Gene Editing and Modulation: the Holy Grail for the Genetic Epilepsies?

Epilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. Here we consider mutations in some of the most 'common' rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation could serve as an effective therapeutic strategy and discuss whether a single gene corrective approach could hold therapeutic potential in the context of homeostatic compensation in the developing, highly dynamic brain. Despite an incomplete understanding of the mechanisms of the genetic epilepsies and current limitations of gene editing tools, CRISPR-mediated approaches have game-changing potential in the treatment of genetic epilepsy over the next decade

DIRK Schemes with High Weak Stage Order

Runge-Kutta time-stepping methods in general suffer from order reduction: the observed order of convergence may be less than the formal order when applied to certain stiff problems. Order reduction can be avoided by using methods with high stage order. However, diagonally-implicit Runge-Kutta (DIRK) schemes are limited to low stage order. In this paper we explore a weak stage order criterion, which for initial boundary value problems also serves to avoid order reduction, and which is compatible with a DIRK structure. We provide specific DIRK schemes of weak stage order up to 3, and demonstrate their performance in various examples.Comment: 10 pages, 5 figure

The voltage-gated channelopathies as a paradigm for studying epilepsy-causing genes

‘Channelopathies’, or mutations in ion channels, are long-established causes of epilepsy. Comprehensive genetic, mechanistic and clinical data for SCN1A, a voltage-gated sodium channel, has highlighted the differing contributions of neuronal sub-types in epilepsy and confirmed that genotype-phenotype relations, even for monogenic epilepsies, are strongly influenced by modifier genes and environmental factors. An emerging population of de novo mutations in voltage-gated potassium channels has defined two novel potassium channelopathies (KCNA2 and KCNC1), which may benefit from mechanistic insights from SCN1A. Meanwhile, increasing genetic evidence has strengthened the long-standing association of voltage-gated calcium channels with epilepsy. Finally, an integrative approach for the characterisation of genetic variation in NMDA receptors has created a new standard for predicting functional effects of novel epilepsy genes

Flow-induced elastic anisotropy of metallic glasses

As-cast bulk metallic glasses are isotropic, but anisotropy can be induced by thermomechanical treatments. For example, the diffraction halo in the structure function S(Q) observed in transmission becomes elliptical (rather than circular) after creep in uniaxial tension or compression. Published studies associate this with frozen-in anelastic strain and bond-orientational anisotropy. Results so far are inconsistent on whether viscoplastic flow of metallic glasses can induce anisotropy. Preliminary diffraction data suggest that the anisotropy, if any, is very low, while measurements of the elastic properties suggest that there is induced anisotropy, opposite in sign to that due to anelastic strain. We study three bulk metallic glasses, Ce65Al10Cu20Co5, La55Ni10Al35, and Pd40Ni30Cu10P20. By using resonant ultrasound spectroscopy to determine the full elasticity tensor, the effects of relaxation and rejuvenation can be reliably separated from uniaxial anisotropy (of either sign). The effects of viscoplastic flow in tension are reported for the first time. We find that viscoplastic flow of bulk metallic glasses, particularly in tension, can induce significant anisotropy that is distinct from that associated with frozen-in anelastic strain. The conditions for inducing such anisotropy are explored in terms of the Weissenberg number (ratio of relaxation times for primary relaxation and for shear strain rate). There is a clear need for further work to characterize the structural origins of flow-induced anisotropy and to explore the prospects for improved mechanical and other properties through induced anisotropy.This research was supported by the Engineering and the Engineering and Physical Sciences Research Council, UK (grant EP/I035404/1). Y.H.S. acknowledges support from a China Scholarship Council (CSC) scholarship. The authors thank Z. Lu, H. Y. Bai and W. H. Wang for the supply of the Ce65Al10Cu20Co5 and La55Ni20Al25 metallic glasses.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.actamat.2016.04.02

Choice Architecture to Improve Financial Decision Making

This is the author accepted manuscript. The final version is available from MIT Press via the DOI in this recordWe exploit the principles of choice architecture to evaluate interventions in the market for reloadable prepaid cards. Participants are randomized into three card menu presentation treatments - the market status quo, a regulation-inspired reform, or an enhanced reform designed to minimize attribute overload - and offered choices based on prior structural estimation of individual preferences. Consumers routinely choose incorrectly under the status quo, with tentative evidence the regulation-inspired presentation may increase best card choice, and clear evidence the enhanced reform reduces worst card choice. Welfare analysis suggests the regulation-inspired presentation offers modest gains, while the enhanced policy generates substantial benefits

Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy

OBJECTIVE: Mutations in KCNC1 can cause severe neurological dysfunction, including intellectual disability, epilepsy, and ataxia. The Arg320His variant, which occurs in the voltage-sensing domain of the channel, causes a highly penetrant and specific form of progressive myoclonus epilepsy with severe ataxia, designated myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). KCNC1 encodes the voltage-gated potassium channel KV 3.1, a channel that is important for enabling high-frequency firing in interneurons, raising the possibility that MEAK is associated with reduced interneuronal function. METHODS: To determine how this variant triggers MEAK, we expressed KV 3.1bR320H in cortical interneurons in vitro and investigated the effects on neuronal function and morphology. We also performed electrophysiological recordings of oocytes expressing KV 3.1b to determine whether the mutation introduces gating pore currents. RESULTS: Expression of the KV 3.1bR320H variant profoundly reduced excitability of mature cortical interneurons, and cells expressing these channels were unable to support high-frequency firing. The mutant channel also had an unexpected effect on morphology, severely impairing neurite development and interneuron viability, an effect that could not be rescued by blocking KV 3 channels. Oocyte recordings confirmed that in the adult KV 3.1b isoform, R320H confers a dominant negative loss-of-function effect by slowing channel activation, but does not introduce potentially toxic gating pore currents. SIGNIFICANCE: Overall, our data suggest that, in addition to the regulation of high-frequency firing, KV 3.1 channels play a hitherto unrecognized role in neuronal development. MEAK may be described as a developmental dendritopathy

A laboratory characterisation of inorganic iodine emissions from the sea surface: dependence on oceanic variables and parameterisation for global modelling

Reactive iodine compounds play a significant role in the atmospheric chemistry of the oceanic boundary layer by influencing the oxidising capacity through catalytically removing O3 and altering the HOx and NOx balance. The sea-to-air flux of iodine over the open ocean is therefore an important quantity in assessing these impacts on a global scale. This paper examines the effect of a number of relevant environmental parameters, including water temperature, salinity and organic compounds, on the magnitude of the HOI and I2 fluxes produced from the uptake of O3 and its reaction with iodide ions in aqueous solution. The results of these laboratory experiments and those reported previously (Carpenter et al., 2013), along with sea surface iodide concentrations measured or inferred from measurements of dissolved total iodine and iodate reported in the literature, were then used to produce parameterised expressions for the HOI and I2 fluxes as a function of wind speed, sea-surface temperature and O3. These expressions were used in the Tropospheric HAlogen chemistry MOdel (THAMO) to compare with MAX-DOAS measurements of iodine monoxide (IO) performed during the HaloCAST-P cruise in the eastern Pacific ocean (Mahajan et al., 2012). The modelled IO agrees reasonably with the field observations, although significant discrepancies are found during a period of low wind speeds (< 3 m s&minus;1), when the model overpredicts IO by up to a factor of 3. The inorganic iodine flux contributions to IO are found to be comparable to, or even greater than, the contribution of organo-iodine compounds and therefore its inclusion in atmospheric models is important to improve predictions of the influence of halogen chemistry in the marine boundary layer

Incomplete Punishment Networks in Public Goods Games: Experimental Evidence

Abundant evidence suggests that high levels of contributions to public goods can be sustained through self-governed monitoring and sanctioning. This experimental study investigates the effectiveness of decentralized sanctioning institutions in alternative punishment networks. Our results show that the structure of punishment network significantly affects allocations to the public good. In addition, we observe that network configurations are more important than punishment capacities for the levels of public good provision, imposed sanctions and economic efficiency. Lastly, we show that targeted revenge is a major driver of anti-social punishment

Adolescents’ responses to the promotion and flavouring of e-cigarettes

Objectives The purpose of the study is to examine adolescents’ awareness of e-cigarette marketing and investigate the impact of e-cigarette flavour descriptors on perceptions of product harm and user image. Methods Data come from the 2014 Youth Tobacco Policy Survey, a cross-sectional in-home survey conducted with 11–16 year olds across the UK (n = 1205). Adolescents’ awareness of e-cigarette promotion, brands, and flavours was assessed. Perceptions of product harm, and likely user of four examples of e-cigarette flavours was also examined. Results Some participants had tried e-cigarettes (12 %) but regular use was low (2 %) and confined to adolescents who had also smoked tobacco. Most were aware of at least one promotional channel (82 %) and that e-cigarettes came in different flavours (69 %). Brand awareness was low. E-cigarettes were perceived as harmful (M = 3.54, SD = 1.19) but this was moderated by product flavours. Fruit and sweet flavours were perceived as more likely to be tried by young never smokers than adult smokers trying to quit (p < 0.001). Conclusions There is a need to monitor the impact of future market and regulatory change on youth uptake and perceptions of e-cigarettes

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies