The Link between General Relativity and Shape Dynamics

We show that one can construct two equivalent gauge theories from a linking theory and give a general construction principle for linking theories which we use to construct a linking theory that proves the equivalence of General Relativity and Shape Dynamics, a theory with fixed foliation but spatial conformal invariance. This streamlines the rather complicated construction of this equivalence performed previously. We use this streamlined argument to extend the result to General Relativity with asymptotically flat boundary conditions. The improved understanding of linking theories naturally leads to the Lagrangian formulation of Shape Dynamics, which allows us to partially relate the degrees of freedom.Comment: 19 pages, LaTeX, no figure

Close kinship within multiple-genotype malaria parasite infections

Malaria infections containing multiple parasite genotypes are ubiquitous in nature, and play a central role in models of recombination, intra-host dynamics, virulence, sex ratio, immunity and drug resistance evolution in Plasmodium. While these multiple infections (MIs) are often assumed to result from superinfection (bites from multiple infected mosquitoes), we know remarkably little about their composition or generation. We isolated 336 parasite clones from eight patients from Malawi (high transmission) and six from Thailand (low transmission) by dilution cloning. These were genotyped using 384 single-nucleotide polymorphisms, revealing 22 independent haplotypes in Malawi (2–6 per MI) and 15 in Thailand (2–5 per MI). Surprisingly, all six patients from Thailand and six of eight from Malawi contained related haplotypes, and haplotypes were more similar within- than between-infections. These results argue against a simple superinfection model. Instead, the observed kinship patterns may be explained by inoculation of multiple related haploid sporozoites from single mosquito bites, by immune suppression of parasite subpopulations within infections, and serial transmission of related parasites between people. That relatedness is maintained in endemic areas in the face of repeated bites from infected mosquitoes has profound implications for understanding malaria transmission, immunity and intra-host dynamics of co-infecting parasite genotypes

Einstein gravity as a 3D conformally invariant theory

We give an alternative description of the physical content of general relativity that does not require a Lorentz invariant spacetime. Instead, we find that gravity admits a dual description in terms of a theory where local size is irrelevant. The dual theory is invariant under foliation preserving 3-diffeomorphisms and 3D conformal transformations that preserve the 3-volume (for the spatially compact case). Locally, this symmetry is identical to that of Horava-Lifshitz gravity in the high energy limit but our theory is equivalent to Einstein gravity. Specifically, we find that the solutions of general relativity, in a gauge where the spatial hypersurfaces have constant mean extrinsic curvature, can be mapped to solutions of a particular gauge fixing of the dual theory. Moreover, this duality is not accidental. We provide a general geometric picture for our procedure that allows us to trade foliation invariance for conformal invariance. The dual theory provides a new proposal for the theory space of quantum gravity.Comment: 27 pages. Published version (minor changes and corrections

Inferred relatedness and heritability in malaria parasites

Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability (H2). We evaluate two approaches to measuring H2 in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand–Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H2. Inhibitory concentrations (IC50) for six drugs showed significant H2 (0.24 to 0.79, p = 0.06 to 2.85 × 10−9), demonstrating that this study design has adequate power. However, a phenotype of current interest—parasite clearance following ACT—showed no detectable heritability (H2 = 0–0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H2, analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H2 can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies; and (ii) while drug response (IC50) shows significant H2, parasite clearance following ACT was not heritable in the population studied

Two Different Forms of Arousal in Drosophila Are Oppositely Regulated by the Dopamine D1 Receptor Ortholog DopR via Distinct Neural Circuits

Arousal is fundamental to many behaviors, but whether it is unitary or whether there are different types of behavior-specific arousal has not been clear. In Drosophila, dopamine promotes sleep-wake arousal. However, there is conflicting evidence regarding its influence on environmentally stimulated arousal. Here we show that loss-of-function mutations in the D1 dopamine receptor DopR enhance repetitive startle-induced arousal while decreasing sleep-wake arousal (i.e., increasing sleep). These two types of arousal are also inversely influenced by cocaine, whose effects in each case are opposite to, and abrogated by, the DopR mutation. Selective restoration of DopR function in the central complex rescues the enhanced stimulated arousal but not the increased sleep phenotype of DopR mutants. These data provide evidence for at least two different forms of arousal, which are independently regulated by dopamine in opposite directions, via distinct neural circuits

An optimized microarray platform for assaying genomic variation in Plasmodium falciparum field populations

We present an optimized probe design for copy number variation (CNV) and SNP genotyping in the Plasmodium falciparum genome. We demonstrate that variable length and isothermal probes are superior to static length probes. We show that sample preparation and hybridization conditions mitigate the effects of host DNA contamination in field samples. The microarray and workflow presented can be used to identify CNVs and SNPs with 95% accuracy in a single hybridization, in field samples containing up to 92% human DNA contamination

Arterial spin labelling reveals an abnormal cerebral perfusion pattern in Parkinson's disease

There is a need for objective imaging markers of Parkinson's disease status and progression. Positron emission tomography and single photon emission computed tomography studies have suggested patterns of abnormal cerebral perfusion in Parkinson's disease as potential functional biomarkers. This study aimed to identify an arterial spin labelling magnetic resonance-derived perfusion network as an accessible, non-invasive alternative. We used pseudo-continuous arterial spin labelling to measure cerebral grey matter perfusion in 61 subjects with Parkinson's disease with a range of motor and cognitive impairment, including patients with dementia and 29 age- and sex-matched controls. Principal component analysis was used to derive a Parkinson's disease-related perfusion network via logistic regression. Region of interest analysis of absolute perfusion values revealed that the Parkinson's disease pattern was characterized by decreased perfusion in posterior parieto-occipital cortex, precuneus and cuneus, and middle frontal gyri compared with healthy controls. Perfusion was preserved in globus pallidus, putamen, anterior cingulate and post- and pre-central gyri. Both motor and cognitive statuses were significant factors related to network score. A network approach, supported by arterial spin labelling-derived absolute perfusion values may provide a readily accessible neuroimaging method to characterize and track progression of both motor and cognitive status in Parkinson's diseas

Managing Extreme Heat and Smoke: A Focus Group Study of Vulnerable People in Darwin, Australia

Extreme heat and poor air quality arising from landscape fires are an increasing global concern driven by anthropogenic climate change. Previous studies have shown these environmental conditions are associated with negative health outcomes for vulnerable people. Managing and adapting to these conditions in a warming climate can present substantial difficulties, especially in climates already challenging for human habitation. This study was set in the tropical city of Darwin, Australia. We recruited individuals from population groups vulnerable to outdoor hazards: outdoor workers, teachers and carers, and sportspeople, to participate in focus group discussions. We aimed to gain an understanding of the impacts of extreme heat and poor air quality and how individuals perceived and managed these environmental conditions. We identified a number of key themes relating to impacts on health, work and activity, and adaptive behaviors, while identifying gaps in policy and infrastructure that could improve the lives and protect the health of vulnerable people living, working, and playing in this region. In addition, these outcomes potentially provide direction for other regions with similar environmental challenges. Extreme heat and poor air quality place an additional burden on the lives of people in high-risk settings, such as outdoor workers, teachers and carers, and sportspeople

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome : a prospective randomized multinational study

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95 confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.peer-reviewe

Beta Amyloid Deposition Is Not Associated With Cognitive Impairment in Parkinson's Disease

The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amyloid, contributes to cognitive decline and dementia in Parkinson's disease (PD) is unresolved. Here, we used Florbetaben PET imaging to test for any association between cerebral amyloid deposition and cognitive impairment in PD, in a sample enriched for cases with mild cognitive impairment. This cross-sectional study used Movement Disorders Society level II criteria to classify 115 participants with PD as having normal cognition (PDN, n = 23), mild cognitive impairment (PD-MCI, n = 76), or dementia (PDD, n = 16). We acquired 18F-Florbetaben (FBB) amyloid PET and structural MRI. Amyloid deposition was assessed between the three cognitive groups, and also across the whole sample using continuous measures of both global cognitive status and average performance in memory domain tests. Outcomes were cortical FBB uptake, expressed in centiloids and as standardized uptake value ratios (SUVR) using the Centiloid Project whole cerebellum region as a reference, and regional SUVR measurements. FBB binding was higher in PDD, but this difference did not survive adjustment for the older age of the PDD group. We established a suitable centiloid cut-off for amyloid positivity in Parkinson's disease (31.3), but there was no association of FBB binding with global cognitive or memory scores. The failure to find an association between PET amyloid deposition and cognitive impairment in a moderately large sample, particularly given that it was enriched with PD-MCI patients at risk of dementia, suggests that amyloid pathology is not the primary driver of cognitive impairment and dementia in most patients with PD