Modulation of potassium channels inhibits bunyavirus infection

Bunyaviruses are considered to be emerging pathogens facilitated by the segmented nature of their genome that allows reassortment between different species to generate novel viruses with altered pathogenicity. Bunyaviruses are transmitted via a diverse range of arthropod vectors, as well as rodents, and have established a global disease range with massive importance in healthcare, animal welfare and economics. There are no vaccines or anti-viral therapies available to treat human bunyavirus infections and so development of new anti-viral strategies is urgently required. Bunyamwera virus (BUNV; genus Orthobunyavirus) is the model bunyavirus, sharing aspects of its molecular and cellular biology with all Bunyaviridae family members. Here, we show for the first time that BUNV activates and requires cellular potassium (K+) channels to infect cells. Time of addition assays using K+ channel modulating agents demonstrated that K+ channel function is critical to events shortly after virus entry but prior to viral RNA synthesis/replication. A similar K+ channel dependence was identified for other bunyaviruses namely Schmallenberg virus (Orthobunyavirus) as well as the more distantly related Hazara virus (Nairovirus). Using a rational pharmacological screening regimen, twin-pore domain K+ channels (K2P) were identified as the K+ channel family mediating BUNV K+ channel dependence. As several K2P channel modulators are currently in clinical use, our work suggests they may represent a new and safe drug class for the treatment of potentially lethal bunyavirus disease.

Modulation of equatorial Pacific westerly/easterly wind events by the Madden-Julian oscillation and convectively-coupled Rossby waves

Synoptic wind events in the equatorial Pacific strongly influence the El Niño/Southern Oscillation (ENSO) evolution. This paper characterizes the spatio-temporal distribution of Easterly (EWEs) and Westerly Wind Events (WWEs) and quantifies their relationship with intraseasonal and interannual large-scale climate variability. We unambiguously demonstrate that the Madden–Julian Oscillation (MJO) and Convectively-coupled Rossby Waves (CRW) modulate both WWEs and EWEs occurrence probability. 86 % of WWEs occur within convective MJO and/or CRW phases and 83 % of EWEs occur within the suppressed phase of MJO and/or CRW. 41 % of WWEs and 26 % of EWEs are in particular associated with the combined occurrence of a CRW/MJO, far more than what would be expected from a random distribution (3 %). Wind events embedded within MJO phases also have a stronger impact on the ocean, due to a tendency to have a larger amplitude, zonal extent and longer duration. These findings are robust irrespective of the wind events and MJO/CRW detection methods. While WWEs and EWEs behave rather symmetrically with respect to MJO/CRW activity, the impact of ENSO on wind events is asymmetrical. The WWEs occurrence probability indeed increases when the warm pool is displaced eastward during El Niño events, an increase that can partly be related to interannual modulation of the MJO/CRW activity in the western Pacific. On the other hand, the EWEs modulation by ENSO is less robust, and strongly depends on the wind event detection method. The consequences of these results for ENSO predictability are discussed.

The role of local atmospheric forcing on the modulation of the ocean mixed layer depth in reanalysis and a coupled single column ocean model

The role of the local atmospheric forcing on the ocean mixed layer depth (MLD) over the global oceans is studied using ocean reanalysis data products and a single-column ocean model coupled to an atmospheric general circulation model. The focus of this study is on how the annual mean and the seasonal cycle of the MLD relate to various forcing characteristics in different parts of the world's ocean, and how anomalous variations in the monthly mean MLD relate to anomalous atmospheric forcings. By analysing both ocean reanalysis data and the single-column ocean model, regions with different dominant forcings and different mean and variability characteristics of the MLD can be identified. Many of the global oceans' MLD characteristics appear to be directly linked to different atmospheric forcing characteristics at different locations. Here, heating and wind-stress are identified as the main drivers; in some, mostly coastal, regions the atmospheric salinity forcing also contributes. The annual mean MLD is more closely related to the annual mean wind-stress and the MLD seasonality is more closely to the seasonality in heating. The single-column ocean model, however, also points out that the MLD characteristics over most global ocean regions, and in particular the tropics and subtropics, cannot be maintained by local atmospheric forcings only, but are also a result of ocean dynamics that are not simulated in a single-column ocean model. Thus, lateral ocean dynamics are essentially in correctly simulating observed MLD.

Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1R antagonists. Of further interest are various findings that CB1R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

Corticomuscular coherence modulation with the pattern of finger force coordination

We assess the corticomuscular coherence (CMC) of the contralateral primary motor cortex and the hand muscles during a finger force-tracking task and explore whether the pattern of finger coordination has an impact on the CMC level. Six healthy subjects (three men and three women) were recruited to conduct the force-tracking tasks comprising two finger patterns, i.e., natural combination of index and middle fingers and unnatural combination of index and middle fingers (i.e., simultaneously producing equal force strength in index and middle finger). During the conducting of the tasks with right index and middle finger, MEG and sEMG signals were recorded from left primary motor cortex (M1) and right flexor digitorum superficialis (FDS), respectively; the contralateral CMC was calculated to assess the neuromuscular interaction. Finger force-tracking tasks of Common-IM only induce beta-band CMC, whereas Uncommon-IM tasks produce CMC in both beta and low-gamma band. Compared to the force-tracking tasks of Common-IM, the Uncommon-IM task is associated with the most intensive contralateral CMC. Our study demonstrated that the pattern of finger coordination had significant impact on the CMC between the contralateral M1 and hand muscles, and more corticomuscular interaction was necessary for unnaturally coordinated finger activities to regulate the fixed neural drive of hand muscles.

Peptide based hydrogels for cancer drug release: modulation of stiffness, drug release and proteolytic stability of hydrogels by incorporating D-amino acid residue(s)

Synthetic tripeptide based noncytotoxic hydrogelators have been discovered for releasing an anticancer drug at physiological pH and temparature. Interestingly, gel stiffness, drug release capacity and proteolytic stability of these hydrogels have been successfully modulated by incorporating D-amino acid residues, indicating their potential use for drug delivery in the future.