Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Exploration of the Antiplatelet Activity Profile of Betulinic Acid on Human Platelets

Betulinic acid, a natural pentacyclic triterpene acid, presents a diverse mode of biological actions including antiretroviral, antibacterial, antimalarial, and anti-inflammatory activities. The potency of betulinic acid as an inhibitor of human platelet activation was evaluated, and its antiplatelet profile against in vitro platelet aggregation, induced by several platelet agonists (adenosine diphosphate, thrombin receptor activator peptide-14, and arachidonic acid), was explored. Flow cytometric analysis was performed to examine the effect of betulinic acid on P-selectin membrane expression and PAC-1 binding to activated platelets. Betulinic acid potently inhibits platelet aggregation and also reduced PAC-1 binding and the membrane expression of P-selectin. Principal component analysis was used to screen, on the chemical property space, for potential common pharmacophores of betulinic acid with approved antithrombotic drugs. A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists (PGI2), and the importance of its carboxylate group in its antiplatelet activity was determined. The present results indicate that betulinic acid has potential use as an antithrombotic compound and suggest that the mechanism underlying the antiplatelet effects of betulinic acid is similar to that of the PGI2 receptor agonists, a hypothesis that deserves further investigation.

Analog circuit synthesis performing fast Pareto frontier exploration and analysis through 3D graphs

This paper presents a technique for performing analog design synthesis at circuit level providing feedback to the designer through the exploration of the Pareto frontier. A modified simulated annealing which is able to perform crossover with past anchor points when a local minimum is found which is used as the optimization algorithm on the initial synthesis procedure. After all specifications are met, the algorithm searches for the extreme points of the Pareto frontier in order to obtain a non-exhaustive exploration of the Pareto front. Finally, multi-objective particle swarm optimization is used to spread the results and to find a more accurate frontier. Piecewise linear functions are used as single-objective cost functions to produce a smooth and equal convergence of all measurements to the desired specifications during the composition of the aggregate objective function. To verify the presented technique two circuits were designed, which are: a Miller amplifier with 96 dB Voltage gain, 15.48 MHz unity gain frequency, slew rate of 19.2 V/mu s with a current supply of 385.15 mu A, and a complementary folded cascode with 104.25 dB Voltage gain, 18.15 MHz of unity gain frequency and a slew rate of 13.370 MV/mu s. These circuits were synthesized using a 0.35 mu m technology. The results show that the method provides a fast approach for good solutions using the modified SA and further good Pareto front exploration through its connection to the particle swarm optimization algorithm.

Space and Motion Perception and Discomfort in Air Travel

RAMOS RT, MATTOS DA, REBOUCAS ITS, RANVAUD RD. Space and motion perception and discomfort in air travel. Aviat Space Environ Med 2012; 83:1162-6. Introduction: The perception of comfort during air trips is determined by several factors. External factors like cabin design and environmental parameters (temperature, humidity, air pressure, noise, and vibration) interact with individual characteristics (anxiety traits, fear of flying, and personality) from arrival at the airport to landing at the destination. In this study, we investigated the influence of space and motion discomfort (SMD), fear of heights, and anxiety on comfort perception during all phases of air travel. Methods: We evaluated 51 frequent air travelers through a modified version of the Flight Anxiety Situations Questionnaire (FAS), in which new items were added and where the subjects were asked to report their level of discomfort or anxiety (not fear) for each phase of air travel (Chronbach's alpha = 0.974). Correlations were investigated among these scales: State-Trait Anxiety Inventory (STAB, Cohen's Acrophobia Questionnaire, and the Situational Characteristics Questionnaire (SitQ, designed to estimate SMD levels). Results: Scores of SitQ correlated with discomfort in situations involving space and movement perception (Pearson's rho = 0.311), while discomfort was associated with cognitive mechanisms related to scores in the anxiety scales (Pearson's rho = 0.375). Anxiety traits were important determinants of comfort perception before and after flight, while the influence of SMD was more significant during the time spent in the aircraft cabin. Discussion: SMD seems to be an important modulator of comfort perception in air travel. Its influence on physical well being and probably on cognitive performance, with possible effects on flight safety, deserves further investigation.

A tuple space implementation for large-scale infrastructures

Coordinating activities in a distributed system is an open research topic. Several models have been proposed to achieve this purpose such as message passing, publish/subscribe, workflows or tuple spaces. We have focused on the latter model, trying to overcome some of its disadvantages. In particular we have applied spatial database techniques to tuple spaces in order to increase their performance when handling a large number of tuples. Moreover, we have studied how structured peer to peer approaches can be applied to better distribute tuples on large networks. Using some of these result, we have developed a tuple space implementation for the Globus Toolkit that can be used by Grid applications as a coordination service. The development of such a service has been quite challenging due to the limitations imposed by XML serialization that have heavily influenced its design. Nevertheless, we were able to complete its implementation and use it to implement two different types of test applications: a completely parallelizable one and a plasma simulation that is not completely parallelizable. Using this last application we have compared the performance of our service against MPI. Finally, we have developed and tested a simple workflow in order to show the versatility of our service.

Design methodologies of microwawe integrated circuits for satellite telecommunications

The running innovation processes of the microwave transistor technologies, used in the implementation of microwave circuits, have to be supported by the study and development of proper design methodologies which, depending on the applications, will fully exploit the technology potentialities. After the choice of the technology to be used in the particular application, the circuit designer has few degrees of freedom when carrying out his design; in the most cases, due to the technological constrains, all the foundries develop and provide customized processes optimized for a specific performance such as power, low-noise, linearity, broadband etc. For these reasons circuit design is always a “compromise”, an investigation for the best solution to reach a trade off between the desired performances. This approach becomes crucial in the design of microwave systems to be used in satellite applications; the tight space constraints impose to reach the best performances under proper electrical and thermal de-rated conditions, respect to the maximum ratings provided by the used technology, in order to ensure adequate levels of reliability. In particular this work is about one of the most critical components in the front-end of a satellite antenna, the High Power Amplifier (HPA). The HPA is the main power dissipation source and so the element which mostly engrave on space, weight and cost of telecommunication apparatus; it is clear from the above reasons that design strategies addressing optimization of power density, efficiency and reliability are of major concern. Many transactions and publications demonstrate different methods for the design of power amplifiers, highlighting the availability to obtain very good levels of output power, efficiency and gain. Starting from existing knowledge, the target of the research activities summarized in this dissertation was to develop a design methodology capable optimize power amplifier performances complying all the constraints imposed by the space applications, tacking into account the thermal behaviour in the same manner of the power and the efficiency. After a reminder of the existing theories about the power amplifier design, in the first section of this work, the effectiveness of the methodology based on the accurate control of the dynamic Load Line and her shaping will be described, explaining all steps in the design of two different kinds of high power amplifiers. Considering the trade-off between the main performances and reliability issues as the target of the design activity, we will demonstrate that the expected results could be obtained working on the characteristics of the Load Line at the intrinsic terminals of the selected active device. The methodology proposed in this first part is based on the assumption that designer has the availability of an accurate electrical model of the device; the variety of publications about this argument demonstrates that it is so difficult to carry out a CAD model capable to taking into account all the non-ideal phenomena which occur when the amplifier operates at such high frequency and power levels. For that, especially for the emerging technology of Gallium Nitride (GaN), in the second section a new approach for power amplifier design will be described, basing on the experimental characterization of the intrinsic Load Line by means of a low frequency high power measurements bench. Thanks to the possibility to develop my Ph.D. in an academic spin-off, MEC – Microwave Electronics for Communications, the results of this activity has been applied to important research programs requested by space agencies, with the aim support the technological transfer from universities to industrial world and to promote a science-based entrepreneurship. For these reasons the proposed design methodology will be explained basing on many experimental results.

Substructuring approache in state space models for dynamic system parameters identification

In the recent decade, the request for structural health monitoring expertise increased exponentially in the United States. The aging issues that most of the transportation structures are experiencing can put in serious jeopardy the economic system of a region as well as of a country. At the same time, the monitoring of structures is a central topic of discussion in Europe, where the preservation of historical buildings has been addressed over the last four centuries. More recently, various concerns arose about security performance of civil structures after tragic events such the 9/11 or the 2011 Japan earthquake: engineers looks for a design able to resist exceptional loadings due to earthquakes, hurricanes and terrorist attacks. After events of such a kind, the assessment of the remaining life of the structure is at least as important as the initial performance design. Consequently, it appears very clear that the introduction of reliable and accessible damage assessment techniques is crucial for the localization of issues and for a correct and immediate rehabilitation. The System Identification is a branch of the more general Control Theory. In Civil Engineering, this field addresses the techniques needed to find mechanical characteristics as the stiffness or the mass starting from the signals captured by sensors. The objective of the Dynamic Structural Identification (DSI) is to define, starting from experimental measurements, the modal fundamental parameters of a generic structure in order to characterize, via a mathematical model, the dynamic behavior. The knowledge of these parameters is helpful in the Model Updating procedure, that permits to define corrected theoretical models through experimental validation. The main aim of this technique is to minimize the differences between the theoretical model results and in situ measurements of dynamic data. Therefore, the new model becomes a very effective control practice when it comes to rehabilitation of structures or damage assessment. The instrumentation of a whole structure is an unfeasible procedure sometimes because of the high cost involved or, sometimes, because it’s not possible to physically reach each point of the structure. Therefore, numerous scholars have been trying to address this problem. In general two are the main involved methods. Since the limited number of sensors, in a first case, it’s possible to gather time histories only for some locations, then to move the instruments to another location and replay the procedure. Otherwise, if the number of sensors is enough and the structure does not present a complicate geometry, it’s usually sufficient to detect only the principal first modes. This two problems are well presented in the works of Balsamo [1] for the application to a simple system and Jun [2] for the analysis of system with a limited number of sensors. Once the system identification has been carried, it is possible to access the actual system characteristics. A frequent practice is to create an updated FEM model and assess whether the structure fulfills or not the requested functions. Once again the objective of this work is to present a general methodology to analyze big structure using a limited number of instrumentation and at the same time, obtaining the most information about an identified structure without recalling methodologies of difficult interpretation. A general framework of the state space identification procedure via OKID/ERA algorithm is developed and implemented in Matlab. Then, some simple examples are proposed to highlight the principal characteristics and advantage of this methodology. A new algebraic manipulation for a prolific use of substructuring results is developed and implemented.

Design and development of new green catalytic methodologies for the synthesis of enantiomerically enriched molecules

The following Ph.D work was mainly focused on catalysis, as a key technology, to achieve the objectives of sustainable (green) chemistry. After introducing the concepts of sustainable (green) chemistry and an assessment of new sustainable chemical technologies, the relationship between catalysis and sustainable (green) chemistry was briefly discussed and illustrated via an analysis of some selected and relevant examples. Afterwards, as a continuation of the ongoing interest in Dr. Marco Bandini’s group on organometallic and organocatalytic processes, I addressed my efforts to the design and development of novel catalytic green methodologies for the synthesis of enantiomerically enriched molecules. In the first two projects the attention was focused on the employment of solid supports to carry out reactions that still remain a prerogative of omogeneous catalysis. Firstly, particular emphasis was addressed to the discovery of catalytic enantioselective variants of nitroaldol condensation (commonly termed Henry reaction), using a complex consisting in a polyethylene supported diamino thiopene (DATx) ligands and copper as active species. In the second project, a new class of electrochemically modified surfaces with DATx palladium complexes was presented. The DATx-graphite system proved to be efficient in promoting the Suzuki reaction. Moreover, in collaboration with Prof. Wolf at the University of British Columbia (Vancouver), cyclic voltammetry studies were reported. This study disclosed new opportunities for carbon–carbon forming processes by using heterogeneous, electrodeposited catalyst films. A straightforward metal-free catalysis allowed the exploration around the world of organocatalysis. In fact, three different and novel methodologies, using Cinchona, Guanidine and Phosphine derivatives, were envisioned in the three following projects. An interesting variant of nitroaldol condensation with simple trifluoromethyl ketones and also their application in a non-conventional activation of indolyl cores by Friedel-Crafts-functionalization, led to two novel synthetic protocols. These approaches allowed the preparation of synthetically useful trifluoromethyl derivatives bearing quaternary stereocenters. Lastly, in the sixth project the first γ-alkylation of allenoates with conjugated carbonyl compounds was envisioned. In the last part of this Ph.D thesis bases on an extra-ordinary collaboration with Prof. Balzani and Prof. Gigli, I was involved in the synthesis and characterization of a new type of heteroleptic cyclometaled-Ir(III) complexes, bearing bis-oxazolines (BOXs) as ancillary ligands. The new heteroleptic complexes were fully characterized and in order to examine the electroluminescent properties of FIrBOX(CH2), an Organic Light Emitting Device was realized.

Troposphere Calibration Techniques for Deep Space Probe Tracking

Ground-based Earth troposphere calibration systems play an important role in planetary exploration, especially to carry out radio science experiments aimed at the estimation of planetary gravity fields. In these experiments, the main observable is the spacecraft (S/C) range rate, measured from the Doppler shift of an electromagnetic wave transmitted from ground, received by the spacecraft and coherently retransmitted back to ground. If the solar corona and interplanetary plasma noise is already removed from Doppler data, the Earth troposphere remains one of the main error sources in tracking observables. Current Earth media calibration systems at NASA’s Deep Space Network (DSN) stations are based upon a combination of weather data and multidirectional, dual frequency GPS measurements acquired at each station complex. In order to support Cassini’s cruise radio science experiments, a new generation of media calibration systems were developed, driven by the need to achieve the goal of an end-to-end Allan deviation of the radio link in the order of 3×〖10〗^(-15) at 1000 s integration time. The future ESA’s Bepi Colombo mission to Mercury carries scientific instrumentation for radio science experiments (a Ka-band transponder and a three-axis accelerometer) which, in combination with the S/C telecommunication system (a X/X/Ka transponder) will provide the most advanced tracking system ever flown on an interplanetary probe. Current error budget for MORE (Mercury Orbiter Radioscience Experiment) allows the residual uncalibrated troposphere to contribute with a value of 8×〖10〗^(-15) to the two-way Allan deviation at 1000 s integration time. The current standard ESA/ESTRACK calibration system is based on a combination of surface meteorological measurements and mathematical algorithms, capable to reconstruct the Earth troposphere path delay, leaving an uncalibrated component of about 1-2% of the total delay. In order to satisfy the stringent MORE requirements, the short time-scale variations of the Earth troposphere water vapor content must be calibrated at ESA deep space antennas (DSA) with more precise and stable instruments (microwave radiometers). In parallel to this high performance instruments, ESA ground stations should be upgraded to media calibration systems at least capable to calibrate both troposphere path delay components (dry and wet) at sub-centimetre level, in order to reduce S/C navigation uncertainties. The natural choice is to provide a continuous troposphere calibration by processing GNSS data acquired at each complex by dual frequency receivers already installed for station location purposes. The work presented here outlines the troposphere calibration technique to support both Deep Space probe navigation and radio science experiments. After an introduction to deep space tracking techniques, observables and error sources, in Chapter 2 the troposphere path delay is widely investigated, reporting the estimation techniques and the state of the art of the ESA and NASA troposphere calibrations. Chapter 3 deals with an analysis of the status and the performances of the NASA Advanced Media Calibration (AMC) system referred to the Cassini data analysis. Chapter 4 describes the current release of a developed GNSS software (S/W) to estimate the troposphere calibration to be used for ESA S/C navigation purposes. During the development phase of the S/W a test campaign has been undertaken in order to evaluate the S/W performances. A description of the campaign and the main results are reported in Chapter 5. Chapter 6 presents a preliminary analysis of microwave radiometers to be used to support radio science experiments. The analysis has been carried out considering radiometric measurements of the ESA/ESTEC instruments installed in Cabauw (NL) and compared with the requirements of MORE. Finally, Chapter 7 summarizes the results obtained and defines some key technical aspects to be evaluated and taken into account for the development phase of future instrumentation.

An evolutionary approach to the design of experiments for combinatorial optimization with an application to enzyme engineering

In a large number of problems the high dimensionality of the search space, the vast number of variables and the economical constrains limit the ability of classical techniques to reach the optimum of a function, known or unknown. In this thesis we investigate the possibility to combine approaches from advanced statistics and optimization algorithms in such a way to better explore the combinatorial search space and to increase the performance of the approaches. To this purpose we propose two methods: (i) Model Based Ant Colony Design and (ii) Naïve Bayes Ant Colony Optimization. We test the performance of the two proposed solutions on a simulation study and we apply the novel techniques on an appplication in the field of Enzyme Engineering and Design.

Definition, realization and evaluation of a software reference architecture for use in space applications

A recent initiative of the European Space Agency (ESA) aims at the definition and adoption of a software reference architecture for use in on-board software of future space missions. Our PhD project placed in the context of that effort. At the outset of our work we gathered all the industrial needs relevant to ESA and all the main European space stakeholders and we were able to consolidate a set of technical high-level requirements for the fulfillment of them. The conclusion we reached from that phase confirmed that the adoption of a software reference architecture was indeed the best solution for the fulfillment of the high-level requirements. The software reference architecture we set on building rests on four constituents: (i) a component model, to design the software as a composition of individually verifiable and reusable software units; (ii) a computational model, to ensure that the architectural description of the software is statically analyzable; (iii) a programming model, to ensure that the implementation of the design entities conforms with the semantics, the assumptions and the constraints of the computational model; (iv) a conforming execution platform, to actively preserve at run time the properties asserted by static analysis. The nature, feasibility and fitness of constituents (ii), (iii) and (iv), were already proved by the author in an international project that preceded the commencement of the PhD work. The core of the PhD project was therefore centered on the design and prototype implementation of constituent (i), a component model. Our proposed component model is centered on: (i) rigorous separation of concerns, achieved with the support for design views and by careful allocation of concerns to the dedicated software entities; (ii) the support for specification and model-based analysis of extra-functional properties; (iii) the inclusion space-specific concerns.

Space charge and dielectric response measurements to assess insulation aging of low-voltage cables used in nuclear power plants

The current design life of nuclear power plant (NPP) could potentially be extended to 80 years. During this extended plant life, all safety and operationally relevant Instrumentation & Control (I&C) systems are required to meet their designed performance requirements to ensure safe and reliable operation of the NPP, both during normal operation and subsequent to design base events. This in turn requires an adequate and documented qualification and aging management program. It is known that electrical insulation of I&C cables used in safety related circuits can degrade during their life, due to the aging effect of environmental stresses, such as temperature, radiation, vibration, etc., particularly if located in the containment area of the NPP. Thus several condition monitoring techniques are required to assess the state of the insulation. Such techniques can be used to establish a residual lifetime, based on the relationship between condition indicators and ageing stresses, hence, to support a preventive and effective maintenance program. The object of this thesis is to investigate potential electrical aging indicators (diagnostic markers) testing various I&C cable insulations subjected to an accelerated multi-stress (thermal and radiation) aging.

The school environment as a teacher. The role of space and place in enhancing ecological literacy and social competence development in children and young people

Can space and place foster child development, and in particular social competence and ecological literacy? If yes, how can space and place do that? This study shows that the answer to the first question is positive and then tries to explain the way space and place can make a difference. The thesis begins with the review of literature from different disciplines – child development and child psychology, education, environmental psychology, architecture and landscape architecture. Some bridges among such disciplines are created and in some cases the ideas from the different areas of research merge: thus, this is an interdisciplinary study. The interdisciplinary knowledge from these disciplines is translated into a range of design suggestions that can foster the development of social competence and ecological literacy. Using scientific knowledge from different disciplines is a way of introducing forms of evidence into the development of design criteria. However, the definition of design criteria also has to pass through the study of a series of school buildings and un-built projects: case studies can give a positive contribution to the criteria because examples and good practices can help “translating” the theoretical knowledge into design ideas and illustrations. To do that, the different case studies have to be assessed in relation to the various themes that emerged in the literature review. Finally, research by design can be used to help define the illustrated design criteria: based on all the background knowledge that has been built, the role of the architect is to provide a series of different design solutions that can give answers to the different “questions” emerged in the literature review.

Innovative architecture of on-board and on-ground radio systems for space communication

The radio communication system is one of the most critical system of the overall satellite platform: it often represents the only way of communication, between a spacecraft and the Ground Segment or among a constellation of satellites. This thesis focuses on specific innovative architectures for on-board and on-ground radio systems. In particular, this work is an integral part of a space program started in 2004 at the University of Bologna, Forlì campus, which led to the completion of the microsatellite ALMASat-1, successfully launched on-board the VEGA maiden flight. The success of this program led to the development of a second microsatellite, named ALMASat-EO, a three-axis stabilized microsatellite able to capture images of the Earth surface. Therefore, the first objective of this study was focused on the investigation of an innovative, efficient and low cost architecture for on-board radio communication systems. The TT&C system and the high data rate transmitter for images downlink design and realization are thoroughly described in this work, together with the development of the embedded hardware and the adopted antenna systems. Moreover, considering the increasing interest in the development of constellations of microsatellite, in particular those flying in close formations, a careful analysis has been carried out for the development of innovative communication protocols for inter-satellite links. Furthermore, in order to investigate the system aspects of space communications, a study has been carried out at ESOC having as objective the design, implementation and test of two experimental devices for the enhancement of the ESA GS. Thus, a significant portion of this thesis is dedicated to the description of the results of a method for improving the phase stability of GS radio frequency equipments by means of real-time phase compensation and a new way to perform two antennas arraying tracking using already existing ESA tracking stations facilities.

Hardware/Software Design of Dynamic Real-Time Schedulers for Embedded Multiprocessor Systems

The new generation of multicore processors opens new perspectives for the design of embedded systems. Multiprocessing, however, poses new challenges to the scheduling of real-time applications, in which the ever-increasing computational demands are constantly flanked by the need of meeting critical time constraints. Many research works have contributed to this field introducing new advanced scheduling algorithms. However, despite many of these works have solidly demonstrated their effectiveness, the actual support for multiprocessor real-time scheduling offered by current operating systems is still very limited. This dissertation deals with implementative aspects of real-time schedulers in modern embedded multiprocessor systems. The first contribution is represented by an open-source scheduling framework, which is capable of realizing complex multiprocessor scheduling policies, such as G-EDF, on conventional operating systems exploiting only their native scheduler from user-space. A set of experimental evaluations compare the proposed solution to other research projects that pursue the same goals by means of kernel modifications, highlighting comparable scheduling performances. The principles that underpin the operation of the framework, originally designed for symmetric multiprocessors, have been further extended first to asymmetric ones, which are subjected to major restrictions such as the lack of support for task migrations, and later to re-programmable hardware architectures (FPGAs). In the latter case, this work introduces a scheduling accelerator, which offloads most of the scheduling operations to the hardware and exhibits extremely low scheduling jitter. The realization of a portable scheduling framework presented many interesting software challenges. One of these has been represented by timekeeping. In this regard, a further contribution is represented by a novel data structure, called addressable binary heap (ABH). Such ABH, which is conceptually a pointer-based implementation of a binary heap, shows very interesting average and worst-case performances when addressing the problem of tick-less timekeeping of high-resolution timers.