of knowledge (e.g., intensifications of knowledge interaction). 4. The study demonstrates the significant role of aspects of the host-country culture (e.g., Chinese guanxi) in U-I collaboration and knowledge interaction. This is evident, for instance, in issues related to interpersonal relationships and trust, true interest and the relatedness of the research, mutual commitment and learning, communication intensity and interaction, and awareness of cultural and knowledge-related differences between collaboration partners. Theoretical and practical implications of the findings are suggested and discussed.

Management of interdependency in project portfolio

Project management has evolved in recent decades. Project portfolio management, together with multi project management, is an emerging area in the project management field in practice, and correspondingly in academic research and forums. In multi project management, projects cannot be handled isolated from each other, as they often have interdependencies that have to be taken into account. If the interdependencies between projects are evaluated during the selection process, the success rate of the project portfolio is increased. Interdependencies can be human resources, technological, and/or market based. Despite of the fact that interdependency as a phenomenon has roots in the 1960s and is related to famous management theories, it has not been much studied, although in practice most companies use it to great extent. There exists some research on interdependency, but prior publications have not emphasized the phenomenon per se, because a practical orientation practitioner techniques prevails in the literature. This research applies the method triangulation, electronic surveys and multiple case study. The research concentrates on small to large companies in Estonia and Finland, mainly in construction, engineering, ICT, and machinery industries. The literature review reveals that interdependencies are deeply involved in R&D and innovation. Survey analysis shows that companies are aware of interdependency issues in general, but they i have lack of detailed knowledge to use it thoroughly. Empirical evidence also indicates that interdependency techniques influence the success rate and other efficiency aspects to different extents. There are a lot of similarities in interdependency related managerial issues in companies of varying sizes and countries in Northern Europe. Differences found in the study are for instance the fact that smaller companies face more difficulties in implementing and evaluating interdependency procedures. Country differences between Estonia and Finland stem from working solutions to manage interdependencies on a daily basis.historical and cultural reasons, such as the special features of a transition country compared to a mature country. An overview of the dominant problems, best practices, and commonly used techniques associated with interdependency is provided in the study. Empirical findings show that many interdependency techniques are not used in practice. A multiple case study was performed in the study to find out how interdependencies are managed in real life on a daily basis. The results show that interdependencies are mostly managed in an informal manner. A description of managing the interdependencies and implementation procedures is given. Interdependency procedures are hard to implement, especially in smaller companies. Companies have difficulties in implementing interdependency procedures and evaluating them. The study contains detailed results on how companies have implemented working solutions to manage interdependencies on a daily basis

Innovations of ageing and societal transition : Dynamics of change of the socio-technical regime of ageing

The purpose of this dissertation is to examine the dynamics of the socio-technical system in the field of ageing. The study stems from the notion that the ageing of the population as a powerful megatrend has wide societal effects, and is not just a matter for the social and health sector. The central topic in the study is change: not only the age structures and structures of society are changing, but also at the same time there is constant development, for instance, in technologies, infrastructures and cultural perceptions. The changing concept of innovation has widened the understanding of innovations related to ageing from medical and assistive technological innovations to service and social innovations, as well as systemic innovations at different levels, which means the intertwined and co-evolutionary change in technologies, structures, services and thinking models. By the same token, the perceptions of older people and old age are becoming more multi-faceted: old age is no longer equated to illnesses and decline, but visions of active ageing and a third age have emerged, which are framed by choices, opportunities, resources and consumption in later life. The research task in this study is to open up the processes and mechanisms of change in the field of ageing, which are studied as a complex, multi-level and interrelated socio-technical system. The question is about co-effective elements consisting of macro-level landscape changes, the existing socio-technical regime (the rule system, practices and structures) and bottom-up niche-innovations. Societal transitions do not account for the things inside the regime alone, or for the long-term changes in the landscape, nor for the radical innovations, but for the interplay between all these levels. The research problem is studied through five research articles, which offer micro-level case studies to macro-level phenomenon. Each of the articles focus on different aspects related to ageing and change, and utilise various datasets. The framework of this study leans on the studies of socio-technical systems and multi-level perspective on transitions mainly developed by Frank Geels. Essential factors in transition from one socio-technological regime to another are the co-evolutionary processes between landscape changes, regime level and experimental niches. Landscape level changes, like the ageing of the population, destabilise the regime in the forms of coming pressures. This destabilization offers windows for opportunity to niche-innovations outside or at fringe of the regime, which, through their breakthrough, accelerate the transition process. However, the change is not easy because of various kinds of lock-ins and inertia, which tend to maintain the stability of the regime. In this dissertation, a constructionist approach of society is applied leaning mainly to the ideas of Anthony Giddens’ theory of structuration, with the dual nature of structures. The change is taking place in the interplay between actors and structures: structures shape people’s practices, but at the same time these practices constitute and reproduce social systems. Technology and other material aspects, as part of socio-technical systems, and the use of them, also take part in the structuration process. The findings of the study point out that co-evolutionary and co-effective relationships between economic, cultural, technological and institutional fields, as well as relationships between landscape changes, changes in the local and regime-level practices and rule systems, are a very complex and multi-level dynamic socio-technical phenomenon. At the landscape level of ageing, which creates the pressures and triggers to the regime change, there are three remarkable megatrends: demographic change, changes in the global economy and the development of technologies. These exert pressures to the socio-technical regime, which as a rule system is experiencing changes in the form of new markets and consumer habits, new ways of perceiving ageing, new models of organising the health care and other services and as new ways of considering innovation and innovativeness. There are also inner dynamics in the relationships between these aspects within the regime. These are interrelated and coconstructed: the prevailing perceptions of ageing and innovation, for instance, reflect the ageing policies, innovation policies, societal structures, organising models, technology and scientific discussion, and vice versa. Technology is part of the inner dynamics of the sociotechnological regime. Physical properties of the artefacts set limitations and opportunities with regard to their functions and uses. The use of and discussion about technology, contributes producing and reproducing the perceptions of old age. For societal transition, micro-level changes are also needed, in form of niche-innovations, for instance new services, organisational models or new technologies, Regimes, as stabilitystriven systems, tend to generate incremental innovations, but radically new innovations are generated in experimental niches protected from ‘normal’ market selection. The windows of opportunity for radical novelties may be opened if the circumstances are favourable for instance by tensions in the socio-technical regime affected by landscape level changes. This dissertation indicates that a change is taking place, firstly, in the dynamic interactionbetween levels, as a result of purposive action and governance to some extent. Breaking the inertia and using the window of opportunity for change and innovation offered by dynamics between levels, presupposes the actors’ special capabilities and actions such as dynamic capabilities and distance management. Secondly, the change is taking place the socio-technological negotiations inside the regime: interaction between technological and social, which is embodied in the use of technology. The use of technology includes small-level contextual scripts that also participate in forming broader societal scripts (for instance defining old age at the society level), which in their turn affect the formation of policies for innovation and ageing. Thirdly, the change is taking place by the means of active formation of the multi-actor innovation networks, where the role of distance management is crucial to facilitate the communication between actors coming from different backgrounds as well as to help the niches born outside the regime to utilise the window of opportunity offered by regime destabilisation. This dissertation has both theoretical and practical contributions. This study participates in the discussion of action-oriented view on transition by opening up of the socio-technological, coevolutionary processes of the multi-faceted phenomenon of ageing, which has lacked systematic analyses. The focus of this study, however, is not on the large-scale coordination and governance, but rather on opening up the incremental elements and structuration processes, which contribute to the transition little by little, and which can be affected to. This increases the practical importance of this dissertation, by highlighting the importance of very tiny, everyday elements in the change processes in the long run.

Control of Asian soybean rust with mancozeb, a multi-site fungicide

An experiment conducted in the field the action of mancozeb, a fungicide of multi-site action was tested, to control soybean rust caused by Phakopsora pachyrhizi. Its performance was compared to that of the mixture cyproconazole (DMI) + azoxystrobin (QoI). The soybean cultivar NA 7337 RR was used with a population of 400,000 plants/ha cultivated in 20m2 plots. Treatments consisted of mancozeb levels (1.5 and 2.0 kg/ha) applied four, six and eight times. The DMI + QoI mixture was applied three times at 0.3 L/ha + Nimbus. Rust severity was assessed six times in the plots and data were integrated as the area under the disease progress curve (AUDPC). The plots were harvested and grain yield was expressed as kg/ha. Data on AUDPC and yield were subjected to analysis of variance and means compared according to Turkey's test (p = 0.005). Treatments with mancozeb were superior to DMI + QoI mixture both for rust control and grain yield. Four applications of 2.0 k/ha mancozeb were more efficient than three applications of the mixture used as standard. Mancozeb has the potential to be added to fungicide mixtures in the establishment of soybean rust anti-resistance strategy.