Nicholas Charles Handy. 17 June 1941 - 2 October 2012

Nicholas Handy made significant contributions in the applications of quantum mechanics to molecules. In an academic career at Cambridge University he was involved with many advances in the computational methods that have turned quantum chemistry into a central tool for understanding modern molecular science

Evolution of foot-and-mouth disease virus intra-sample sequence diversity during serial transmission in bovine hosts

RNA virus populations within samples are highly heterogeneous, containing a large number of minority sequence variants which can potentially be transmitted to other susceptible hosts. Consequently, consensus genome sequences provide an incomplete picture of the within- and between-host viral evolutionary dynamics during transmission. Foot-and-mouth disease virus (FMDV) is an RNA virus that can spread from primary sites of replication, via the systemic circulation, to found distinct sites of local infection at epithelial surfaces. Viral evolution in these different tissues occurs independently, each of them potentially providing a source of virus to seed subsequent transmission events. This study employed the Illumina Genome Analyzer platform to sequence 18 FMDV samples collected from a chain of sequentially infected cattle. These data generated snap-shots of the evolving viral population structures within different animals and tissues. Analyses of the mutation spectra revealed polymorphisms at frequencies >0.5% at between 21 and 146 sites across the genome for these samples, while 13 sites acquired mutations in excess of consensus frequency (50%). Analysis of polymorphism frequency revealed that a number of minority variants were transmitted during host-to-host infection events, while the size of the intra-host founder populations appeared to be smaller. These data indicate that viral population complexity is influenced by small intra-host bottlenecks and relatively large inter-host bottlenecks. The dynamics of minority variants are consistent with the actions of genetic drift rather than strong selection. These results provide novel insights into the evolution of FMDV that can be applied to reconstruct both intra- and inter-host transmission routes

Approximate solutions in space mission design

In this paper, we address multi-objective space mission design problems. From a practical point of view, it is often the case that,during the preliminary phase of the design of a space mission, the solutions that are actually considered are not 'optimal' (in the Pareto sense)but belong to the basin of attraction of optimal ones (i.e. they are nearly optimal). This choice is motivated either by additional requirements that the decision maker has to take into account or, more often, by robustness considerations. For this, we suggest a novel MOEA which is a modification of the well-known NSGA-II algorithm equipped with a recently proposed archiving strategy which aims at storing the set of approximate solutions of a given MOP. Using this algorithm we will examine some space trajectory design problems and demonstrate the benefit of the novel approach

Radiocarbon evidence for the stability of polar ocean overturning during the Holocene

Funding: T.C. acknowledges support from the Strategic Priority Research Program of Chinese Academy of Sciences (XDB40010200), Fundamental Research Funds for the Central Universities (020614380116) and National Natural Science Foundation of China (41991325, 41822603 and 42021001). L.F.R. acknowledges support from the Natural Environment Research Council (NE/S001743/1, NE/R005117/1, NE/N003861/1 and NE/X00127X/1).Proxy-based studies have linked the pre-industrial atmospheric pCO2 rise of ∼20 ppmv in the mid- to late Holocene to an inferred increase in the Southern Ocean overturning and associated biogeochemical changes. However, the history of polar ocean overturning and ventilation through the Holocene remains poorly constrained, leaving important gaps in the assessment of the feedbacks between changes in ocean circulation and the carbon cycle in a warm climate state. The deep-ocean radiocarbon content, which provides a measure of ventilation, responds to circulation changes on centennial to millennial time scales. Here we present absolutely dated deep-sea coral radiocarbon records from the Drake Passage, between South America and Antarctica, and Reykjanes Ridge, south of Iceland, over the Holocene. Our data suggest that ventilation in the Antarctic circumpolar waters and North Atlantic Deep Water is surprisingly invariant within proxy uncertainties at our sampling resolution. Our findings indicate that long-term, large-scale polar ocean overturning has not been disturbed to a level resolvable by radiocarbon and is probably not responsible for the millennial atmosphere pCO2 evolution through the Holocene. Instead, continuous nutrient and carbon redistribution within the water column following deglaciation, as well as changes in land organic carbon stock, might have regulated atmospheric CO2 budget during this period.Publisher PDFPeer reviewe

Practical Considerations in High-Precision Compound-Specific Radiocarbon Analyses:Eliminating the Effects of Solvent and Sample Cross-Contamination on Accuracy and Precision

Preparative capillary gas chromatography (pcGC) is widely used for the isolation of single compounds for radiocarbon determinations. While being effective at isolating compounds, there are still genuine concerns relating to contamination associated with the isolation procedure, such as incomplete removal of solvent used to recover isolated compounds from the traps and cross-contamination, which can lead to erroneous 14C determinations. Herein we describe new approaches to identifying and removing these two sources of contamination. First, we replaced the common “U” trap design, which requires recovery of compounds using organic solvent, with a novel solventless trapping system (STS), consisting of a simple glass tube containing a glass wool plug, allowing condensation of a target compound in the wool and its solventless recovery by pushing the glass wool directly into a foil capsule for graphitization. With the STS trap, an average of 95.7% of the target compound was recovered, and contamination from column bleed was reduced. In addition, comparison of 14C determinations of fatty acid methyl ester (FAME) standards determined offline to those isolated by pcGC in STS traps showed excellent reproducibility and accuracy compared to those isolated using the commercial “U” traps. Second, “coldspots” were identified in the instrument, i.e., the termini of capillaries in the preparative unit, which can be cleaned of compounds condensed from earlier runs using a heat gun. Our new procedure, incorporating these two modifications, was tested on archeological fat hoards, producing 14C dates on isolated C16:0 and C18:0 fatty acids statistically consistent with the bulk dates of the archeological material

Modelling mucociliary clearance

Mathematical modelling of the fluid mechanics of mucociliary clearance (MCC) is reviewed and future challenges for researchers are discussed. The morphology of the bronchial and tracheal airway surface liquid (ASL) and ciliated epithelium are briefly introduced. The cilia beat cycle, beat frequency and metachronal coordination are described, along with the rheology of the mucous layer. Theoretical modelling of MCC from the late 1960s onwards is reviewed, and distinctions between ‘phenomenological’, ‘slender body theory’ and recent ‘fluid–structure interaction’ models are explained.\ud \ud The ASL consists of two layers, an overlying mucous layer and underlying watery periciliary layer (PCL) which bathes the cilia. Previous models have predicted very little transport of fluid in the PCL compared with the mucous layer. Fluorescent tracer transport experiments on human airway cultures conducted by Matsui et al. [Matsui, H., Randell, S.H., Peretti, S.W., Davis, C.W., Boucher, R.C., 1998. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J. Clin. Invest. 102 (6), 1125–1131] apparently showed equal transport in both the PCL and mucous layer. Recent attempts to resolve this discrepancy by the present authors are reviewed, along with associated modelling findings. These findings have suggested new insights into the interaction of cilia with mucus due to pressure gradients associated with the flat PCL/mucus interface. This phenomenon complements previously known mechanisms for ciliary propulsion. Modelling results are related to clinical findings, in particular the increased MCC observed in patients with pseudohypoaldosteronism. Recent important advances by several groups in modelling the fluid–structure interaction by which the cilia movement and fluid transport emerge from specification of internal mechanics, viscous and elastic forces are reviewed. Finally, we discuss the limitations of existing work, and the challenges for the next generation of models, which may provide further insight into this complex and vital system

Multi-objective optimisation for receiver operating characteristic analysis

Copyright © 2006 Springer-Verlag Berlin Heidelberg. The final publication is available at link.springer.comBook title: Multi-Objective Machine LearningSummary Receiver operating characteristic (ROC) analysis is now a standard tool for the comparison of binary classifiers and the selection operating parameters when the costs of misclassification are unknown. This chapter outlines the use of evolutionary multi-objective optimisation techniques for ROC analysis, in both its traditional binary classification setting, and in the novel multi-class ROC situation. Methods for comparing classifier performance in the multi-class case, based on an analogue of the Gini coefficient, are described, which leads to a natural method of selecting the classifier operating point. Illustrations are given concerning synthetic data and an application to Short Term Conflict Alert

Nontuberculous mycobacteria: II: Nested-cohort study of impact on cystic fibrosis lung disease

The prevalence of nontuberculous mycobacteria (NTM) is high (approximately 13%) in sputum of patients with cystic fibrosis (CF), but the impact on lung disease is unknown. We followed 60 incident NTM-positive and 99 culture-negative patients with CF for 15 months and assessed clinical impact of NTM by FEV1 and high-resolution computed tomography (HRCT) of the chest. Mycobacterium avium complex was seen in 75% of NTM-positive subjects. The annual rate of decline in FEV1 was not different among control versus NTM-positive subjects who did not, or did, meet American Thoracic Society microbiologic criteria for NTM disease (3 ± 1, 3 ± 2, and 5 ± 2%, respectively). More subjects with three or more positive cultures for NTM had two or more characteristic findings on entry HRCT (60%, 9/15) as compared with subjects with two positive cultures or less (32%) or negative cultures (19%; p < 0.02). All subjects with three or more positive cultures and exit HRCTs (n = 6) showed progression of HRCT findings, whereas only 17% of subjects with two positive cultures or less had progression (p = 0.0006). In summary, no significant short-term effect on FEV1 was detected in patients with multiple positive NTM cultures, but an abnormal HRCT was predictive of progression. Patients with CF and multiple positive NTM cultures, characteristic HRCT findings, and progression of HRCT changes should be monitored closely and considered for antimycobacterial therapy

Reinterpreting radiocarbon records in bamboo corals ? New insights from the tropical North Atlantic

Deep-sea bamboo corals (family Isididae) have been used as archives for reconstructing changes in the past ocean. However, uncertainties remain regarding the interpretation of geochemical signals from their organic nodes, specifically the water depth of the signals recorded by the coral. Here we explore this question by measuring radiocarbon (14C) and nitrogen (15N) isotopic compositions of the organic nodes in six bamboo corals collected from the central and eastern tropical Atlantic between 700 m and 2000 m water depth. By comparing coral 14C to measured seawater data, regional shallow-water coral records and climate-model outputs, we find contrasting results between the two regions. Our bamboo coral 14C results from the eastern tropical Atlantic support previous studies that suggest organic node carbon is sourced primarily from the mixed layer of the ocean. By contrast, the 14C of bamboo coral organic nodes from the oligotrophic central Atlantic better correlates with the 14C content of the subsurface deep chlorophyll maximum layer rather than the surface mixed layer. Combined with nitrogen isotope data, this observation suggests that sinking and/or ambient zooplankton feeding on phytoplankton from the deep chlorophyll maximum layer can contribute a significant proportion of the diet of bamboo corals. These results suggest that the carbon source for bamboo corals organic nodes may not always reside in the mixed layer, especially in oligotrophic regions, which has implications for 14C-based age model development in bamboo corals