Modelling the natural history of Huntington's disease progression.

BACKGROUND: The lack of reliable biomarkers to track disease progression is a major problem in clinical research of chronic neurological disorders. Using Huntington's disease (HD) as an example, we describe a novel approach to model HD and show that the progression of a neurological disorder can be predicted for individual patients. METHODS: Starting with an initial cohort of 343 patients with HD that we have followed since 1995, we used data from 68 patients that satisfied our filtering criteria to model disease progression, based on the Unified Huntington's Disease Rating Scale (UHDRS), a measure that is routinely used in HD clinics worldwide. RESULTS: Our model was validated by: (A) extrapolating our equation to model the age of disease onset, (B) testing it on a second patient data set by loosening our filtering criteria, (C) cross-validating with a repeated random subsampling approach and (D) holdout validating with the latest clinical assessment data from the same cohort of patients. With UHDRS scores from the past four clinical visits (over a minimum span of 2 years), our model predicts disease progression of individual patients over the next 2 years with an accuracy of 89-91%. We have also provided evidence that patients with similar baseline clinical profiles can exhibit very different trajectories of disease progression. CONCLUSIONS: This new model therefore has important implications for HD research, most obviously in the development of potential disease-modifying therapies. We believe that a similar approach can also be adapted to model disease progression in other chronic neurological disorders.This study was supported by the Cotswold Trust, the Rosetrees Trust, donations to the Huntington’s disease clinic in the John van Geest Centre for Brain Repair, and NIHR award of the Biomedical Research Centre - Cambridge University NHS Foundation Trust. This project was also supported by EPSRC through projects EP/I03210X/1 and EP/G066477/1.This article has been accepted for publication in Journal of Neurology, Neurosurgery, and Psychiatry, following peer review. The definitive copyedited, typeset version J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2014-308153 is available online at: http://jnnp.bmj.com/content/early/2014/12/16/jnnp-2014-308153.long

Homochirality and the need of energy

The mechanisms for explaining how a stable asymmetric chemical system can be formed from a symmetric chemical system, in the absence of any asymmetric influence other than statistical fluctuations, have been developed during the last decades, focusing on the non-linear kinetic aspects. Besides the absolute necessity of self-amplification processes, the importance of energetic aspects is often underestimated. Going down to the most fundamental aspects, the distinction between a single object -- that can be intrinsically asymmetric -- and a collection of objects -- whose racemic state is the more stable one -- must be emphasized. A system of strongly interacting objects can be described as one single object retaining its individuality and a single asymmetry; weakly or non-interacting objects keep their own individuality, and are prone to racemize towards the equilibrium state. In the presence of energy fluxes, systems can be maintained in an asymmetric non-equilibrium steady-state. Such dynamical systems can retain their asymmetry for times longer than their racemization time.Comment: 8 pages, 7 figures, submitted to Origins of Life and Evolution of Biosphere

The All-Loop Integrand For Scattering Amplitudes in Planar N=4 SYM

We give an explicit recursive formula for the all L-loop integrand for scattering amplitudes in N=4 SYM in the planar limit, manifesting the full Yangian symmetry of the theory. This generalizes the BCFW recursion relation for tree amplitudes to all loop orders, and extends the Grassmannian duality for leading singularities to the full amplitude. It also provides a new physical picture for the meaning of loops, associated with canonical operations for removing particles in a Yangian-invariant way. Loop amplitudes arise from the "entangled" removal of pairs of particles, and are naturally presented as an integral over lines in momentum-twistor space. As expected from manifest Yangian-invariance, the integrand is given as a sum over non-local terms, rather than the familiar decomposition in terms of local scalar integrals with rational coefficients. Knowing the integrands explicitly, it is straightforward to express them in local forms if desired; this turns out to be done most naturally using a novel basis of chiral, tensor integrals written in momentum-twistor space, each of which has unit leading singularities. As simple illustrative examples, we present a number of new multi-loop results written in local form, including the 6- and 7-point 2-loop NMHV amplitudes. Very concise expressions are presented for all 2-loop MHV amplitudes, as well as the 5-point 3-loop MHV amplitude. The structure of the loop integrand strongly suggests that the integrals yielding the physical amplitudes are "simple", and determined by IR-anomalies. We briefly comment on extending these ideas to more general planar theories.Comment: 46 pages; v2: minor changes, references adde

Bat accelerated regions identify a bat forelimb specific enhancer in the HoxD locus

Author Summary: The limb is a classic example of vertebrate homology and is represented by a large range of morphological structures such as fins, legs and wings. The evolution of these structures could be driven by alterations in gene regulatory elements that have critical roles during development. To identify elements that may contribute to bat wing development, we characterized sequences that are conserved between vertebrates, but changed significantly in the bat lineage. We then overlapped these sequences with predicted developing limb enhancers as determined by ChIP-seq, finding 166 bat accelerated sequences (BARs). Five BARs that were tested for enhancer activity in mice all drove expression in the limb. Testing the mouse orthologous sequence showed that three had differences in their limb enhancer activity as compared to the bat sequence. Of these, BAR116 was of particular interest as it is located near the HoxD locus, an essential gene complex required for proper spatiotemporal patterning of the developing limb. The bat BAR116 sequence drove robust forelimb expression but the mouse BAR116 sequence did not show enhancer activity. These experiments correspond to analyses of HoxD gene expressions in developing bat limbs, which had strong forelimb versus weak hindlimb expression for Hoxd10 - 11 . Combined, our studies highlight specific genomic regions that could be important in shaping the morphological differences that led to the development of the bat wing

High genetic diversity at the extreme range edge: nucleotide variation at nuclear loci in Scots pine (Pinus sylvestris L.) in Scotland

Nucleotide polymorphism at 12 nuclear loci was studied in Scots pine populations across an environmental gradient in Scotland, to evaluate the impacts of demographic history and selection on genetic diversity. At eight loci, diversity patterns were compared between Scottish and continental European populations. At these loci, a similar level of diversity (θsil=~0.01) was found in Scottish vs mainland European populations, contrary to expectations for recent colonization, however, less rapid decay of linkage disequilibrium was observed in the former (ρ=0.0086±0.0009, ρ=0.0245±0.0022, respectively). Scottish populations also showed a deficit of rare nucleotide variants (multi-locus Tajima's D=0.316 vs D=−0.379) and differed significantly from mainland populations in allelic frequency and/or haplotype structure at several loci. Within Scotland, western populations showed slightly reduced nucleotide diversity (πtot=0.0068) compared with those from the south and east (0.0079 and 0.0083, respectively) and about three times higher recombination to diversity ratio (ρ/θ=0.71 vs 0.15 and 0.18, respectively). By comparison with results from coalescent simulations, the observed allelic frequency spectrum in the western populations was compatible with a relatively recent bottleneck (0.00175 × 4Ne generations) that reduced the population to about 2% of the present size. However, heterogeneity in the allelic frequency distribution among geographical regions in Scotland suggests that subsequent admixture of populations with different demographic histories may also have played a role

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

Biology of Francisella tularensis Subspecies holarctica Live Vaccine Strain in the Tick Vector Dermacentor variabilis

Background: The c-proteobacterium Francisella tularensis is the etiologic agent of seasonal tick-transmitted tularemia epizootics in rodents and rabbits and of incidental infections in humans. The biology of F. tularensis in its tick vectors has not been fully described, particularly with respect to its quanta and duration of colonization, tissue dissemination, and transovarial transmission. A systematic study of the colonization of Dermacentor variabilis by the F. tularensis subsp. holarctica live vaccine strain (LVS) was undertaken to better understand whether D. variabilis may serve as an inter-epizootic reservoir for F. tularensis. Methodology/Principal Findings: Colony-reared larva, nymph, and adult D. variabilis were artificially fed LVS via glass capillary tubes fitted over the tick mouthparts, and the level of colonization determined by microbial culture. Larvae and nymphs were initially colonized with 8.860.8610 1 and 1.160.03610 3 CFU/tick, respectively. Post-molting, a significant increase in colonization of both molted nymphs and adults occurred, and LVS persisted in 42 % of molted adult ticks at 126 days post-capillary tube feeding. In adult ticks, LVS initially colonized the gut, disseminated to hemolymph and salivary glands by 21 days, and persisted up to 165 days. LVS was detected in the salivary secretions of adult ticks after four days post intra-hemocoelic inoculation, and LVS recovered from salivary gland was infectious to mice with an infectious dose 50 % of 3 CFU. LVS in gravid female ticks colonized via the intra-hemocoelic route disseminated to the ovaries and then t

Free energy of binding of coiled-coil complexes with different electrostatic environments: the influence of force field polarisation and capping

Coiled-coils are well known protein–protein interaction motifs, with the leucine zipper region of activator protein-1 (AP-1) consisting of the c-Jun and c-Fos proteins being a typical example. Molecular dynamics (MD) simulations using the MM/GBSA method have been used to predict the free energy of interaction of these proteins. The influence of force field polarisation and capping on the predicted free energy of binding of complexes with different electrostatic environments (net charge) were investigated. Although both force field polarisation and peptide capping are important for the prediction of the absolute free energy of binding, peptide capping has the largest influence on the predicted free energy of binding. Polarisable simulations appear better suited to determine structural properties of the complexes of these proteins while non-polarisable simulations seem to give better predictions of the associated free energies of bindin

A Low-Cost GPS GSM/GPRS Telemetry System: Performance in Stationary Field Tests and Preliminary Data on Wild Otters (Lutra lutra)

Background: Despite the increasing worldwide use of global positioning system (GPS) telemetry in wildlife research, it has never been tested on any freshwater diving animal or in the peculiar conditions of the riparian habitat, despite this latter being one of the most important habitat types for many animal taxa. Moreover, in most cases, the GPS devices used have been commercial and expensive, limiting their use in low-budget projects. Methodology/Principal Findings: We have developed a low-cost, easily constructed GPS GSM/GPRS (Global System for Mobile Communications/General Packet Radio Service) and examined its performance in stationary tests, by assessing the influence of different habitat types, including the riparian, as well as water submersion and certain climatic and environmental variables on GPS fix-success rate and accuracy. We then tested the GPS on wild diving animals, applying it, for the first time, to an otter species (Lutra lutra). The rate of locations acquired during the stationary tests reached 63.2%, with an average location error of 8.94 m (SD = 8.55). GPS performance in riparian habitats was principally affected by water submersion and secondarily by GPS inclination and position within the riverbed. Temporal and spatial correlations of location estimates accounted for some variation in the data sets. GPS-tagged otters also provided accurate locations and an even higher GPS fix-success rate (68.2%). Conclusions/Significance: Our results suggest that GPS telemetry is reliably applicable to riparian and even divin