Energetics of discrete selectivity bands and mutation-induced transitions in the calcium-sodium ion channels family

We use Brownian dynamics (BD) simulations to study the ionic conduction and valence selectivity of a generic electrostatic model of a biological ion channel as functions of the fixed charge Qf at its selectivity filter. We are thus able to reconcile the discrete calcium conduction bands recently revealed in our BD simulations, M0 (Qf = 1e), M1 (3e), M2 (5e), with a set of sodium conduction bands L0 (0.5e), L1 (1.5e), thereby obtaining a completed pattern of conduction and selectivity bands vs Qf for the sodium-calcium channels family. An increase of Qf leads to an increase of calcium selectivity: L0 (sodium-selective, nonblocking channel) → M0 (nonselective channel) → L1 (sodium-selective channel with divalent block) → M1 (calcium-selective channel exhibiting the anomalous mole fraction effect). We create a consistent identification scheme where the L0 band is putatively identified with the eukaryotic sodium channel The scheme created is able to account for the experimentally observed mutation-induced transformations between nonselective channels, sodium selective channels, and calcium-selective channels, which we interpret as transitions between different rows of the identification table. By considering the potential energy changes during permeation, we show explicitly that the multi-ion conduction bands of calcium and sodium channels arise as the result of resonant barrierless conduction. The pattern of periodic conduction bands is explained on the basis of sequential neutralization taking account of self-energy, as Qf (z,i) = ze(1/2 + i), where i is the order of the band and z is the valence of the ion. Our results confirm the crucial influence of electrostatic interactions on conduction and on the Ca2+/Na+ valence selectivity of calcium and sodium ion channels. The model and results could be also applicable to biomimetic nanopores with charged walls

Stochastic dynamics of remote knock-on permeation in biological ion channels

Brownian dynamics simulations provide evidence for a remote knock-on mechanism facilitating the permeation of a biological ion channel by an ion that is initially trapped at the selectivity filter (SF). Unlike the case of conventional direct knock-on, the second ion that instigates permeation does not need to enter the channel. Nor does it necessarily take the place of the permeating ion at the SF, and it can even be of a different ionic species. The study is based on the simultaneous, self-consistent, solution of the coupled Poisson and Langevin equations for a simple generic model, taking account of all the charges present. The new permeation mechanism involves electrostatic amplification attributable to the permittivity mismatch between water and protein: the arrival of the instigating ion at the channel entrance reduces the exit barrier for the ion trapped at the SF, facilitating escape

Self-organized enhancement of conductivity in biological ion channels

We discuss an example of self-organization in a biological system. It arises from long-range ion–ion interactions, and it leads us to propose a new kind of enhanced conduction in ion channels. The underlying mechanism involves charge fluctuations near the channel mouth, amplified by the mismatch between the relative permittivities of water and the protein of the channel walls. We use Brownian dynamics simulations to show that, as in conventional 'knock on' permeation, these interactions can strongly enhance the channel current; but unlike the conventional mechanism, the enhancement occurs without the instigating bath ion entering the channel. The transition between these two mechanisms is clearly demonstrated, emphasizing their distinction. A simple model accurately reproduces the observed phenomena. We point out that electrolyte plus protein of low relative permittivity are universal in living systems, so that long-range ion–ion correlations of the kind considered must be common

The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes.

Activation of the inflammasome pathway is crucial for effective intracellular host defense. The mitochondrial network plays an important role in inflammasome regulation but the mechanisms linking mitochondrial homeostasis to attenuation of inflammasome activation are not fully understood. Here, we report that the Parkinson\u27s disease-associated mitochondrial serine protease HtrA2 restricts the activation of ASC-dependent NLRP3 and AIM2 inflammasomes, in a protease activity-dependent manner. Consistently, disruption of the protease activity of HtrA2 results in exacerbated NLRP3 and AIM2 inflammasome responses in macrophages ex vivo and systemically in vivo. Mechanistically, we show that the HtrA2 protease activity regulates autophagy and controls the magnitude and duration of inflammasome signaling by preventing prolonged accumulation of the inflammasome adaptor ASC. Our findings identify HtrA2 as a non-redundant mitochondrial quality control effector that keeps NLRP3 and AIM2 inflammasomes in check

Making sense of methods – a conversation about qualitative research in library and information studies

Currently there is an embarrassment of riches with regards to the range of research methods appropriate for library and information studies [LIS]; including qualitative and quantitative methods as well as ‘mixed methods’. All of this provides a rich body of resources for researchers, but this abundance also has a downside since it can also result in confusion and perplexity amongst researchers as they plan their investigative studies. Contributions such as this special issue are welcome opportunities to resolve and ameliorate this situation, and so in our contribution we seek to address some of these issues in the form of an interchange between two researchers with interests that include, but are not limited to, research in LIS. Between us we have a wide range of publications, as well as 80 plus PhD completions, many of which fall under the heading of LIS – broadly conceived. In particular we would claim specific expertise in Grounded Theory [Bryant] and Action Research [Abbott-Halpin]. Our aim is to seek clarification of some of the key methodological issues; although we realize that this is unlikely to provide any definitive outcome, it may assist those seeking guidance on these matters

Production of Acacia auriculiformis A. Cunn. ex Benth. for reforestation in southern Benin

The viability of Acacia auriculiformis production system in southern Benin was studied from an analytical perspective combining the production techniques and the financial profitability. The driving research question was as follows: "Will the nurseries be able to supply the seedlings suited to successful reforestation programmes?" A survey was carried out among nursery holders in the Atlantique Department. The snowball sampling method enabled to survey 55 nursery holders, based on semi-structured interviews. Respondents provided data on the organisation of production, production techniques, production costs, and sales revenues. There were two types of nurseries: individual nurseries and collective nurseries. The stages of acacia seedlings production were as follows: seed collection, dormancy breaking, sowing, and cares for young seedlings. Overall, the production techniques used by nursery holders were effective. The net revenue for 1000 seedlings ranged between XOF 9000 and 26000. Collective nurseries had lower production costs, hence higher revenues, compared to individual nurseries. It is essential to support nursery holders through capacity strengthening training and the availability of good quality seeds

Reducing Delirium in Patients with COVID-19

The purpose of our critically appraised topic is to synthesize the best current evidence regarding interventions that would be effective in reducing delirium in patients with COVID-19 in the acute care setting. The final portfolio contains a total of five research articles. Study designs include three randomized controlled trials, one non randomized controlled trial, and one quasi-experimental quantitative design. All studies relate directly to interventions within the OT scope of practice and were implemented in the acute care setting. Due to limited research on the novel coronavirus, these findings apply to critically ill patients but are not specific to patients with COVID-19. Early and intensive OT intervention in combination with multicomponent intervention strategies were found to significantly decrease delirium. Promising evidence can be used to draft new practice guidelines for decreasing delirium in critically ill patients within the acute care setting. In addition, modified implementation of slow tempo music and family participation/visitation interventions are recommended for patients with COVID-19. Due to the minimal time for therapy interventions within the acute care setting, implementation of these interventions as frequently as possible is recommended

Apparent Densities of Stomoxys Species (Diptera, Muscidae) of Different Physiological Ages Caught with Vavoua Trap Differ With Landscape and Trapping Period

Stable flies (Stomoxys spp.) are common pests of livestock in the peri-urban rangelands of Vina Division of the Adamawa Plateau. No documented information is available on their diurnal dynamics in relation to physiological age and landscape. The main aim of this study was to determine the trap apparent density (ADT) of Stomoxys and associate it to their diurnal activity rhythm and landscape. Vavoua traps (n=12) were used for Stomoxys collection. Trapping was carried out for seven days i.e. three days consecutively in August and four days consecutively in October, 2016.Three traps were pitched in each of the three biotopes (river, cattle corral and gallery forest) of the four study sites (Galim, Mbidjoro, Velambai and Soukourwo). All female Stomoxys captured underwent ovarian dissection for the determination of their physiological ages (parous or nulliparous). A total of 218 Stomoxys were caught and identified into four species (S. niger niger, S. omega, S. calcitrans, and S.xanthomelas) with an overall ADT of 2.59 flies per trap per day and Stomoxys niger niger (1.13 s.n.n. per trap per day) recorded the highest ADT. Species richness was study site dependent.Higher catches of females 113 (51.83%) were made than that of their male 105 (48.17%) counterparts. Galim recorded the highest Stomoxys apparent density (4.90) as compared to other sites with a statistically significant difference (P<0.05). The proportion of parous 87 (59.30%) was higher than that of their nulliparous 46 (40.71%) counterparts. Parity differed with landscape and capture periods. S. n. niger was the most frequent in all biotopes and Galim recorded the highest ADT. The population of female flies was made up of adults (parous) with a bimodal diurnal activity rhythm whereas males had a unimodal activity rhythm.

Epistasis not needed to explain low dN/dS

An important question in molecular evolution is whether an amino acid that occurs at a given position makes an independent contribution to fitness, or whether its effect depends on the state of other loci in the organism's genome, a phenomenon known as epistasis. In a recent letter to Nature, Breen et al. (2012) argued that epistasis must be "pervasive throughout protein evolution" because the observed ratio between the per-site rates of non-synonymous and synonymous substitutions (dN/dS) is much lower than would be expected in the absence of epistasis. However, when calculating the expected dN/dS ratio in the absence of epistasis, Breen et al. assumed that all amino acids observed in a protein alignment at any particular position have equal fitness. Here, we relax this unrealistic assumption and show that any dN/dS value can in principle be achieved at a site, without epistasis. Furthermore, for all nuclear and chloroplast genes in the Breen et al. dataset, we show that the observed dN/dS values and the observed patterns of amino acid diversity at each site are jointly consistent with a non-epistatic model of protein evolution.Comment: This manuscript is in response to "Epistasis as the primary factor in molecular evolution" by Breen et al. Nature 490, 535-538 (2012

Exploring the Performance of Methods to Deal Multicollinearity: Simulation and Real Data in Radiation Epidemiology Area

The issue of multicollinearity has long been acknowledged in statistical modelling; however, it is often untreated in the most of published papers. Indeed, the use of methods for multicollinearity correction is still scarce. One important reason is that despite many proposed methods, little is known about their strength or performance. We compare the statistical properties and performance of four main techniques to correct multicollinearity, i.e., Ridge Regression (R-R), Principal Components Regression (PC-R), Partial Least Squares Regression (PLS-R), and Lasso Regression (L-R), in both a simulation study and two real data examples used for modelling volumes of heart and Thyroid as a function of clinical and anthropometric parameters. We find that when the statistical approaches were used to address different levels of collinearity, we observed that R-R, PC-R and PLS-R appeared to have a somewhat similar behavior, with a slight advantage for the PLS-R. Indeed, in all implemented cases, the PLS-R always provided the smallest value of root mean square error (RMSE). When the degree of collinearity was moderate, low or very low, the L-R method had also somewhat similar performance to other methods. Furthermore, correction methods allowed us to provide stable and trustworthy parameter estimates for predictors in the modelling of heart and Thyroid volumes. Therefore, this work will contribute to highlighting performances of methods used only for situations ranging from low to very high multicollinearity