The Role of Second Generation Antiretroviral Drugs in HIV-1 Subtype B and non-B Variants Harboring Natural Polymorphisms and Drug Resistance Mutations.

Cette thèse traite de la résistance du VIH-1 aux antirétroviraux, en particulier de l'activité antivirale de plusieurs inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) ainsi que des inhibiteurs de protéase (IP). Nous avons exploré l’émergence et la spécificité des voies de mutations qui confèrent la résistance contre plusieurs nouveaux INNTI (étravirine (ETR) et rilpivirine (RPV)) (chapitres 2 et 3). En outre, le profil de résistance et le potentiel antirétroviral d'un nouvel IP, PL-100, est présenté dans les chapitres 4 et 5. Pour le premier projet, nous avons utilisé des sous-types B et non-B du VIH-1 pour sélectionner des virus résistants à ETR, et ainsi montré que ETR favorise l’émergence des mutations V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y et M230L, et ce, en 18 semaines. Fait intéressant, E138K a été la première mutation à émerger dans la plupart des cas. Les clones viraux contenant E138K ont montré un faible niveau de résistance phénotypique à ETR (3,8 fois) et une diminution modeste de la capacité de réplication (2 fois) par rapport au virus de type sauvage. Nous avons également examiné les profils de résistance à ETR et RPV dans les virus contenant des mutations de résistance aux INNTI au début de la sélection. Dans le cas du virus de type sauvage et du virus contenant la mutation unique K103N, les premières mutations à apparaître en présence d’ETR ou de RPV ont été E138K ou E138G suivies d’autres mutations de résistance aux INNTI. À l’inverse, dans les mêmes conditions, le virus avec la mutation Y181C a évolué pour produire les mutations V179I/F ou A62V/A, mais pas E138K/G. L'ajout de mutations à la position 138 en présence de Y181C n'augmente pas les niveaux de résistance à ETR ou RPV. Nous avons également observé que la combinaison de Y181C et E138K peut conduire à un virus moins adapté par rapport au virus contenant uniquement Y181C. Sur la base de ces résultats, nous suggérons que les mutations Y181C et E138K peuvent être antagonistes. L’analyse de la résistance au PL-100 des virus de sous-type C et CRF01_AE dans les cellules en culture est décrite dans le chapitre 4. Le PL-100 sélectionne pour des mutations de résistance utilisant deux voies distinctes, l'une avec les mutations V82A et L90M et l'autre avec T80I, suivi de l’addition des mutations M46I/L, I54M, K55R, L76F, P81S et I85V. Une accumulation d'au moins trois mutations dans le rabat protéique et dans le site actif est requise dans chaque cas pour qu’un haut niveau de résistance soit atteint, ce qui démontre que le PL-100 dispose d'une barrière génétique élevée contre le développement de la résistance. Dans le chapitre 5, nous avons évalué le potentiel du PL-100 en tant qu’inhibiteur de protéase de deuxième génération. Les virus résistants au PL-100 émergent en 8-48 semaines alors qu’aucune mutation n’apparaît avec le darunavir (DRV) sur une période de 40 semaines. La modélisation moléculaire montre que la haute barrière génétique du DRV est due à de multiples interactions avec la protéase dont des liaison hydrogènes entre les groupes di-tétrahydrofuranne (THF) et les atomes d'oxygène des acides aminés A28, D29 et D30, tandis que la liaison de PL-100 est principalement basée sur des interactions polaires et hydrophobes délocalisées à travers ses groupes diphényle. Nos données suggèrent que les contacts de liaison hydrogène et le groupe di-THF dans le DRV, ainsi que le caractère hydrophobe du PL-100, contribuent à la liaison à la protéase ainsi qu’à la haute barrière génétique contre la résistance et que la refonte de la structure de PL-100 pour inclure un groupe di-THF pourrait améliorer l’activité antivirale et le profil de résistance.

Queues with retrial/self-generation of priorities /postponement of work and some related reliability problems

Application of Queueing theory in areas like Computer networking, ATM facilities, Telecommunications and to many other numerous situation made people study Queueing models extensively and it has become an ever expanding branch of applied probability. The thesis discusses Reliability of a ‘k-out-of-n system’ where the server also attends external customers when there are no failed components (main customers), under a retrial policy, which can be explained in detail. It explains the reliability of a ‘K-out-of-n-system’ where the server also attends external customers and studies a multi-server infinite capacity Queueing system where each customer arrives as ordinary but can generate into priority customer which waiting in the queue. The study gives details on a finite capacity multi-server queueing system with self-generation of priority customers and also on a single server infinite capacity retrial Queue where the customer in the orbit can generate into a priority customer and leaves the system if the server is already busy with a priority generated customer; else he is taken for service immediately. Arrival process is according to a MAP and service times follow MSP.

Paper industry in Kerala: An evaluation of labour absorption,capacity utilisation, and environmental pollution

Paper industry is one of the oldest and largest industries in Kerala. Despite the developments in the industry in terms of growth in output , value added and employment generation, many of the units face grave problems. Irrespective of the size of the plant, the problems of the industry are general in nature. The problems are galore in the supply, not the demand side. Amomg the problems, the important ones are: raw material scarcity, energy deficiency and obsolete technology. Further, the industry is subject to many controls by the Government — price control, product control and raw materials control — which result in the dwindling of profits and investments. Equally important are the reservations against the industry for polluting the environment byeffluent disposal on the one hand and affecting ecological balance by depleting the existing forest on the other. Apart from the large, medium and small pulp and paper mills, there are about 30 hand made paper units in Kerala which can be categorised as village and cottage industry. Almost all of these units began at the initiative and support of Khadi and Village Industries Commission. The primary purpose of these units is employment generation, and not profit making. Currently many of these units are in the red and many others are on the verge of closure. Therefore, a separate analysis of the growth performance, and problems and prospects of the hand made paper industry has also been attempted. It is analysed separately because of the very small size of the hand made paper units

Seismic behavior of capacity designed masonry walls in low seismicity regions

Eurocode 8 representing a new generation of structural design codes in Europe defines ‎requirements for the design of buildings against earthquake action. In Central and ‎Western Europe, the newly defined earthquake zones and corresponding design ground ‎acceleration values, will lead in many cases to earthquake actions which are remarkably ‎higher than those defined so far by the design codes used until now in Central Europe. ‎ In many cases, the weak points of masonry structures during an earthquake are the corner ‎regions of the walls. Loading of masonry walls by earthquake action leads in most cases ‎to high shear forces. The corresponding bending moment in such a wall typically causes a ‎significant increase of the eccentricity of the normal force in the critical wall cross ‎section. This in turn leads ultimately to a reduction of the size of the compression zone in ‎unreinforced walls and a high concentration of normal stresses and shear stresses in the ‎corner regions. ‎ Corner-Gap-Elements, consisting of a bearing beam located underneath the wall and ‎made of a sufficiently strong material (such as reinforced concrete), reduce the effect of ‎the eccentricity of the normal force and thus restricts the pinching effect of the ‎compression zone. In fact, the deformation can be concentrated in the joint below the ‎bearing beam. According to the principles of the Capacity Design philosophy, the ‎masonry itself is protected from high stresses as a potential cause of brittle failure. ‎ Shaking table tests at the NTU Athens Earthquake Engineering Laboratory have proven ‎the effectiveness of the Corner-Gap-Element. The following presentation will cover the ‎evaluation of various experimental results as well as a numerical modeling of the ‎observed phenomena.‎

Energy generation and consumption in Ghana

Electricity consumption in Ghana is estimated to be increasing by 10% per annum due to the demand from the growing population. However, current sources of production (hydro and thermal facilities) generate only 66% of the current demand. Considering current trends, it is difficult to substantiate these basic facts, because of the lack of information. As a result, research into the existing sources of generating electricity, electricity consumption and prospective projects has been performed. This was achieved using three key techniques; review of literature, empirical studies and modelling. The results presented suggest that, current annual installed capacity of energy generation (i.e. 1960 MW) must be increased to 9,405.59 MW, assuming 85% plant availability. This is then capable to coop with the growing demand and it would give access to the entire population as well as support commercial and industrial activities for the growth of the economy. The prospect of performing this research is with the expectation to present an academic research agenda for further exploration into the subject area, without which the growth of the country would be stagnant.

Energy overview of Botswana: generation and consumption

Botswana has a basic need to explore its energy concept, this being its energy sources, generation and percentage of the population with access to electricity. At present, Botswana generates electricity from coal, which supplies about 29% (on average) of the country’s demand. The other 71% is imported mainly from South Africa (Eskom). Consequently, the dependence of Botswana on imports posses threats to the security of its energy supply. As a result, there is the need to understand the bases for a possible generation expansion that would substantiate existing documentation. In view of this need, this study investigates the existing energy sources as well as energy consumption and production levels in Botswana. The study would be further developed by making projections of the energy demand up until the year 2020. The key techniques that were used include; literature review, questionnaire survey and an empirical study. The results presented indicated that, current dependable operation capacity (i.e. 100MW) should be increased to 2,595 MW or more assuming 85% plant efficiency. This would then be able to meet the growing demand for energy use. In addition, the installed capacity would be able to support commercial and mining activities for the growth of the economy.

Toward a new generation of world climate research and computing facilities

The impending threat of global climate change and its regional manifestations is among the most important and urgent problems facing humanity. Society needs accurate and reliable estimates of changes in the probability of regional weather variations to develop science-based adaptation and mitigation strategies. Recent advances in weather prediction and in our understanding and ability to model the climate system suggest that it is both necessary and possible to revolutionize climate prediction to meet these societal needs. However, the scientific workforce and the computational capability required to bring about such a revolution is not available in any single nation. Motivated by the success of internationally funded infrastructure in other areas of science, this paper argues that, because of the complexity of the climate system, and because the regional manifestations of climate change are mainly through changes in the statistics of regional weather variations, the scientific and computational requirements to predict its behavior reliably are so enormous that the nations of the world should create a small number of multinational high-performance computing facilities dedicated to the grand challenges of developing the capabilities to predict climate variability and change on both global and regional scales over the coming decades. Such facilities will play a key role in the development of next-generation climate models, build global capacity in climate research, nurture a highly trained workforce, and engage the global user community, policy-makers, and stakeholders. We recommend the creation of a small number of multinational facilities with computer capability at each facility of about 20 peta-flops in the near term, about 200 petaflops within five years, and 1 exaflop by the end of the next decade. Each facility should have sufficient scientific workforce to develop and maintain the software and data analysis infrastructure. Such facilities will enable questions of what resolution, both horizontal and vertical, in atmospheric and ocean models, is necessary for more confident predictions at the regional and local level. Current limitations in computing power have placed severe limitations on such an investigation, which is now badly needed. These facilities will also provide the world's scientists with the computational laboratories for fundamental research on weather–climate interactions using 1-km resolution models and on atmospheric, terrestrial, cryospheric, and oceanic processes at even finer scales. Each facility should have enabling infrastructure including hardware, software, and data analysis support, and scientific capacity to interact with the national centers and other visitors. This will accelerate our understanding of how the climate system works and how to model it. It will ultimately enable the climate community to provide society with climate predictions, which are based on our best knowledge of science and the most advanced technology.

An aggregated wind power generation model based on MERRA reanalysis data: MATLAB model and example data for the April 2014 wind farm distribution of Great Britain.

The MATLAB model is contained within the compressed folders (versions are available as .zip and .tgz). This model uses MERRA reanalysis data (>34 years available) to estimate the hourly aggregated wind power generation for a predefined (fixed) distribution of wind farms. A ready made example is included for the wind farm distribution of Great Britain, April 2014 ("CF.dat"). This consists of an hourly time series of GB-total capacity factor spanning the period 1980-2013 inclusive. Given the global nature of reanalysis data, the model can be applied to any specified distribution of wind farms in any region of the world. Users are, however, strongly advised to bear in mind the limitations of reanalysis data when using this model/data. This is discussed in our paper: Cannon, Brayshaw, Methven, Coker, Lenaghan. "Using reanalysis data to quantify extreme wind power generation statistics: a 33 year case study in Great Britain". Submitted to Renewable Energy in March, 2014. Additional information about the model is contained in the model code itself, in the accompanying ReadMe file, and on our website: http://www.met.reading.ac.uk/~energymet/data/Cannon2014/

The impact of monsoon intraseasonal variability on renewable power generation in India

India is increasingly investing in renewable technology to meet rising energy demands, with hydropower and other renewables comprising one-third of current installed capacity. Installed wind-power is projected to increase 5-fold by 2035 (to nearly 100GW) under the International Energy Agency’s New Policies scenario. However, renewable electricity generation is dependent upon the prevailing meteorology, which is strongly influenced by monsoon variability. Prosperity and widespread electrification are increasing the demand for air conditioning, especially during the warm summer. This study uses multi-decadal observations and meteorological reanalysis data to assess the impact of intraseasonal monsoon variability on the balance of electricity supply from wind-power and temperature-related demand in India. Active monsoon phases are characterised by vigorous convection and heavy rainfall over central India. This results in lower temperatures giving lower cooling energy demand, while strong westerly winds yield high wind-power output. In contrast, monsoon breaks are characterised by suppressed precipitation, with higher temperatures and hence greater demand for cooling, and lower wind-power output across much of India. The opposing relationship between wind-power supply and cooling demand during active phases (low demand, high supply) and breaks (high demand, low supply) suggests that monsoon variability will tend to exacerbate fluctuations in the so-called demand-net-wind (i.e., electrical demand that must be supplied from non-wind sources). This study may have important implications for the design of power systems and for investment decisions in conventional schedulable generation facilities (such as coal and gas) that are used to maintain the supply/demand balance. In particular, if it is assumed (as is common) that the generated wind-power operates as a price-taker (i.e., wind farm operators always wish to sell their power, irrespective of price) then investors in conventional facilities will face additional weather-volatility through the monsoonal impact on the length and frequency of production periods (i.e. their load-duration curves).

Challenges in quantifying wind generation's contribution to securing peak demand

Wind generation's contribution to supporting peak electricity demand is one of the key questions in wind integration studies. Differently from conventional units, the available outputs of different wind farms cannot be approximated as being statistically independent, and hence near-zero wind output is possible across an entire power system. This paper will review the risk model structures currently used to assess wind's capacity value, along with discussion of the resulting data requirements. A central theme is the benefits from performing statistical estimation of the joint distribution for demand and available wind capacity, focusing attention on uncertainties due to limited histories of wind and demand data; examination of Great Britain data from the last 25 years shows that the data requirements are greater than generally thought. A discussion is therefore presented into how analysis of the types of weather system which have historically driven extreme electricity demands can help to deliver robust insights into wind's contribution to supporting demand, even in the face of such data limitations. The role of the form of the probability distribution for available conventional capacity in driving wind capacity credit results is also discussed.

Protoporphyrin IX Nanoparticle Carrier: Preparation, Optical Properties, and Singlet Oxygen Generation

The present study is focused on developing a nanoparticle carrier for the photosensitizer protoporphyrin IX for use in photodynamic therapy. The entrapment of protoporphyrin IX (Pp IX) in silica spheres was achieved by modification of Pp IX molecules with an organosilane reagent. The immobilized drug preserved its optical properties and the capacity to generate singlet oxygen, which was detected by a direct method from its characteristic phosphorescence decay curve at near-infrared and by a chemical method using 1,3-diphenylisobenzofuran to trap singlet oxygen. The lifetime of singlet oxygen when a suspension of Pp IX-loaded particles in acetonitrile was excited at 532 nm was determined as 52 mu s, which is in good agreement with the value determined for methylene blue in acetonitrile solution under the same conditions. The Pp IX-loaded silica particles have an efficiency of singlet oxygen generation (eta Delta) higher than the quantum yield of free porphyrins. This high efficiency of singlet oxygen generation was attributed to changes on the monomer-dimer equilibrium after photosentisizer immobilization.

A column generation approach to capacitated p-median problems

The Capacitated p-median problem (CPMP) seeks to solve the optimal location of p facilities, considering distances and capacities for the service to be given by each median. In this paper we present a column generation approach to CPMP. The identified restricted master problem optimizes the covering of 1-median clusters satisfying the capacity constraints, and new columns are generated considering knapsack subproblems. The Lagrangean/surrogate relaxation has been used recently to accelerate subgradient like methods. In this work the Lagrangean/surrogate relaxation is directly identified from the master problem dual and provides new bounds and new productive columns through a modified knapsack subproblem. The overall column generation process is accelerated, even when multiple pricing is observed. Computational tests are presented using instances taken from real data from Sao Jose dos Campos' city.

Life-cycle inventory for hydroelectric generation: a Brazilian case study

Representative Life-Cycle Inventories (LCIs) are essential for Life-Cycle Assessments (LCAs) quality and readiness. Because energy is such an important element of LCAs, appropriate LCIs on energy are crucial, and due to the prevalence of hydropower on Brazilian electricity mix, the frequently used LCIs are not representative of the Brazilian conditions. The present study developed a LCI of the Itaipu Hydropower Plant, the major hydropower plant in the world, responsible for producing 23.8% of Brazil's electricity consumption. Focused on the capital investments to construct and operate the dam, the LCI was designed to serve as a database for the LCAs of Brazilian hydroelectricity production. The life-cycle boundaries encompass the construction and operation of the dam, as well as the life-cycles of the most important material and energy consumptions (cement, steel, copper, diesel oil, lubricant oil), as well as construction site operation, emissions from reservoir flooding, material and workers transportation, and earthworks. As a result, besides the presented inventory, it was possible to determine the following processes, and respective environmental burdens as the most important life-cycle hotspots: reservoir filling (CO(2) and CH(4) emission: land use); steel life-cycle (water and energy consumption; CO, particulates, SO(x) and NO(x) emissions); cement life-cycle (water and energy consumption; CO(2) and particulate emissions); and operation of civil construction machines (diesel consumption; NO(x) emissions). Compared with another hydropower studies, the LCI showed magnitude adequacy, with better results than small hydropower, which reveals a scale economy for material and energy exchanges in the case of ltaipu Power Plant. (C) 2009 Elsevier Ltd. All rights reserved.

A multi-objective evaluation of the impact of the penetration of Distributed Generation

This paper proposes a methodology to consider the effects of the integration of DG on planning. Since DG has potential to defer investments in networks, the impact of DG on grid capacity is evaluated. A multi-objective optimization tool based on the meta-heuristic MEPSO is used, supporting an alternative approach to exploiting the Pareto front features. Tests were performed in distinct conditions with two well-known distribution networks: IEEE-34 and IEEE-123. The results combined minimization and maximization in order to produce different Pareto fronts and determine the extent of the impact caused by DG. The analysis provides useful information, such as the identification of futures that should be considered in planning. A future means a set of realizations of all uncertainties. MEPSO also presented a satisfactory performance in obtaining the Pareto fronts. © 2011 IEEE.

Power system capacity expansion planning model considering carbon emissions constraints

This paper presents a power system capacity expansion planning modelconsidering carbon emissions constraints. In addition to the traditionaltechnical and economical issues usually considered in the planning process, two environmental policies that consist on the taxation and the annual limitsof carbon dioxide (CO 2) emissions are considered. Furthermore, the gradualretirement of old inefficient generation plants has been included. The approachguarantees a cleaner electricity production in the expanded power system ata relatively low cost. The proposed model considers the transmission systemand is applied to a 4-region and 11-region power systems over a 20-yearplanning horizon. Results show practical investment decisions in terms of sustainability and costs.