A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Identification of hip fracture patients from radiographs using Fourier analysis of the trabecular structure: a cross-sectional study

Peer reviewedPublisher PD

Integer Least-squares Theory for the GNSS Compass

Global navigation satellite system (GNSS) carrier phase integer ambiguity resolution is the key to high-precision positioning and attitude determination. In this contribution, we develop new integer least-squares (ILS) theory for the GNSS compass model, together with efficient integer search strategies. It extends current unconstrained ILS theory to the nonlinearly constrained case, an extension that is particularly suited for precise attitude determination. As opposed to current practice, our method does proper justice to the a priori given information. The nonlinear baseline constraint is fully integrated into the ambiguity objective function, thereby receiving a proper weighting in its minimization and providing guidance for the integer search. Different search strategies are developed to compute exact and approximate solutions of the nonlinear constrained ILS problem. Their applicability depends on the strength of the GNSS model and on the length of the baseline. Two of the presented search strategies, a global and a local one, are based on the use of an ellipsoidal search space. This has the advantage that standard methods can be applied. The global ellipsoidal search strategy is applicable to GNSS models of sufficient strength, while the local ellipsoidal search strategy is applicable to models for which the baseline lengths are not too small. We also develop search strategies for the most challenging case, namely when the curvature of the non-ellipsoidal ambiguity search space needs to be taken into account. Two such strategies are presented, an approximate one and a rigorous, somewhat more complex, one. The approximate one is applicable when the fixed baseline variance matrix is close to diagonal. Both methods make use of a search and shrink strategy. The rigorous solution is efficiently obtained by means of a search and shrink strategy that uses non-quadratic, but easy-to-evaluate, bounding functions of the ambiguity objective function. The theory presented is generally valid and it is not restricted to any particular GNSS or combination of GNSSs. Its general applicability also applies to the measurement scenarios (e.g. single-epoch vs. multi-epoch, or single-frequency vs. multi-frequency). In particular it is applicable to the most challenging case of unaided, single frequency, single epoch GNSS attitude determination. The success rate performance of the different methods is also illustrated

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity

Purpose of Review: There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Recent Findings: Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Summary: Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment

Sequence Diversity in the Dickeya fliC Gene: Phylogeny of the Dickeya Genus and TaqMan® PCR for 'D. solani', New Biovar 3 Variant on Potato in Europe

Worldwide, Dickeya (formerly Erwinia chrysanthemi) is causing soft rot diseases on a large diversity of crops and ornamental plants. Strains affecting potato are mainly found in D. dadantii, D. dianthicola and D. zeae, which appear to have a marked geographical distribution. Furthermore, a few Dickeya isolates from potato are attributed to D. chrysanthemi and D. dieffenbachiae. In Europe, isolates of Erwinia chrysanthemi biovar 1 and biovar 7 from potato are now classified in D. dianthicola. However, in the past few years, a new Dickeya biovar 3 variant, tentatively named ‘Dickeya solani’, has emerged as a common major threat, in particular in seed potatoes. Sequences of a fliC gene fragment were used to generate a phylogeny of Dickeya reference strains from culture collections and with this reference backbone, to classify pectinolytic isolates, i.e. Dickeya spp. from potato and ornamental plants. The reference strains of the currently recognized Dickeya species and ‘D. solani’ were unambiguously delineated in the fliC phylogram. D. dadantii, D. dianthicola and ‘D. solani’ displayed unbranched clades, while D. chrysanthemi, D. zeae and D. dieffenbachiae branched into subclades and lineages. Moreover, Dickeya isolates from diagnostic samples, in particular biovar 3 isolates from greenhouse ornamentals, formed several new lineages. Most of these isolates were positioned between the clade of ‘D. solani’ and D. dadantii as transition variants. New lineages also appeared in D. dieffenbachiae and in D. zeae. The strains and isolates of D. dianthicola and ‘D. solani’ were differentiated by a fliC sequence useful for barcode identification. A fliC TaqMan®real-time PCR was developed for ‘D. solani’ and the assay was provisionally evaluated in direct analysis of diagnostic potato samples. This molecular tool can support the efforts to control this particular phytopathogen in seed potato certification

G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo

Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential

A case of serendipity*

An account is given of how a sensitive bioassay system for measurement of the neurotransmitter acetylcholine serendipitously led to the identification of adenosine triphosphate (ATP) released in vitro from active skeletal muscle. Subsequent application of the identification procedures to exercising human muscle in vivo, cardiac muscle cells in vitro, and human erythrocytes exposed to hypoxia gave rise to the general concept of ATP as a molecule that could influence cell function from the extracellular direction. Mechanisms of ATP release from cells in terms of “trigger” events such as mechanical distortion of the membrane, depolarization of the membrane, and exposure to hypoxia are discussed. Potential therapeutic uses of extracellular ATP in cancer therapy, radiation therapy, and a possible influence upon aging are discussed. Possible roles (distant and local) of extracellular ATP released from muscle during whole body exercise are discussed