A cis-regulatory sequence driving metabolic insecticide resistance in mosquitoes: Functional characterisation and signatures of selection

Although cytochrome P450 (CYP450) enzymes are frequently up-regulated in mosquitoes resistant to insecticides, no regulatory motifs driving these expression differences with relevance to wild populations have been identified. Transposable elements (TEs) are often enriched upstream of those CYP450s involved in insecticide resistance, leading to the assumption that they contribute regulatory motifs that directly underlie the resistance phenotype. A partial CuRE1 (Culex Repetitive Element 1) transposable element is found directly upstream of CYP9M10, a cytochrome P450 implicated previously in larval resistance to permethrin in the ISOP450 strain of Cx. quinquefasciatus, but is absent from the equivalent genomic region of a susceptible strain. Via expression of CYP9M10 in E.coli we have now demonstrated time- and NADPH-dependant permethrin metabolism, prerequisites for confirmation of a role in metabolic resistance, and through qPCR shown that CYP9M10 is >20-fold over-expressed in ISOP450 compared to a susceptible strain. In a fluorescent reporter assay the region upstream of CYP9M10 from ISOP450 drove 10x expression compared to the equivalent region (lacking CuRE1) from the susceptible strain. Close correspondence with the gene expression fold-change implicates the upstream region including CuRE1 as a cis-regulatory element involved in resistance. Only a single CuRE1 bearing allele, identical to the CuRE1 bearing allele in the resistant strain, is found throughout Sub-Saharan Africa, in contrast to the diversity encountered in non-CuRE1 alleles. This suggests a single origin and subsequent spread due to selective advantage. CuRE1 is detectable using a simple diagnostic. When applied to Cx. quinquefasciatus larvae from Ghana we have demonstrated a significant association with permethrin resistance in multiple field sites (mean Odds Ratio = 3.86) suggesting this marker has relevance to natural populations of vector mosquitoes. However, when CuRE1 was excised from the allele used in the reporter assay through fusion PCR, expression was unaffected, indicating that the TE has no direct role in resistance and hence that CuRE1 is acting only as a marker of an as yet unidentified regulatory motif in the association analysis. This suggests that a re-evaluation of the assumption that TEs contribute regulatory motifs involved in gene expression may be necessary

Markers of criticality in phase synchronization

The concept of the brain as a critical dynamical system is very attractive because systems close to criticality are thought to maximize their dynamic range of information processing and communication. To date, there have been two key experimental observations in support of this hypothesis: (i) neuronal avalanches with power law distribution of size and (ii) long-range temporal correlations (LRTCs) in the amplitude of neural oscillations. The case for how these maximize dynamic range of information processing and communication is still being made and because a significant substrate for information coding and transmission is neural synchrony it is of interest to link synchronization measures with those of criticality. We propose a framework for characterizing criticality in synchronization based on an analysis of the moment-to-moment fluctuations of phase synchrony in terms of the presence of LRTCs. This framework relies on an estimation of the rate of change of phase difference and a set of methods we have developed to detect LRTCs. We test this framework against two classical models of criticality (Ising and Kuramoto) and recently described variants of these models aimed to more closely represent human brain dynamics. From these simulations we determine the parameters at which these systems show evidence of LRTCs in phase synchronization. We demonstrate proof of principle by analysing pairs of human simultaneous EEG and EMG time series, suggesting that LRTCs of corticomuscular phase synchronization can be detected in the resting state and experimentally manipulated. The existence of LRTCs in fluctuations of phase synchronization suggests that these fluctuations are governed by non-local behavior, with all scales contributing to system behavior. This has important implications regarding the conditions under which one should expect to see LRTCs in phase synchronization. Specifically, brain resting states may exhibit LRTCs reflecting a state of readiness facilitating rapid task-dependent shifts toward and away from synchronous states that abolish LRTCs

Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics

cited By 0Balance between excitation (E) and inhibition (I) is a key principle for neuronal network organization and information processing. Consistent with this notion, excitation-inhibition imbalances are considered a pathophysiological mechanism in many brain disorders including autism spectrum disorder (ASD). However, methods to measure E/I ratios in human brain networks are lacking. Here, we present a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it in healthy subjects and children with ASD. We define structural E/I ratio in an in silico neuronal network, investigate how it relates to power and long-range temporal correlations (LRTC) of the network's activity, and use these relationships to design the fE/I algorithm. Application of this algorithm to the EEGs of healthy adults showed that fE/I is balanced at the population level and is decreased through GABAergic enforcement. In children with ASD, we observed larger fE/I variability and stronger LRTC compared to typically developing children (TDC). Interestingly, visual grading for EEG abnormalities that are thought to reflect E/I imbalances revealed elevated fE/I and LRTC in ASD children with normal EEG compared to TDC or ASD with abnormal EEG. We speculate that our approach will help understand physiological heterogeneity also in other brain disorders.Peer reviewe

Hyperpolarised xenon MRI and time-resolved X-ray computed tomography studies of structure-transport relationships in hierarchical porous media

© 2020 Elsevier B.V. Catalysed diesel particulate filter (DPF) monoliths are hierarchical porous solids, as demonstrated by mercury porosimetry. Establishing structure-transport relationships, including assessing the general accessibility of the catalyst, is challenging, and, thus, a comprehensive approach is necessary. Contributions, from each porosity level, to transport have been established using hyperpolarised (hp) xenon-129 magnetic resonance imaging (MRI) of gas dispersion within DPF monoliths at variable water saturation, since X-ray Computerised-Tomography, and 1H and 2H NMR methods, have shown that porosity levels dry out progressively. At high saturation, hp 129Xe MRI showed gas transport between the channels of the monolith is predominantly taking place at channel wall intersections with high macroporosity. The walls themselves make a relatively small contribution to through transport due to the distribution of the micro-/meso-porous washcoat layer away from intersections. Only at low saturation, when the smallest pores are opened, do hp 129Xe MR images became strongly affected by relaxation. This observation indicates accessibility of paramagnetic (catalytic) centres for gases arises only once the smallest pores are open

Blocking the evolution of insecticide-resistant malaria vectors with a microsporidian

Finding a way to block the evolution insecticide resistance would be a major breakthrough for the control of malaria. We suggest that this may be possible by introducing a stress into mosquito populations that restores the sensitivity of genetically resistant mosquitoes and that decreases their longevity when they are not exposed to insecticide. We use a mathematical model to show that, despite the intense selection pressure imposed by insecticides, moderate levels of stress might tip the evolutionary balance between costs and benefits of resistance toward maintaining sensitivity. Our experimental work with the microsporidian parasite Vavraia culicis infecting two lines of resistant mosquitoes and a sensitive line suggests that it may indeed be possible to stress the mosquitoes in the required way. The mortality of resistant mosquitoes 24 h after exposure to the insecticide was up to 8.8 times higher in infected than in uninfected ones; if mosquitoes were not exposed to the insecticide, resistant mosquitoes infected by the microsporidian lived about half as long as uninfected ones and insecticide-sensitive mosquitoes (with or without the parasite). Our results suggest that biopesticides or other insecticides that interfere with the expression of resistance may help to manage insecticide resistance in programs of malaria control

Modeling the ongoing dynamics of short and long-range temporal correlations in broadband EEG during movement

Electroencephalogram (EEG) undergoes complex temporal and spectral changes during voluntary movement intention. Characterization of such changes has focused mostly on narrowband spectral processes such as Event-Related Desynchronization (ERD) in the sensorimotor rhythms because EEG is mostly considered as emerging from oscillations of the neuronal populations. However, the changes in the temporal dynamics, especially in the broadband arrhythmic EEG have not been investigated for movement intention detection. The Long-Range Temporal Correlations (LRTC) are ubiquitously present in several neuronal processes, typically requiring longer timescales to detect. In this paper, we study the ongoing changes in the dynamics of long- as well as short-range temporal dependencies in the single trial broadband EEG during movement intention. We obtained LRTC in 2 s windows of broadband EEG and modeled it using the Autoregressive Fractionally Integrated Moving Average (ARFIMA) model which allowed simultaneous modeling of short- and long-range temporal correlations. There were significant (p < 0.05) changes in both broadband long- and short-range temporal correlations during movement intention and execution. We discovered that the broadband LRTC and narrowband ERD are complementary processes providing distinct information about movement because eliminating LRTC from the signal did not affect the ERD and conversely, eliminating ERD from the signal did not affect LRTC. Exploring the possibility of applications in Brain Computer Interfaces (BCI), we used hybrid features with combinations of LRTC, ARFIMA, and ERD to detect movement intention. A significantly higher (p < 0.05) classification accuracy of 88.3 ± 4.2% was obtained using the combination of ARFIMA and ERD features together, which also predicted the earliest movement at 1 s before its onset. The ongoing changes in the long- and short-range temporal correlations in broadband EEG contribute to effectively capturing the motor command generation and can be used to detect movement successfully. These temporal dependencies provide different and additional information about the movement

The Parkinsonian subthalamic network: measures of power, linear, and non-linear synchronization and their relationship to L-DOPA treatment and OFF state motor severity

In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5–12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15–20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics