Late-onset Lafora disease with prominent parkinsonism due to a rare mutation in EPM2A

Lafora disease (LD) is an autosomal recessive form of progressive myoclonic epilepsy that is caused by mutations in EPM2A, encoding laforin, and NHLRC1 (EPM2B), encoding malin.(1) LD is classically described with onset in early teenage years. Patients develop myoclonus, epilepsy, visual hallucinations, and psychosis. Dementia is a prominent feature and often occurs in the late teenage years. LD typically progresses quickly, and patients become bedridden and dependent within 10 years of symptom onset, with life expectancy in the early 20s.(2,3) Only a small number of late-onset cases of LD have been described. Even then, these so-called late-onset cases have typically presented in the 20s, with dementia occurring in the early 30s. We describe a patient with extremely late onset and extended survival with prominent parkinsonism due to a novel EPM2A variant

Using the UM dynamical cores to reproduce idealised 3-D flows

This is the final version of the article. Available from the publisher via the DOI in this record.Published by Copernicus Publications on behalf of the European Geosciences UnionWe demonstrate that both the current (New Dynamics), and next generation (ENDGame) dynamical cores of the UK Met Office global circulation model, the UM, reproduce consistently, the long-term, large-scale flows found in several published idealised tests. The cases presented are the Held-Suarez test, a simplified model of Earth (including a stratosphere), and a hypothetical tidally locked Earth. Furthermore, we show that using simplifications to the dynamical equations, which are expected to be justified for the physical domains and flow regimes we have studied, and which are supported by the ENDGame dynamical core, also produces matching long-term, large-scale flows. Finally, we present evidence for differences in the detail of the planetary flows and circulations resulting from improvements in the ENDGame formulation over New Dynamics.We would like to thank Paul Ullrich and Kevin Heng for their valuable comments, when reviewing this manuscript. We would also like to thank Tom Melvin for his expert advice, and both Charline Marzin and Douglas Boyd for technical help. This work is supported by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013 Grant Agreement no. 247060) and by the Consolidated STFC grant ST/J001627/1. This work is also partly supported by the Royal Society award WM090065. The calculations for this paper were performed on the DiRAC Facility jointly funded by STFC, the Large Facilities Capital Fund of BIS, and the University of Exeter

Grouping of tooth surfaces by susceptibility to caries: a study in 5–16 year-old children

BACKGROUND: The decline in caries has slowed and this may be indicative of variation in the susceptibility of differing teeth to caries. This study tests the hypothesis that in children, there are groups of tooth sites that exhibit differences in caries susceptibility. METHODS: Probit analysis of caries data collected from a 4-year longitudinal study of 20,000 schoolchildren aged between 5 and 16 years in 10 differing locations in the United States. RESULTS: The development of dental caries within the mouth followed a fixed hierarchy indicating that tooth surfaces show variation in caries susceptibility. Certain teeth and tooth sites have similar susceptibilities and can be grouped, the sizes of the groups vary. The most susceptible group consists of six tooth surfaces: the buccal pits and occlusal fissured surfaces of the first molar teeth. The second group consisted of 12 sites on the second molar and premolar teeth. The group formed by the least susceptible sites included the largest number of tooth surfaces and consists of the majority of the lower anterior teeth and canines. CONCLUSION: Variation in the caries susceptibility of tooth surfaces exists. Surfaces can be grouped according to caries susceptibility. An effect that reduces the cariogenic challenge of one of the sites within a group is likely to affect all the other sites within the particular group

Monoclonal antibody levels and protection from COVID-19

Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies (mAb) in preventing symptomatic SARS-CoV-2 infection. We use data on the in vivo concentration of mAb and the associated protection from COVID-19 over time to model the dose-response relationship of mAb for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a mAb concentration of 96-fold of the in vitro IC50 (95% CI: 32—285). This relationship provides a tool for predicting the prophylactic efficacy of new mAb and against SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either mAb treatment or vaccination. We find no significant difference between the 50% protective titer for mAb and vaccination, although sample sizes limited the power to detect a difference

Mouse models for preeclampsia: disruption of redox-regulated signaling

The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-Omethyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD

An extragalactic supernebula confined by gravity

Little is known about the origins of the giant star clusters known as globular clusters. How can hundreds of thousands of stars form simultaneously in a volume only a few light years across the distance of the sun to its nearest neighbor? Radiation pressure and winds from luminous young stars should disperse the star-forming gas and disrupt the formation of the cluster. Globular clusters in our Galaxy cannot provide answers; they are billions of years old. Here we report the measurement of infrared hydrogen recombination lines from a young, forming super star cluster in the dwarf galaxy, NGC 5253. The lines arise in gas heated by a cluster of an estimated million stars, so young that it is still enshrouded in gas and dust, hidden from optical view. We verify that the cluster contains 4000-6000 massive, hot "O" stars. Our discovery that the gases within the cluster are bound by gravity may explain why these windy and luminous O stars have not yet blown away the gases to allow the cluster to emerge from its birth cocoon. Young clusters in "starbursting" galaxies in the local and distant universe may be similarly gravitationally confined and cloaked from view.Comment: Letter to Natur

Menstrual cycle phase does not predict political conservatism

Recent authors have reported a relationship between women's fertility status, as indexed by menstrual cycle phase, and conservatism in moral, social and political values. We conducted a survey to test for the existence of a relationship between menstrual cycle day and conservatism. 2213 women reporting regular menstrual cycles provided data about their political views. Of these women, 2208 provided information about their cycle date, 1260 provided additional evidence of reliability in self-reported cycle date, and of these, 750 also indicated an absence of hormonal disruptors such as recent hormonal contraception use, breastfeeding or pregnancy. Cycle day was used to estimate day-specific fertility rate (probability of conception); political conservatism was measured via direct self-report and via responses to the "Moral Foundations” questionnaire. We also recorded relationship status, which has been reported to interact with menstrual cycle phase in determining political preferences. We found no evidence of a relationship between estimated cyclical fertility changes and conservatism, and no evidence of an interaction between relationship status and cyclical fertility in determining political attitudes. Our findings were robust to multiple inclusion/exclusion criteria and to different methods of estimating fertility and measuring conservatism. In summary, the relationship between cycle-linked reproductive parameters and conservatism may be weaker or less reliable than previously thought