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.

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.

Montagem de um sistema para medidas galvanostáticas simultâneas em mais de uma célula

The present work deals with the design and construction of an equipment for muti-cell accelerated stability test measurements (AST) of dimensionally stable anodes (DSA). The equipment was built using only components that were available in the laboratory. Measurements of three electrochemical cells can be performed using the developed software. The acquisition time interval and the cut-off potencial can be set by the user. Experimental data for RuO2 electrodes obtained with the built equipment are in agreement with the literature.

Machine Learning and Clinical Text. Supporting Health Information Flow

Fluent health information flow is critical for clinical decision-making. However, a considerable part of this information is free-form text and inabilities to utilize it create risks to patient safety and cost-­effective hospital administration. Methods for automated processing of clinical text are emerging. The aim in this doctoral dissertation is to study machine learning and clinical text in order to support health information flow.First, by analyzing the content of authentic patient records, the aim is to specify clinical needs in order to guide the development of machine learning applications.The contributions are a model of the ideal information flow,a model of the problems and challenges in reality, and a road map for the technology development. Second, by developing applications for practical cases,the aim is to concretize ways to support health information flow. Altogether five machine learning applications for three practical cases are described: The first two applications are binary classification and regression related to the practical case of topic labeling and relevance ranking.The third and fourth application are supervised and unsupervised multi-class classification for the practical case of topic segmentation and labeling.These four applications are tested with Finnish intensive care patient records.The fifth application is multi-label classification for the practical task of diagnosis coding. It is tested with English radiology reports.The performance of all these applications is promising. Third, the aim is to study how the quality of machine learning applications can be reliably evaluated.The associations between performance evaluation measures and methods are addressed,and a new hold-out method is introduced.This method contributes not only to processing time but also to the evaluation diversity and quality. The main conclusion is that developing machine learning applications for text requires interdisciplinary, international collaboration. Practical cases are very different, and hence the development must begin from genuine user needs and domain expertise. The technological expertise must cover linguistics,machine learning, and information systems. Finally, the methods must be evaluated both statistically and through authentic user-feedback.

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

Evaluating End-User Training Effectiveness in ERP System Implementation

Today’s business world demands more and more internal and external integration and transparency among companies at all fields. Integrated ERP (enterprise resource planning) systems offer a possibility to improve business practices and procedures by providing a unified view on the business including all functions and departments. Due to the obvious benefits, the popularity of integrated ERP systems keeps growing. The implementation of ERP systems has however proven risky. The implementation projects tend to be long, extensive, and costly – and often they end up in a failure. Due to the significant task and role changes ERP implementation brings to almost everybody in the company, training has been identified as one of the most critical success factors of an ERP implementation. To ensure that the training is conducted in the most effective and successful manner, the training outcomes should be evaluated. So far, training evaluation has however gained only limited attention at most companies investing in different training programs. Uponor corporation has initiated a large ERP implementation and process harmonization program in 2004. Thousands of end-users have been trained during this project so far, and the work still continues until the project is completed in 2010. In this thesis, the evaluation of end-user training in Uponor’s ERP program is brought further from the current state of performing the basic participant satisfaction survey in the end of each class. The results show that in order to reach reliable training effectiveness evaluation results, not only the reaction towards training but also transfer of skills and attitudes and the final results of the training program should be evaluated.

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.

Improving and User Interface to E-Procurement Software Used in Asset Accounting and Investigating Effects to Efficiency

This diploma thesis has been done to international organization which takes care from the accounting actions of two major companies. In this organization are used three different purchasing tools which are used when new asset master data is wanted to input to SAP R/3- system. The aim of this thesis is to find out how much changing the user interface of one of these three e-procurement programs will affect to overall efficiency in asset accounting. As an addition will be introduced project framework which can be used in future projects and which help to avoid certain steps in the development process. At the moment data needs to be inputted manually with many useless mouse clicks and data needs to be searched from many various resources which slow down the process. Other organization has better tools at the moment than the myOrders system which is under investigation Research was started by exploring the main improvement areas. After this possible defects were traced. Suggested improvements were thought by exploring literature which has been written from usability design and research. Meanwhile also directional calculations from the benefits of the project were done alongside with the analysis of the possible risks and threats. After this NSN IT approved the changes which they thought was acceptable. The next step was to program them into tool and test them before releasing to production environment. The calculations were made also from implemented improvements and compared them to planned ones From whole project was made a framework which can be utilized also to other similar projects. The complete calculation was not possible because of time schedule of the project. Important observation in the project was that efficiency is not improved not only by changing the GUI but also improving processes without any programming. Feedback from end user should be also listened more in development process. End-user is after all the one who knows the best how the program should look like.

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.