The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1

Background The synthetic chemical 1,4-dioxane is used as industrial solvent, food, and care product additive. 1,4-Dioxane has been noted to influence the nervous system in long-term animal experiments and in humans, but the molecular mechanisms underlying its effects on animals were not previously known. Results Here, we report that 1,4-dioxane potentiates the capsaicin-sensitive transient receptor potential (TRP) channel TRPV1, thereby causing hyperalgesia in mouse model. This effect was abolished by CRISPR/Cas9-mediated genetic deletion of TRPV1 in sensory neurons, but enhanced under inflammatory conditions. 1,4-Dioxane lowered the temperature threshold for TRPV1 thermal activation and potentiated the channel sensitivity to agonistic stimuli. 1,3-dioxane and tetrahydrofuran which are structurally related to 1,4-dioxane also potentiated TRPV1 activation. The residue M572 in the S4-S5 linker region of TRPV1 was found to be crucial for direct activation of the channel by 1,4-dioxane and its analogs. A single residue mutation M572V abrogated the 1,4-dioxane-evoked currents while largely preserving the capsaicin responses. Our results further demonstrate that this residue exerts a gating effect through hydrophobic interactions and support the existence of discrete domains for multimodal gating of TRPV1 channel. Conclusions Our results suggest TRPV1 is a co-receptor for 1,4-dioxane and that this accounts for its ability to dysregulate body nociceptive sensation.

Drug-Induced Phase Separation in Polyelectrolyte Microgels

Polyelectrolyte microgels may undergo volume phase transition upon loading and the release of amphiphilic molecules, a process important in drug delivery. The new phase is “born” in the outermost gel layers, whereby it grows inward as a shell with a sharp boundary to the “mother” phase (core). The swelling and collapse transitions have previously been studied with microgels in large solution volumes, where they go to completion. Our hypothesis is that the boundary between core and shell is stabilized by thermodynamic factors, and thus that collapsed and swollen phases should be able to also coexist at equilibrium. We investigated the interaction between sodium polyacrylate (PA) microgel networks (diameter: 400–850 µm) and the amphiphilic drug amitriptyline hydrochloride (AMT) in the presence of NaCl/phosphate buffer of ionic strength (I) 10 and 155 mM. We used a specially constructed microscopy cell and micromanipulators to study the size and internal morphology of single microgels equilibrated in small liquid volumes of AMT solution. To probe the distribution of AMT micelles we used the fluorescent probe rhodamine B. The amount of AMT in the microgel was determined by a spectrophotometric technique. In separate experiments we studied the binding of AMT and the distribution between different microgels in a suspension. We found that collapsed, AMT-rich, and swollen AMT-lean phases coexisted in equilibrium or as long-lived metastable states at intermediate drug loading levels. In single microgels at I = 10 mM, the collapsed phase formed after loading deviated from the core-shell configuration by forming either discrete domains near the gel boundary or a calotte shaped domain. At I = 155 mM, single microgels, initially fully collapsed, displayed a swollen shell and a collapsed core after partial release of the AMT load. Suspensions displayed a bimodal distribution of swollen and collapsed microgels. The results support the hypothesis that the boundary between collapsed and swollen phases in the same microgel is stabilized by thermodynamic factors.

Attraction Basins in Metaheuristics: A Systematic Mapping Study

Context: In this study, we report on a Systematic Mapping Study (SMS) for attraction basins in the domain of metaheuristics. Objective: To identify research trends, potential issues, and proposed solutions on attraction basins in the field of metaheuristics. Research goals were inspired by the previous paper, published in 2021, where attraction basins were used to measure exploration and exploitation. Method: We conducted the SMS in the following steps: Defining research questions, conducting the search in the ISI Web of Science and Scopus databases, full-text screening, iterative forward and backward snowballing (with ongoing full-text screening), classifying, and data extraction. Results: Attraction basins within discrete domains are understood far better than those within continuous domains. Attraction basins on dynamic problems have hardly been investigated. Multi-objective problems are investigated poorly in both domains, although slightly more often within a continuous domain. There is a lack of parallel and scalable algorithms to compute attraction basins and a general framework that would unite all different definitions/implementations used for attraction basins. Conclusions: Findings regarding attraction basins in the field of metaheuristics reveal that the concept alone is poorly exploited, as well as identify open issues where researchers may improve their research.

Decision branch joint venture ex-fold T-z re-validation

Comparing classifier performances may seem a banal affair but makes a side show in machine learning. Usually the paired t-test is used. It requires that two classifiers were run simultaneously or this was simulated. This is not always possible and then entails creating a superstructure only for that purpose. However, the utility of t-test in the given context is altogether doubted. The literature on alternatives is much involved. This does not measure up to the scale of the issue. In this paper the topics in connection with accuracy calculation are surveyed once more, emphasizing the result variation. The known technique of multifold cross-validation is exemplified. A simplified methodology for comparison of classifier performances is proposed. It is based on the accuracy mean and variance and calculating differences between objects defined in these terms. It is being applied to the naive Bayesian and decision tree classifiers implemented on different platforms. The lazy learning approach, applicable to decision trees in discrete domains, is closely followed with an imposition of how it can be improved. Examples are given from the field of health diagnostics.

‘Are We An Experiment?’ Informality as Indispensable for Syrians’ Resettlement in the UK

This article unpacks the status and significance of informal social infrastructures within the Syrian Vulnerable Person’s Resettlement Scheme (SVPRS) in one region of the UK to offer a case study exemplifying an enduring and renewed political embeddedness of informalities as an idiosyncratically British way of governing migrant incorporation and producing social order. From the perspective of the scheme’s formal design, this was ‘bottom-up’, ‘community-led’ activity for community or ‘social’ integration. For refugees this was the existence and availability of a quality of sociality productive of a sense of existence and a viable and possible life, in other words, defining – above and beyond discrete domains or material things - what had been hoped for and expected from resettlement. Where this ‘informal social infrastructure’ was available, refugees conveyed an experience of positive processes of life, resonating with discussions of existential movement. Where unavailable refugees conveyed experience of a persistent or even worsened sense of biographical interruption that forced migration has been likened to. The article aims to contribute to informalities scholarship in relation to the imbrication of informal-formal as means of governance and attest to the significance of informalities to the reduction of uncertainty, production of stability.

Microtubules orchestrate local translation to enable cardiac growth

Hypertension, exercise, and pregnancy are common triggers of cardiac remodeling, which occurs primarily through the hypertrophy of individual cardiomyocytes. During hypertrophy, stress-induced signal transduction increases cardiomyocyte transcription and translation, which promotes the addition of new contractile units through poorly understood mechanisms. The cardiomyocyte microtubule network is also implicated in hypertrophy, but via an unknown role. Here, we show that microtubules are indispensable for cardiac growth via spatiotemporal control of the translational machinery. We find that the microtubule motor Kinesin-1 distributes mRNAs and ribosomes along microtubule tracks to discrete domains within the cardiomyocyte. Upon hypertrophic stimulation, microtubules redistribute mRNAs and new protein synthesis to sites of growth at the cell periphery. If the microtubule network is disrupted, mRNAs and ribosomes collapse around the nucleus, which results in mislocalized protein synthesis, the rapid degradation of new proteins, and a failure of growth, despite normally increased translation rates. Together, these data indicate that mRNAs and ribosomes are actively transported to specific sites to facilitate local translation and assembly of contractile units, and suggest that properly localized translation – and not simply translation rate – is a critical determinant of cardiac hypertrophy. In this work, we find that microtubule based-transport is essential to couple augmented transcription and translation to productive cardiomyocyte growth during cardiac stress.