Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies

Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson’s disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson’s and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.The authors are supported by the NIHR Cambridge Biomedical Research Centre Dementia Theme (146281) and the Rosetrees Trust (M369-F1). AK is supported by the Onassis Foundation and the Alborada Trust. CWG is funded by an MRC Clinician Scientist Fellowship (Grant: MR/R007446/1)

Secondary Sex Ratio among Women Exposed to Diethylstilbestrol in Utero

BACKGROUND. Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio. METHODS. Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child's birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies. RESULTS. The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95-1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65-1.27) for first exposure at ≥ 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71-1.27) for first exposure at ≥ 13 weeks to ≥ 5 g; 1.16 (95% CI, 0.96-1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04-1.48) for first exposure at < 13 weeks to ≥ 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history. CONCLUSIONS. Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose.National Cancer Institute (N01-CP-21168, N01-CP-51017, N01-CP-01289

Gravitational Redshift, Equivalence Principle, and Matter Waves

We review matter wave and clock comparison tests of the gravitational redshift. To elucidate their relationship to tests of the universality of free fall (UFF), we define scenarios wherein redshift violations are coupled to violations of UFF ("type II"), or independent of UFF violations ("type III"), respectively. Clock comparisons and atom interferometers are sensitive to similar effects in type II and precisely the same effects in type III scenarios, although type III violations remain poorly constrained. Finally, we describe the "Geodesic Explorer," a conceptual spaceborne atom interferometer that will test the gravitational redshift with an accuracy 5 orders of magnitude better than current terrestrial redshift experiments for type II scenarios and 12 orders of magnitude better for type III.Comment: Work in progress. 11 page

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

Limits on additional planetary companions to OGLE-2005-BLG-390L

We investigate constraints on additional planets orbiting the distant M-dwarf star OGLE-2005-BLG-390L, around which photometric microlensing data has revealed the existence of the sub-Neptune-mass planet OGLE-2005-BLG-390Lb. We specifically aim to study potential Jovian companions and compare our findings with predictions from core-accretion and disc-instability models of planet formation. We also obtain an estimate of the detection probability for sub-Neptune mass planets similar to OGLE-2005-BLG-390Lb using a simplified simulation of a microlensing experiment. We compute the efficiency of our photometric data for detecting additional planets around OGLE-2005-BLG-390L, as a function of the microlensing model parameters and convert it into a function of the orbital axis and planet mass by means of an adopted model of the Milky Way. We find that more than 50 % of potential planets with a mass in excess of 1 M_J between 1.1 and 2.3 AU around OGLE-2005-BLG-390L would have revealed their existence, whereas for gas giants above 3 M_J in orbits between 1.5 and 2.2 AU, the detection efficiency reaches 70 %; however, no such companion was observed. Our photometric microlensing data therefore do not contradict the existence of gas giant planets at any separation orbiting OGLE-2005-BLG-390L. Furthermore we find a detection probability for an OGLE-2005-BLG-390Lb-like planet of around 2-5 %. In agreement with current planet formation theories, this quantitatively supports the prediction that sub-Neptune mass planets are common around low-mass stars.Comment: 10 pages, 4 figures, accepted by A&

A systematic fitting scheme for caustic-crossing microlensing events

We outline a method for fitting binary-lens caustic-crossing microlensing events based on the alternative model parameterisation proposed and detailed in Cassan (2008). As an illustration of our methodology, we present an analysis of OGLE-2007-BLG-472, a double-peaked Galactic microlensing event with a source crossing the whole caustic structure in less than three days. In order to identify all possible models we conduct an extensive search of the parameter space, followed by a refinement of the parameters with a Markov Chain-Monte Carlo algorithm. We find a number of low-chi2 regions in the parameter space, which lead to several distinct competitive best models. We examine the parameters for each of them, and estimate their physical properties. We find that our fitting strategy locates several minima that are difficult to find with other modelling strategies and is therefore a more appropriate method to fit this type of events.Comment: 12 pages, 11 figure

A broad distribution of the alternative oxidase in microsporidian parasites

Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of ironsulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX), a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1) as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin-resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosome

OGLE-2005-BLG-018: Characterization of Full Physical and Orbital Parameters of a Gravitational Binary Lens

We present the analysis result of a gravitational binary-lensing event OGLE-2005-BLG-018. The light curve of the event is characterized by 2 adjacent strong features and a single weak feature separated from the strong features. The light curve exhibits noticeable deviations from the best-fit model based on standard binary parameters. To explain the deviation, we test models including various higher-order effects of the motions of the observer, source, and lens. From this, we find that it is necessary to account for the orbital motion of the lens in describing the light curve. From modeling of the light curve considering the parallax effect and Keplerian orbital motion, we are able to measure not only the physical parameters but also a complete orbital solution of the lens system. It is found that the event was produced by a binary lens located in the Galactic bulge with a distance $6.7\pm 0.3$ kpc from the Earth. The individual lens components with masses $0.9\pm 0.3\ M_\odot$ and $0.5\pm 0.1\ M_\odot$ are separated with a semi-major axis of $a=2.5 \pm 1.0$ AU and orbiting each other with a period $P=3.1 \pm 1.3$ yr. The event demonstrates that it is possible to extract detailed information about binary lens systems from well-resolved lensing light curves.Comment: 19 pages, 6 figure

Violation of multi-particle Bell inequalities for low and high flux parametric amplification using both vacuum and entangled input states

We show how polarisation measurements on the output fields generated by parametric down conversion will reveal a violation of multi-particle Bell inequalities, in the regime of both low and high output intensity. In this case each spatially separated system, upon which a measurement is performed, is comprised of more than one particle. In view of the formal analogy with spin systems, the proposal provides an opportunity to test the predictions of quantum mechanics for spatially separated higher spin states. Here the quantum behaviour possible even where measurements are performed on systems of large quantum (particle) number may be demonstrated. Our proposal applies to both vacuum-state signal and idler inputs, and also to the quantum-injected parametric amplifier as studied by De Martini et al. The effect of detector inefficiencies is included.Comment: 12 pages, 12 figure

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study

Background PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. Methods Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. Results Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported ‘being deferred’ as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. Conclusion The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study