Molecular dynamics simulations of HIV-1 protease complexed with saquinavir

Inhibition of the Human Immunode�ficiency virus type-1 (HIV-1) protease enzyme blocks HIV-1 replication. Protease inhibitor drugs have successfully been used as a therapy for HIV-infected individuals to reduce their viral loads and slow the progression to Acquired Immune Defi�ciency Syndrome (AIDS). However, mutations readily and rapidly accrue in the protease gene resulting in a reduced sensitivity of the protein to the inhibitor. In this thesis, molecular dynamics simulations (MDS) were run on HIV proteases complexed with the protease inhibitor saquinavir, and the strength of affinity calculated through MMPBSA and normal mode analysis. We show in this thesis that at least 13 residues can be computationally mutated in the proteases sequence without adversely aff�ecting its structure or dynamics, and can still replicate the change in binding affinity to saquinavir caused by said mutations. Using 6 protease genotypes with an ordered decrease in saquinavir sensitivity we use MDS to calculate drug binding affinity. Our results show that single 10ns simulations of the systems resulted in good concurrence for the wild-type (WT) system, but an overall strong anti-correlation to biochemically derived results. Extension of the WT and multi-drug resistant (MDR) systems to 50ns yielded no improvement in the correlation to experimental. However, expansion of these systems to a 10-repetition ensemble MDS considerably improved the MDR binding affinity compared to the biochemical result. Principle components analysis on the simulations revealed that a much greater confi�gurational sampling was achieved through ensemble MD than simulation extension. These data suggest a possible mechanism for saquinavir resistance in the MDR system, where a transitioning to a lower binding-affinity configuration than WT occurs. Furthermore, we show that ensembles of 1ns in length sample a significant proportion of the con�figurations adopted over 10ns, and generate sufficiently similar binding affinities

Common Peroneal Nerve Injury During Varicose Vein Operation

AbstractCommon peroneal nerve (CPN) injury produces considerable and serious disability. The nerve is most frequently damaged as a result of trauma (sharp or blunt, traction, fracture, laceration, and avulsion). Less often iatrogenic injury is the cause of damage (application of tight plaster, retraction injury, division during operation).Even rarer is the complete or partial division of CPN during varicose vein operations. In the UK, on average 34 patients every year begin legal action against their medical attendants in connection with the treatment of varicose veins, on a background of an estimated 100,000 procedures performed. Nerve damage is the most frequent of all major complications that result in legal action; it is cited in 15% of cases. The commonest nerve injury, accounting for about half the cases, is to the common peroneal nerve just before or, as it crosses the neck of the fibula. We present three examples in two cases, which outline the risk of CPN injury, the spectrum of clinical presentation and the problems produced by a failure to recognise the deficit immediately. Regional anatomy, consequences of nerve damage and management options is discussed

Parenting stress, maternal depression and child mental health in a Melbourne cohort before and during the COVID‐19 pandemic

Aim This paper aims to examine the maternal and child mental health and parenting outcomes in the context of COVID-19 pandemic conditions using a sample from Melbourne, Australia – a city exposed to one of the longest lockdowns world-wide in response to the pandemic. Methods This study utilises observational data from a prospective, pregnancy cohort, Mercy Pregnancy Emotional Wellbeing Study and includes 468 women and their children followed up in Melbourne to 3–4 years postpartum pre-COVID pandemic and compared to those followed up during the COVID-19 pandemic. Results When compared to mothers followed up at 3–4 years postpartum pre-pandemic, those followed up during the COVID-19 pandemic showed higher depressive symptoms with a steep incline in their symptom trajectory (EMMdifference = 1.72, Bonferroni-corrected P < 0.01, d = 0.35) and had a three times higher risk of scoring 13 or above on the EPDS (aRR = 3.22, Bonferroni-corrected P < 0.01). Although this increase was not associated with the variation in the duration of exposure to pandemic conditions, the steep increase in depressive symptoms was more pronounced in those with pre-existing depressive disorders. There was no difference in parenting stress or adjusted childhood mental health symptoms or disorder. Conclusions Our findings highlight the vulnerability of those with pre-existing clinical mental health disorders and the need for adequate clinical care for this vulnerable group. Equally, our study indicates the possibility that parenting and early childhood mental health outcomes, at least in the short term, may be resilient

The Financial Benefits of Various Catastrophic Failure Prevention Strategies in a Wind Farm: Two market studies (UK-Spain)

Operation of wind farms is driven by the overall aim of minimising costs while maximising energy sales. However, in certain circumstances investments are required to guarantee safe operation and survival of an asset. In this paper, we discuss the merits of various catastrophic failure prevention strategies in a Spanish wind farm. The wind farm operator was required to replace blades in two phases: temporary and final repair. We analyse the power performance of the turbine in the different states and investigate four scenarios with different timing of temporary and final repair during one year. The financial consequences of the scenarios are compared with a baseline by using a discounted cash flow analysis that considers the wholesale electricity market selling prices and interest rates. A comparison with the UK electricity market is conducted to highlight differences in the rate of return in the two countries

Rurality as a predictor of perinatal mental health and well‐being in an Australian cohort

Objective Perinatal emotional well-being is more than the presence or absence of depressive and anxiety disorders; it encompasses a wide range of factors that contribute to emotional well-being. This study compares perinatal well-being between women living in metropolitan and rural regions. Design Prospective, longitudinal cohort. Participants/setting Eight hundred and six women from Victoria and Western Australia recruited before 20 weeks of pregnancy and followed up to 12 months postpartum. Main outcome measures Rurality was assessed using the Modified Monash Model (MM Model) with 578 in metropolitan cities MM1, 185 in regional and large rural towns MM2-MM3 and 43 in rural to remote MM4-MM7. The Structured Clinical Interview for DSM-IV (SCID-IV) was administered at recruitment to assess depression, and symptoms of depression and anxiety were measured using the Edinburgh Post-natal Depression Scale and the State and Trait Anxiety Scale, respectively. Other measures included stressful events, diet, exercise, partner support, parenting and sleep. Results The prevalence of depressive disorders did not differ across rurality. There was also no difference in breastfeeding cessation, exercise, sleep or partner support. Women living in rural communities and who also had depression reported significantly higher parenting stress than metropolitan women and lower access to parenting activities. Conclusions Our study suggests while many of the challenges of the perinatal period were shared between women in all areas, there were important differences in parenting stress and access to activities. Furthermore, these findings suggest that guidelines and interventions designed for perinatal mental health should consider rurality

On the Behavior of the Effective QCD Coupling alpha_tau(s) at Low Scales

The hadronic decays of the tau lepton can be used to determine the effective charge alpha_tau(m^2_tau') for a hypothetical tau-lepton with mass in the range 0 < m_tau' < m_tau. This definition provides a fundamental definition of the QCD coupling at low mass scales. We study the behavior of alpha_tau at low mass scales directly from first principles and without any renormalization-scheme dependence by looking at the experimental data from the OPAL Collaboration. The results are consistent with the freezing of the physical coupling at mass scales s = m^2_tau' of order 1 GeV^2 with a magnitude alpha_tau ~ 0.9 +/- 0.1.Comment: 15 pages, 4 figures, submitted to Physical Review D, added references, some text added, no results nor figures change

Fixing the conformal window in QCD

A physical characterization of Landau singularities is emphasized, which should trace the lower boundary N_f^* of the conformal window in QCD and supersymmetric QCD. A natural way to disentangle ``perturbative'' from ``non-perturbative'' contributions to amplitudes below N_f^* is suggested. Assuming an infrared fixed point persists in the perturbative part of the QCD coupling even below N_f^* leads to the condition \gamma(N_f^*)=1, where \gamma is the critical exponent. Using the Banks-Zaks expansion, one gets 4<N_f^*<6. This result is incompatible with the existence of an analogue of Seiberg duality in QCD. The presence of a negative ultraviolet fixed point is required both in QCD and in supersymmetric QCD to preserve causality within the conformal window. Evidence for the existence of such a fixed point in QCD is provided.Comment: 10 pages, 1 figure, extended version of a talk given at the QCDNET2000 meeting, Paris, September 11-14 2000; main new material added is evidence for negative ultraviolet fixed point in QC

Pinch Technique and the Batalin-Vilkovisky formalism

In this paper we take the first step towards a non-diagrammatic formulation of the Pinch Technique. In particular we proceed into a systematic identification of the parts of the one-loop and two-loop Feynman diagrams that are exchanged during the pinching process in terms of unphysical ghost Green's functions; the latter appear in the standard Slavnov-Taylor identity satisfied by the tree-level and one-loop three-gluon vertex. This identification allows for the consistent generalization of the intrinsic pinch technique to two loops, through the collective treatment of entire sets of diagrams, instead of the laborious algebraic manipulation of individual graphs, and sets up the stage for the generalization of the method to all orders. We show that the task of comparing the effective Green's functions obtained by the Pinch Technique with those computed in the background field method Feynman gauge is significantly facilitated when employing the powerful quantization framework of Batalin and Vilkovisky. This formalism allows for the derivation of a set of useful non-linear identities, which express the Background Field Method Green's functions in terms of the conventional (quantum) ones and auxiliary Green's functions involving the background source and the gluonic anti-field; these latter Green's functions are subsequently related by means of a Schwinger-Dyson type of equation to the ghost Green's functions appearing in the aforementioned Slavnov-Taylor identity.Comment: 45 pages, uses axodraw; typos corrected, one figure changed, final version to appear in Phys.Rev.

Differential effects of lower limb revascularisation on organ injury and the role of the amino acid taurine

Lower torso revascularisation following ischaemia results in a systemic inflammatory response. Endothelial barrier function is disrupted by neutrophil-derived proteases and oxidants. Taurine, an amino acid found in large quantities in neutrophils, is a powerful endogeneous anti-oxidant. The aims of this study were to investigate the systemic effects of reperfusion following lower limb revascularisation and to evaluate the role of taurine administration in preventing this injury. A rat model of aortic occlusion (30 min) followed by 2 h of reperfusion was used. Animals were randomised to one of three groups (n = 10 per group): control; ischaemia reperfusion untreated (IR) and taurine-treated. Taurine (4% solution) was administrated orally for 48 h prior to the experiment. Neutrophil infiltration and microvascular permeability were assessed by measuring tissue myeloperoxidase activity and wet/dry weights respectively in lung, liver, kidney, and in cardiac and skeletal muscle. Statistical analysis was by means of analysis of variance (ANOVA). Reperfusion resulted in pulmonary and renal microvascular injury as assessed by organ oedema. Hepatic tissue, skeletal and cardiac muscle were unaffected by lower limb revascularisation. Taurine was effective in preventing neutrophil-mediated pulmonary but not renal microvascular injury. These data suggest that, whilst reperfusion-induced pulmonary injury is predominantly neutrophilmediated, agents other than neutrophil-derived oxidative metabolites, capable of independently causing organ injury through direct endothelial damage, are produced during reperfusion

A unified approach to Performance Assessment (PA) of geological CO2 storage

AbstractPerformance Assessment (PA) evaluates the effectiveness of a specified system or sub-system relative to some criteria of interest to particular stakeholders. A flexible PA approach has been developed for geological CO2 storage, by which qualitative information, quantitative data, output from numerical models and expert judgments are combined within a decision-support framework. The methodology has been implemented in three software tools: (1) TESLA, which is used to construct decision trees, propagate evidence and record the logic underlying a decision; (2) an on-line database of Features, Events and Processes (FEPs) targeted at CO2 storage; and (3) QPAC-CO2, for modelling system performance