Major Modes of Variability

This chapter focused on major modes of variability which serve the key role in controlling the regional climate. In terms of tropospheric variability, it defined and discussed ENSO (El Niño Southern Oscillation), NAO (North Atlantic Oscillation), AO and AAO (Arctic Oscillation, Antarctic Oscillation), Indian Monsoon, Indian Ocean Dipole (IOD), PDO (Pacific Decadal Oscillation) and AMO (Atlantic Multidecadal Oscillation). Later it attended stratosphere variability; this constitutes QBO (quasi-biennial oscillation) and SSW (stratospheric sudden warming). Main characteristic features of each of these modes were elaborately discussed

Void Growth in BCC Metals Simulated with Molecular Dynamics using the Finnis-Sinclair Potential

The process of fracture in ductile metals involves the nucleation, growth, and linking of voids. This process takes place both at the low rates involved in typical engineering applications and at the high rates associated with dynamic fracture processes such as spallation. Here we study the growth of a void in a single crystal at high rates using molecular dynamics (MD) based on Finnis-Sinclair interatomic potentials for the body-centred cubic (bcc) metals V, Nb, Mo, Ta, and W. The use of the Finnis-Sinclair potential enables the study of plasticity associated with void growth at the atomic level at room temperature and strain rates from 10^9/s down to 10^6/s and systems as large as 128 million atoms. The atomistic systems are observed to undergo a transition from twinning at the higher end of this range to dislocation flow at the lower end. We analyze the simulations for the specific mechanisms of plasticity associated with void growth as dislocation loops are punched out to accommodate the growing void. We also analyse the process of nucleation and growth of voids in simulations of nanocrystalline Ta expanding at different strain rates. We comment on differences in the plasticity associated with void growth in the bcc metals compared to earlier studies in face-centred cubic (fcc) metals.Comment: 24 pages, 12 figure

Path integral Monte Carlo simulations for rigid rotors and their application to water

In this work the path integral formulation for rigid rotors, proposed by M\"user and Berne [Phys. Rev. Lett. {\bf 77}, 2638 (1996)], is described in detail. It is shown how this formulation can be used to perform Monte Carlo simulations of water. Our numerical results show that whereas some properties of water can be accurately reproduced using classical simulations with an empirical potential which, implicitly, includes quantum effects, other properties can only be described quantitatively when quantum effects are explicitly incorporated. In particular, quantum effects are extremely relevant when it comes to describing the equation of state of the ice phases at low temperatures, the structure of the ices at low temperatures, and the heat capacity of both liquid water and the ice phases. They also play a minor role in the relative stability of the ice phases.Comment: to appear in Molecular Physics (2011

Brain penetrant LRRK2 inhibitor

This is the author accepted manuscript. The final version is available from ACS via the DOI in this record. Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5- chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 μM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg. © 2012 American Chemical Society.NIHMedical Research CouncilMichael J Fox foundation for Parkinson’s disease researchPharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer

The impact of endogenous annexin A1 on glucocorticoid control of in ammatory arthritis

This work was supported by a Wellcome Trust (UK) project grant 083551. SMO is funded by Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (Grant 2011/00128-1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq (Grant 302768/2010-6)

Early childhood wheezing phenotypes and determinants in a South African birth cohort: longitudinal analysis of the Drakenstein Child Health Study

BACKGROUND: Developmental trajectories of childhood wheezing in low-income and middle-income countries (LMICs) have not been well described. We aimed to derive longitudinal wheeze phenotypes from birth to 5 years in a South African birth cohort and compare those with phenotypes derived from a UK cohort. METHODS: We used data from the Drakenstein Child Health Study (DCHS), a longitudinal birth cohort study in a peri-urban area outside Cape Town, South Africa. Pregnant women (aged ≥18 years) were enrolled during their second trimester at two public health clinics. We followed up children from birth to 5 years to derive six multidimensional indicators of wheezing (including duration, temporal sequencing, persistence, and recurrence) and applied Partition Around Medoids clustering to derive wheeze phenotypes. We compared phenotypes with a UK cohort (the Avon Longitudinal Study of Parents and Children [ALSPAC]). We investigated associations of phenotypes with early-life exposures, including all-cause lower respiratory tract infection (LRTI) and virus-specific LRTI (respiratory syncytial virus, rhinovirus, adenovirus, influenza, and parainfluenza virus) up to age 5 years. We investigated the association of phenotypes with lung function at 6 weeks and 5 years. FINDINGS: Between March 5, 2012, and March 31, 2015, we enrolled 1137 mothers and there were 1143 livebirths. Four wheeze phenotypes were identified among 950 children with complete data: never (480 children [50%]), early transient (215 children [23%]), late onset (104 children [11%]), and recurrent (151 children [16%]). Multivariate adjusted analysis indicated that LRTI and respiratory syncytial virus-LRTI, but not other respiratory viruses, were associated with increased risk of recurrent wheeze (odds ratio [OR] 2·79 [95% CI 2·05-3·81] for all LTRIs; OR 2·59 [1·30-5·15] for respiratory syncytial virus-LRTIs). Maternal smoking (1·88 [1·12-3·02]), higher socioeconomic status (2·46 [1·23-4·91]), intimate partner violence (2·01 [1·23-3·29]), and male sex (2·47 [1·50-4·04]) were also associated with recurrent wheeze. LRTI and respiratory syncytial virus-LRTI were also associated with early transient and late onset clusters. Wheezing illness architecture differed between DCHS and ALSPAC; children included in ALSPAC in the early transient cluster wheezed for a longer period before remission and late-onset wheezing started at an older age, and no persistent phenotype was identified in DCHS. At 5 years, airway resistance was higher in children with early or recurrent wheeze compared with children who had never wheezed. Airway resistance increased from 6 weeks to 5 years among children with recurrent wheeze. INTERPRETATION: Effective strategies to reduce maternal smoking and psychosocial stressors and new preventive interventions for respiratory syncytial virus are urgently needed to optimise child health in LMICs. FUNDING: UK Medical Research Council; The Bill & Melinda Gates Foundation; National Institutes of Health Human Heredity and Health in Africa; South African Medical Research Council; Wellcome Trust

Complete mitochondrial DNA sequences provide new insights into the Polynesian motif and the peopling of Madagascar

More than a decade of mitochondrial DNA (mtDNA) studies have given the 'Polynesian motif' renowned status as a marker for tracing the late-Holocene expansion of Austronesian speaking populations. Despite considerable research on the Polynesian motif in Oceania, there has been little equivalent work on the western edge of its expansion - leaving major issues unresolved regarding the motif's evolutionary history. This has also led to considerable uncertainty regarding the settlement of Madagascar. In this study, we assess mtDNA variation in 266 individuals from three Malagasy ethnic groups: the Mikea, Vezo, and Merina. Complete mtDNA genome sequencing reveals a new variant of the Polynesian motif in Madagascar; two coding region mutations define a Malagasy-specific sub-branch. This newly defined 'Malagasy motif' occurs at high frequency in all three ethnic groups (13-50%), and its phylogenetic position, geographic distribution, and estimated age all support a recent origin, but without conclusively identifying a specific source region. Nevertheless, the haplotype's limited diversity, similar to those of other mtDNA haplogroups found in our Malagasy groups, best supports a small number of initial settlers arriving to Madagascar through the same migratory process. Finally, the discovery of this lineage provides a set of new polymorphic positions to help localize the Austronesian ancestors of the Malagasy, as well as uncover the origin and evolution of the Polynesian motif itself

Misaligned spin and orbital axes cause the anomalous precession of DI Herculis

The orbits of binary stars precess as a result of general relativistic effects, forces arising from the asphericity of the stars, and forces from additional stars or planets in the system. For most binaries, the theoretical and observed precession rates are in agreement. One system, however -- DI Herculis -- has resisted explanation for 30 years. The observed precession rate is a factor of four slower than the theoretical rate, a disagreement that once was interpreted as evidence for a failure of general relativity. Among the contemporary explanations are the existence of a circumbinary planet and a large tilt of the stellar spin axes with respect to the orbit. Here we report that both stars of DI Herculis rotate with their spin axes nearly perpendicular to the orbital axis (contrary to the usual assumption for close binary stars). The rotationally induced stellar oblateness causes precession in the direction opposite to that of relativistic precession, thereby reconciling the theoretical and observed rates.Comment: Nature, in press [11 pg

Examining links between anxiety, reinvestment and walking when talking by older adults during adaptive gait

Falls by older adults often result in reduced quality of life and debilitating fear of further falls. Stopping walking when talking (SWWT) is a significant predictor of future falls by older adults and is thought to reflect age-related increases in attentional demands of walking. We examine whether SWWT is associated with use of explicit movement cues during locomotion, and evaluate if conscious control (i.e., movement specific reinvestment) is causally linked to falls-related anxiety during a complex walking task. We observed whether twenty-four older adults stopped walking when talking when asked a question during an adaptive gait task. After certain trials, participants completed a visual-spatial recall task regarding walkway features, or answered questions about their movements during the walk. In a subsequent experimental condition, participants completed the walking task under conditions of raised postural threat. Compared to a control group, participants who SWWT reported higher scores for aspects of reinvestment relating to conscious motor processing but not movement self-consciousness. The higher scores for conscious motor processing were preserved when scores representing cognitive function were included as a covariate. There were no group differences in measures of general cognitive function, visual spatial working memory or balance confidence. However, the SWWT group reported higher scores on a test of external awareness when walking, indicating allocation of attention away from task-relevant environmental features. Under conditions of increased threat, participants self-reported significantly greater state anxiety and reinvestment and displayed more accurate responses about their movements during the task. SWWT is not associated solely with age-related cognitive decline or generic increases in age-related attentional demands of walking. SWWT may be caused by competition for phonological resources of working memory associated with consciously processing motor actions and appears to be causally linked with fall-related anxiety and increased vigilance.This research was supported by The Royal Society (IE131576) and British Academy (SG132820)