Molecular dynamics simulation of drug resistance in HIV-1 protease and reverse transcriptase

The emergence of drug resistant strains of HIV represents a major challenge in the treatment of patients who contract the virus. We investigate the use of classical molecular dynamics to give quantitative and qualitative molecular insight into the causes of resistance in the two main drug targets in HIV, protease and reverse transcriptase. We initially establish a simulation and free energy analysis protocol for the study of resistance in protease. Focusing on the binding of the inhibitor lopinavir to a series of six mutants with increasing resistance we demonstrate that ensemble simulations exhibit significantly enhanced thermodynamic sampling over single long simulations. We achieve accurate and converged relative binding free energies, reproducible to within 0.5 kcal mol^-1. The experimentally derived ranking of the systems is reproduced with a correlation coefficient of 0.89 and a mean relative deviation from experiment of 0.9 kcal mol^-1. Our protocol is then applied to investigate a patient derived viral sequence for which contradictory resistance assessments for lopinavir were obtained from existing clinical decision support systems (CDSS). Mutations at only three locations (L10I, A71I/V and L90M) in uenced the ranking. Free energies were computed for HXB2 wildtype sequences incorporating each mutation individually and all possible combinations, along with the full patient sequence. Only in the case of the patient sequence was any resistance observed. This observation suggests an explanation for the discordance found using the CDSS. The effects on drug binding of the mutations at positions 10, 71 and 90 appear to be highly dependent on the background mutations present in the remainder of the sequence. In preparation for the extension of our simulation and free energy protocol to reverse transcriptase the impact of binding both natural DNA substrates and two non nucleoside reverse transcriptase inhibitor (NNRTI) class drugs on the dynamics of reverse transcriptase are investigated. Free energies of both inhibitors (efavirenz and neviripine) are determined which are seen to be independent of the subdomain motions of the protein observed during simulation. Preliminary calculations of the free energies for a set of NNRTI resistant mutants bound to efavirenz are also presented

Crafters of kingship: smiths, elite power, and gender in early medieval Europe

In the earliest centuries of the Middle Ages, skilled metalsmiths were greatly valued by cult leaders who required impressive objects to maintain social links and the loyalty of their retainers. Despite their clear importance, smiths were peripheral characters operating on the fringes of elite communities. Such treatment may reflect an attempt to limit the influence of metalworkers, whose craft was seen as supernatural and who themselves were probably spiritual figureheads; archaeological evidence associates smiths and their tools in symbolic processes of creation and destruction, not only of objects but also of buildings and monuments. The Church clearly appropriated these indigenous practices, although conversion eventually saw the pre-eminence of the sacred smith and their practice wane. Anthropological study provides numerous comparators for skilled crafters acting as supernatural leaders, and also suggests that as part of their marginal identity, smiths may have been perceived as a distinct gender

Early medieval settlement and social power: the middle Anglo-Saxon ‘home farm’

The last two decades have witnessed a marked rise in middle Anglo-Saxon settlement research, as archaeologists have become increasingly aware of the way in which this transformative period in English history can be recognised through habitation sites. Though a period during which individuals and institutions seemingly wielded unprecedented new power, archaeologists have struggled to identify many of the processes or ‘motors’ by which such authority was articulated in the landscape. This paper concerns itself with understanding one such driver, demonstrating how early medieval kings shifted power from tribute-orientated regimes to ones rooted in agricultural exploitation. The Church was fundamental to this shift in authority, and was used as a means of consolidating new power relations. In order to sustain more permanent clerical communities, the Church developed core agricultural areas surrounding their centres, known as inland, upon which were established early types of ‘home farm’. In addition to their functional purpose middle Anglo-Saxon ‘home farms’ were subject to exceptionally high degrees of spatial ordering. Such definition of settlement space, which now included property plots and houses defined by boundaries of unprecedented permanence, allowed elites to shape and consolidate perceptions of social order in the landscape. Power was now being materialised, not only through agricultural production but also through the lived experience of rural communities, as a social hierarchy which considered the place of kings as divinely appointed became firmly established

Shaping rural settlements: the early medieval inheritance of the English village

Researchers seeking to establish the origins of medieval villages have typically been divided into two camps. Most scholars argue that villages were founded as part of protracted process which began in the tenth century, but others see them as the product of the seventh or eighth centuries, established as part of a Middle Saxon ‘great re-planning’. Advocates of both chronologies have found ostensible support from the results of excavations undertaken within currently occupied rural settlements, although the organisers of England’s most extensive test-pitting scheme have suggested that there is little evidence for roots before the tenth century. This paper demonstrates, however, that test pits are not an inappropriate means of detecting ephemeral Middle Saxon remains and that some scholars have overemphasised the ability of such methods to accurately reconstruct early medieval settlement sequences. Occupation sites dating to before the ninth century are only likely to be located through more extensive excavation, and indeed, a quantitative assessment of such interventions illustrates the striking regularity with which evidence for Middle Saxon habitation is found. The distinctive character of historic villages so instantly recognisable to landscape archaeologists and historians were not established between the seventh and ninth centuries, however. Rather, this paper shows that medieval villages often emerged only after a two-stage process of settlement evolution, as Middle Saxon centres were later shifted short distances and restructured into their more lasting historic forms from the tenth century. The seventh to ninth centuries can therefore be seen as a period during which both the physical scaffolding and the identity of many rural settlements was established, as Middle Saxon communities provided a lasting legacy upon the landscape of England

Kiwi Entrepreneurs A Study

Entrepreneurship and innovation are important cornerstones of competitive advantage. This paper explores the nature of entrepreneurs in New 'Zealand It looks at the factors that have enabled them to become entrepreneurs, what else would have helped them to be successful or caused failure, their trials and how they overcame them, and in retrospect what they would have done differently. One hundred and twenty-eight in-depth, personal interviews were conducted of entrepreneurs. Most of the interviewees had some experience of using government agencies who had offered training, support and financial assistance. This research highlights the lessons that entrepreneurs have learnt about what it takes to be successful at setting up a new business ( entrepreneurship) and developing new ideas (innovation). It also provides insights into the way government agencies can tailor their assistance to more effectively promote entrepreneurship

Rethinking early medieval 'productive sites' : wealth, trade and tradition at Little Carlton, East Lindsey

The rising popularity of hobbyist metal detecting has provided early medieval scholars with various important new datasets, not least the concentrations of metalwork commonly known as ‘productive sites’. Awareness of these foci derives almost exclusively from archaeological evidence, yet they continue to be interpreted through a documentary lens, and are frequently labelled ‘monasteries’. Using the recently discovered site of Little Carlton, Lincolnshire, as a case study, it is argued that comprehension of metal-rich sites is significantly furthered by turning to archaeologically-orientated research agendas and terminologies. As a consequence, seventh to ninth-century Little Carlton can be understood as one element of a high status ‘meshwork’ within early medieval East Lindsey, in which elite power was articulated in the landscape through a number of contemporary centres. On site, archaeology indicates the presence of occupation, burial, and craft working, but shows that highly symbolic indigenous practices were taking place too, including intentional deposition into a naturally-occurring pond. Evidence for activity either side of the seventh to ninth centuries also stresses the importance of long-term trajectories in shaping the character of places previously celebrated for their finds-rich phases alone

A comparison of CFD and full-scale measurements for analysis of natural ventilation

CFD modelling techniques have been used to simulate the coupled external and internal flow in a cubic building with two dominant openings. CFD predictions of the time-averaged cross ventilation flow rates have been validated against full-scale experimental data under various weather conditions in England. RANS model predictions proved reliable when wind directions were near normal to the vent openings. However, when the fluctuating ventilation rate exceeded the mean flow, RANS models were incapable of predicting the total ventilation rate. Improved results are expected by applying more sophisticated turbulence models, such as LES or weighted quasi-steady approximations

Modeling the dynamic response of conduits

A method for the dynamic modeling of a fluid conduit is developed, based on its discretization into a sequence of well-mixed flow nodes. This enables the time delay produced by the fluid flow to be simply modeled in any time domain simulation. An optimal level of discretization, based on the residence time distribution produced by fully developed turbulent flow, is presented. The model is capable of calculating the response to changes in flow rate, fluid inlet temperature, and species concentration. The thermal response is based on a second-order model for each node, taking account of the thermal capacitance of the fluid and of the conduit inner wall. It is demonstrated that the model predicts a time delay, then a rapid initial response due to flow effects, followed by slower dynamics controlled by the thermal inertia of the walls. An intermodel comparison of output for a prototype duct is made with three published models, and an empirical validation is reported

Power, conflict and ritual on the fen-edge: the anarchy-period castle at Burwell, Cambridgeshire, and its pre-conquest landscape

Burwell, Cambridgeshire is best known as possessing a castle constructed by King Stephen during the mid-twelfth century civil war commonly referred to as ‘the Anarchy’. Documentary sources confirm that the king built a series of fortifications around the East Anglian fen-edge during A.D. 1144 in an attempt to restrict the activities of the rebellious baron Geoffrey de Mandeville, Earl of Essex, who was using the Isle of Ely as a base to raid the surrounding countryside. Written texts also reveal how de Mandeville was mortally wounded during a skirmish or siege which subsequently took place at Burwell. A combination of topographic and geophysical survey, supplemented by documentary analysis, suggests that the castle was constructed in a landscape with a complex earlier history. It is suggested that during the Romano-British period a temple complex was developed on the site, with a spring rising on the edge of the fens providing the likely focus for ritual activity. Burwell later developed into an important early medieval place and the castle itself may have been inserted into a thegnly enclosure — an act which probably sought to appropriate a recognised pre-existing centre of power. The current research provides the most comprehensive assessment of the site to date, and supports existing interpretations which consider the twelfth-century castle to be incomplete. Analysis also gives additional insight into the functional and symbolic significance of the castle at Burwell, and sheds important light on the character of power and conflict in the fenland during the mid-twelfth century

Dominance Based Crossover Operator for Evolutionary Multi-objective Algorithms

In spite of the recent quick growth of the Evolutionary Multi-objective Optimization (EMO) research field, there has been few trials to adapt the general variation operators to the particular context of the quest for the Pareto-optimal set. The only exceptions are some mating restrictions that take in account the distance between the potential mates - but contradictory conclusions have been reported. This paper introduces a particular mating restriction for Evolutionary Multi-objective Algorithms, based on the Pareto dominance relation: the partner of a non-dominated individual will be preferably chosen among the individuals of the population that it dominates. Coupled with the BLX crossover operator, two different ways of generating offspring are proposed. This recombination scheme is validated within the well-known NSGA-II framework on three bi-objective benchmark problems and one real-world bi-objective constrained optimization problem. An acceleration of the progress of the population toward the Pareto set is observed on all problems