Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967

Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs

Analysis of saccharification in Brachypodium distachyon stems under mild conditions of hydrolysis

Analysis of saccharification in Brachypodium distachyon stems unde

Resurgent and Gating Pore Currents Induced by De Novo SCN2A Epilepsy Mutations

Over 150 mutations in the SCN2A gene, which encodes the neuronal Nav1.2 protein, have been implicated in human epilepsy cases. Of these, R1882Q and R853Q are two of the most commonly reported mutations. This study utilized voltage-clamp electrophysiology to characterize the biophysical effects of the R1882Q and R853Q mutations on the hNav1.2 channel, including their effects on resurgent current and gating pore current, which are not typically investigated in the study of Nav1.2 channel mutations. HEK cells transiently transfected with DNA encoding either wild-type (WT) or mutant hNav1.2 revealed that the R1882Q mutation induced a gain-of-function phenotype, including slowed fast inactivation, depolarization of the voltage dependence of inactivation, and increased persistent current. In this model system, the R853Q mutation primarily produced loss-of-function effects, including reduced transient current amplitude and density, hyperpolarization of the voltage dependence of inactivation, and decreased persistent current. The presence of a Navβ4 peptide (KKLITFILKKTREK-OH) in the pipette solution induced resurgent currents, which were increased by the R1882Q mutation and decreased by the R853Q mutation. Further study of the R853Q mutation in Xenopus oocytes indicated a reduced surface expression and revealed a robust gating pore current at negative membrane potentials, a function absent in the WT channel. This not only shows that different epileptogenic point mutations in hNav1.2 have distinct biophysical effects on the channel, but also illustrates that individual mutations can have complex consequences that are difficult to identify using conventional analyses. Distinct mutations may, therefore, require tailored pharmacotherapies in order to eliminate seizures

Females remate more frequently when mated with sperm-deficient males

Polyandry is a source of sexual conflict and males often try to limit female promiscuity. Consequently, male manipulation of receptivity via antiaphrodisiacs and copulatory plugs that prevent female remating can be a source of sexual conflict. This sexual conflict may be intensified when females must remate for fertility insurance. Male red‐sided garter snakes produce a large, gelatinous copulatory plug that has been proposed to 1) physically prevent remating and 2) contain an antiaphrodisiac that reduces female receptivity. These males may become sperm depleted because of their dissociated reproductive pattern. If a female mates with a sperm deficient male and is also rendered unreceptive to further mating, then this represents a serious conflict. We tested whether female remating frequency is affected when females are mated with a male that produces a sperm‐less copulatory plug. We show that females are significantly more likely to remate after mating with vasectomized males than intact males, even though vasectomized males still produce a copulatory plug. These results suggest that the ejaculate material of the plug does not contain an antiaphrodisiac. Instead, females may use sperm as a cue for post‐copulatory mate assessment and seek to remate for the direct benefit of fertility insurance if they have mated with sperm‐depleted males.Keywords: Sexual conflict, Cryptic female choice, Postcopulatory sexual selection, Garter snake, Sperm limitationKeywords: Sexual conflict, Cryptic female choice, Postcopulatory sexual selection, Garter snake, Sperm limitatio

An Analysis of Spikes in Atmospheric Imaging Assembly (AIA) Data

The Atmospheric Imaging Assembly (AIA) onboard the Solar Dynamics Observatory (SDO) returns high-resolution images of the solar atmosphere in seven extreme ultraviolet (EUV) wavelength channels. The images are processed on the ground to remove intensity spikes arising from energetic particles hitting the instrument, and the despiked images are provided to the community. In this article, a three-hour series of images from the 171 Å channel obtained on 28 February 2017 was studied to investigate how often the despiking algorithm gave false positives caused by compact brightenings in the solar atmosphere. The latter were identified through spikes appearing in the same detector pixel for three consecutive frames. 1096 examples were found from the 900 image frames. These “three-spikes” were assigned to 126 dynamic solar features, and it is estimated that the three-spike method identifies 19% of the total number of features affected by despiking. For any ten-minute sequence of AIA 171 Å images there are around 37 solar features that have their intensity modified by despiking. The features are found in active regions, quiet Sun, and coronal holes and, in relation to solar surface area, there is a greater proportion within coronal holes. In 96% of the cases, the despiked structure is a compact brightening with a size of two arcsec or less, and the remaining 4% have narrow, elongated structures. By applying an EUV burst detection algorithm, we found that 96% of the events could be classified as EUV bursts. None of the spike events are rendered invisible by the AIA processing pipeline, but the total intensity over an event’s lifetime can be reduced by up to 67%. Users are recommended to always restore the original intensities in AIA data when studying short-lived or rapidly evolving features that exhibit fine-scale structure

Sexual conflict over mating in red-sided garter snakes (Thamnophis sirtalis) as indicated by experimental manipulation of genitalia

Sexual conflict over mating can result in sex specific morphologies and behaviors that allow each sex to exert control over the outcome of reproduction. Genital traits, in particular, are often directly involved in conflict interactions. Via genital manipulation, we experimentally investigated whether genital traits in red-sided garter snakes influence copulation duration and formation of a copulatory plug. The hemipenes of male red-sided garter snakes have a large basal spine that inserts into the female cloaca during mating. We ablated the spine and found that males were still capable of copulation but copulation duration was much shorter and copulatory plugs were smaller than those produced by intact males. We also anesthetized the female cloacal region and found that anesthetized females copulated longer than control females, suggesting that female cloacal and vaginal contractions play a role in controlling copulation duration. Both results, combined with known aspects of the breeding biology of red-sided garter snakes, strongly support the idea that sexual conflict is involved in mating interactions in this species. Our results demonstrate the complex interactions among male and female traits generated by coevolutionary processes in a wild population. Such complexity highlights the importance of simultaneous examination of male and female traits.Keywords: Sexual conflict, Genitalia, Garter snakes, Copulation duration, Copulatory plugs, Hemipene, Sexual selectio

The structures underpinning vulnerability: examining landscape-society interactions in a smallholder coffee agroforestry system

Smallholder farmers dependent on rain-fed agriculture are particularly vulnerable to extreme climate events and, therefore, it is necessary to identify adaptive measures that would increase farmer resilience to these shocks. The management options in a low-input system, like forest coffee (Coffea arabica), are limited and there are several factors out of farmers' control driving their vulnerability to changing climatic conditions. These can relate to social structures and landscape factors, which can interact to reduce farmers' adaptive capacity, creating a state of contextual vulnerability. We explored the potential synergies of this interaction across elevation, patch area and shade management gradients for smallholder coffee farms around the UNESCO Yayu Coffee Forest Biosphere Reserve in Ethiopia before, during and immediately following the 2015/16 El Niño. We documented a dramatic collapse in coffee yields across all farms, resulting in coffee incomes 29.5 ± 18.0 % and 19.5 ± 10.0 % of 2014 incomes in 2015 and 2016, respectively. We identified farms at elevations between 1500-1600 m with canopy openness between 40-45 % as being consistently low yielding over our study period. We found these farmers had the highest rates of income diversification and, therefore, were already exhibiting adaptive capacity. Farmers with the largest income losses were spatially concentrated between 1600-1700 m, located in larger patch areas with lower canopy openness. Farmers at this elevation have access to poor infrastructure, restrictions on shade management and reported higher dependence on income from coffee, indicating an interaction of biotic and social factors exacerbating their vulnerability. Unfortunately, due to a nationally declared state of emergency, we were unable to survey farmers on the adaptive measures they undertook; therefore, we are limited in assessing their resilience. However, we do show the importance of considering both biotically and socially-mediated influences for assessing smallholder vulnerability, particularly barriers to diversifying incomes

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system