They all rock: A systematic comparison of conformational movements in LeuT-fold transporters.

Many membrane transporters share the LeuT fold-two five-helix repeats inverted across the membrane plane. Despite hundreds of structures, whether distinct conformational mechanisms are supported by the LeuT fold has not been systematically determined. After annotating published LeuT-fold structures, we analyzed distance difference matrices (DDMs) for nine proteins with multiple available conformations. We identified rigid bodies and relative movements of transmembrane helices (TMs) during distinct steps of the transport cycle. In all transporters, the bundle (first two TMs of each repeat) rotates relative to the hash (third and fourth TMs). Motions of the arms (fifth TM) to close or open the intracellular and outer vestibules are common, as is a TM1a swing, with notable variations in the opening-closing motions of the outer vestibule. Our analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock and demonstrate that systematic analyses can provide new insights into large structural datasets.

Residential exposure to traffic pollution and mammographic density in premenopausal women.

BACKGROUND: Mammographic density (MD) is the most important breast cancer biomarker. Ambient pollution is a carcinogen, and its relationship with MD is unclear. This study aims to explore the association between exposure to traffic pollution and MD in premenopausal women. METHODOLOGY: This Spanish cross-sectional study involved 769 women attending gynecological examinations in Madrid. Annual Average Daily Traffic (AADT), extracted from 1944 measurement road points provided by the City Council of Madrid, was weighted by distances (d) between road points and women's addresses to develop a Weighted Traffic Exposure Index (WTEI). Three methods were employed: method-1 (1dAADT), method-2 (1dAADT), and method-3 (e1dAADT). Multiple linear regression models, considering both log-transformed percentage of MD and untransformed MD, were used to estimate MD differences by WTEI quartiles, through two strategies: "exposed (exposure buffers between 50 and 200 m) vs. not exposed (>200 m)"; and "degree of traffic exposure". RESULTS: Results showed no association between MD and traffic pollution according to buffers of exposure to the WTEI (first strategy) for the three methods. The highest reductions in MD, although not statistically significant, were detected in the quartile with the highest traffic exposure. For instance, method-3 revealed a suggestive inverse trend (eßQ1 = 1.23, eßQ2 = 0.96, eßQ3 = 0.85, eßQ4 = 0.85, p-trend = 0.099) in the case of 75 m buffer. Similar non-statistically significant trends were observed with Methods-1 and -2. When we examined the effect of traffic exposure considering all the 1944 measurement road points in every participant (second strategy), results showed no association for any of the three methods. A slightly decreased MD, although not significant, was observed only in the quartile with the highest traffic exposure: eßQ4 = 0.98 (method-1), and eßQ4 = 0.95 (methods-2 and -3). CONCLUSIONS: Our results showed no association between exposure to traffic pollution and MD in premenopausal women. Further research is needed to validate these findings.

They all rock: A systematic comparison of conformational movements in LeuT-fold transporters.

Many membrane transporters share the LeuT fold-two five-helix repeats inverted across the membrane plane. Despite hundreds of structures, whether distinct conformational mechanisms are supported by the LeuT fold has not been systematically determined. After annotating published LeuT-fold structures, we analyzed distance difference matrices (DDMs) for nine proteins with multiple available conformations. We identified rigid bodies and relative movements of transmembrane helices (TMs) during distinct steps of the transport cycle. In all transporters the bundle (first two TMs of each repeat) rotates relative to the hash (third and fourth TMs). Motions of the arms (fifth TM) to close or open the intracellular and outer vestibules are common, as is a TM1a swing, with notable variations in the opening-closing motions of the outer vestibule. Our analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock and demonstrate that systematic analyses can provide new insights into large structural datasets.

Two adjacent NLR genes conferring quantitative resistance to clubroot disease in Arabidopsis are regulated by a stably inherited epiallelic variation.

Clubroot caused by the protist Plasmodiophora brassicae is a major disease affecting cultivated Brassicaceae. Using a combination of quantitative trait locus (QTL) fine mapping, CRISPR-Cas9 validation, and extensive analyses of DNA sequence and methylation patterns, we revealed that the two adjacent neighboring NLR (nucleotide-binding and leucine-rich repeat) genes AT5G47260 and AT5G47280 cooperate in controlling broad-spectrum quantitative partial resistance to the root pathogen P. brassicae in Arabidopsis and that they are epigenetically regulated. The variation in DNA methylation is not associated with any nucleotide variation or any transposable element presence/absence variants and is stably inherited. Variations in DNA methylation at the Pb-At5.2 QTL are widespread across Arabidopsis accessions and correlate negatively with variations in expression of the two genes. Our study demonstrates that natural, stable, and transgenerationally inherited epigenetic variations can play an important role in shaping resistance to plant pathogens by modulating the expression of immune receptors.

Investigating mechanisms of the attentional repulsion effect: A diffusion model analysis.

This article investigates the decisional and attentional drivers of the attentional repulsion effect (ARE) using the diffusion decision model (DDM). The ARE is a phenomenon in which a subjective expansion of space is experienced outside the focus of attention. It is thought to occur due to changes in the functioning of visual cell receptive fields. The DDM is a model of the decision-making process that assumes responses are selected by sequentially sampling an encoded representation of a stimulus until sufficient evidence has been accumulated favoring one response alternative over the other. The model decomposes observed choice and response times into different latent variables corresponding to the rate of evidence accumulation, response caution, response bias, and the time course of stimulus encoding and response execution. In this article, we interpret changes in the rate of evidence accumulation as primarily reflecting perceptual-driven changes in stimulus representation. We interpret changes in response bias as primarily reflecting decision-level changes. We utilize the DDM's ability to estimate these variables independently to explore how they are each affected by cueing manipulations to clarify whether the ARE emerges due to attentional or decisional drivers, or some combination of the two. The results of this study could shed light on the mechanisms underlying the ARE, and has implications in our understanding of spatial attention.

19F-NMR studies of the impact of different detergents and nanodiscs on the A2A adenosine receptor.

For the A2A adenosine receptor (A2AAR), a class A G-protein-coupled receptor (GPCR), reconstituted in n-dodecyl-ß-D-maltoside (DDM)/|||||cholesteryl hemisuccinate (CHS) mixed micelles, previous 19F-NMR studies revealed the presence of multiple simultaneously populated conformational states. Here, we study the influence of a different detergent, lauryl maltose neopentyl glycol (LMNG) in mixed micelles with CHS, and of lipid bilayer nanodiscs on these conformational equilibria. The populations of locally different substates are pronouncedly different in DDM/|||||CHS and LMNG/|||||CHS micelles, whereas the A2AAR conformational manifold in LMNG/|||||CHS micelles is closely similar to that in the lipid bilayer nanodiscs. Considering that nanodiscs represent a closer match of the natural lipid bilayer membrane, these observations support that LMNG/|||||CHS micelles are a good choice for reconstitution trials of class A GPCRs for NMR studies in solution.

The Host Response to Autogenous, Allogeneic, and Xenogeneic Treated Dentin Matrix/Demineralized Dentin Matrix-Oriented Tissue Regeneration.

Dentin is a bone-like matrix that forms the bulk of the tooth. By fabricating dentin with protocols involving demineralization, sterilization, and preservation, treated dentin matrix (TDM)/demineralized dentin matrix (DDM) could be obtained, which is considered as a useful tool for bone and tooth-tissue regeneration. Non-negligible inflammatory and immune responses are reviewed in this article of autogenous, allogeneic, and xenogeneic TDM/DDM for the first time. Both autogenous and allogeneic TDM/DDM showed good biocompatibility in original and clinical studies, while a few cases reported the observation of inflammatory cells around tissue samples. As for xenogeneic TDM/DDM, multiple immune responses were revealed. Immune cells, including eosinocytes, macrophages, lymphocytes, mutinucleated giant cell, M1/M2 macrophages, and Th1-type CTL responses were involved. To avoid these adverse inflammatory responses caused by TDM/DDM implantation, some of the effective fabricating methods are discussed to reduce host immune responses to TDM/DDM.

Modelling decision-making biases.

Biases are a fundamental aspect of everyday life decision-making. A variety of modelling approaches have been suggested to capture decision-making biases. Statistical models are a means to describe the data, but the results are usually interpreted according to a verbal theory. This can lead to an ambiguous interpretation of the data. Mathematical cognitive models of decision-making outline the structure of the decision process with formal assumptions, providing advantages in terms of prediction, simulation, and interpretability compared to statistical models. We compare studies that used both signal detection theory and evidence accumulation models as models of decision-making biases, concluding that the latter provides a more comprehensive account of the decision-making phenomena by including response time behavior. We conclude by reviewing recent studies investigating attention and expectation biases with evidence accumulation models. Previous findings, reporting an exclusive influence of attention on the speed of evidence accumulation and prior probability on starting point, are challenged by novel results suggesting an additional effect of attention on non-decision time and prior probability on drift rate.

Clarifying the nature of stochastic fluctuations and accumulation processes in spontaneous movements.

Experiments on choice-predictive brain signals have played an important role in the debate on free will. In a seminal study, Benjamin Libet and colleagues found that a negative-going EEG signal, the readiness potential (RP), can be observed over motor-related brain regions even hundreds of ms before the time of the conscious decision to move. If the early onset of the readiness potential is taken as an indicator of the "brain's decision to move" this could mean that this decision is made early, by unconscious brain activity, rather than later, at the time when the subject believes to have decided. However, an alternative kind of interpretation, involving ongoing stochastic fluctuations, has recently been brought to light. This stochastic decision model (SDM) takes its inspiration from leaky accumulator models of perceptual decision making. It suggests that the RP originates from an accumulation of ongoing stochastic fluctuations. In this view, the decision happens only at a much later stage when an accumulated noisy signal (plus imperative) reaches a threshold. Here, we clarify a number of confusions regarding both the evidence for the stochastic decision model as well as the interpretation that it offers. We will explore several points that we feel are in need of clarification: (a) the empirical evidence for the role of stochastic fluctuations is so far only indirect; (b) the interpretation of animal studies is unclear; (c) a model that is deterministic during the accumulation stage can explain the data in a similar way; (d) the primary focus in the literature has been on the role of random fluctuations whereas the deterministic aspects of the model have been largely ignored; (e) contrary to the original interpretation, the deterministic component of the model is quantitatively the dominant input into the accumulator; and finally (f) there is confusion regarding the role of "imperative" in the SDM and its link to "evidence" in perceptual decision making. Our aim is not to rehabilitate the role of the RP in the free will debate. Rather we aim to address some confusions regarding the evidence for accumulators playing a role in these preparatory brain processes.

Photochemical model assessment of single source NO2 and O3 plumes using field study data.

Single source contribution to ambient O3 and PM2.5 has been estimated with photochemical grid models to support policy demonstrations for National Ambient Air Quality Standards, regional haze, and permit related programs. Limited field data exists to evaluate model representation of the spatial extent and chemical composition of plumes emitted by specific facilities. New tropospheric column measurements of NO2 and in-plume chemical measurements downwind of specific facilities allows for photochemical model evaluation of downwind plume extent, grid resolution impacts on plume concentration gradients, and source attribution methods. Here, photochemical models were applied with source sensitivity and source apportionment approaches to differentiate single source impacts on NO2 and O3 and compare with field study measurements. Source sensitivity approaches (e.g., brute-force difference method and decoupled direct method (DDM)) captured the spatial extent of NO2 plumes downwind of three facilities and the transition of near-source O3 titration to downwind production. Source apportionment approaches showed variability in terms of attributing the spatial extent of NO2 plumes and downwind O3 production. Each of the Community Multiscale Air Quality (CMAQ) source apportionment options predicted large O3 contribution from a large industrial facility in the flight transects nearest the facility when measurements and source sensitivity approaches suggest titration was outpacing production. In general, CMAQ DDM tends to attribute more O3 to boundary inflow and less to within-domain NOX and VOC sources compared to CMAQ source apportionment. The photochemical modeling system was able to capture single source plumes using 1 to 12 km grid resolution with best representation of plume extent and magnitude at the finer resolutions. When modeled at 1 to 12 km grid resolution, primary and secondary PM2.5 impacts were highest at the source location and decrease as distance increases downwind. The use of coarser grid resolution for single source attribution resulted in predicted impacts highest near the source but lower peak source specific concentrations compared to finer grid resolution simulations because impacts were spread out over a larger area.

Histone variants shape chromatin states in Arabidopsis.

How different intrinsic sequence variations and regulatory modifications of histones combine in nucleosomes remain unclear. To test the importance of histone variants in the organization of chromatin we investigated how histone variants and histone modifications assemble in the Arabidopsis thaliana genome. We showed that a limited number of chromatin states divide euchromatin and heterochromatin into several subdomains. We found that histone variants are as significant as histone modifications in determining the composition of chromatin states. Particularly strong associations were observed between H2A variants and specific combinations of histone modifications. To study the role of H2A variants in organizing chromatin states we determined the role of the chromatin remodeler DECREASED IN DNA METHYLATION (DDM1) in the organization of chromatin states. We showed that the loss of DDM1 prevented the exchange of the histone variant H2A.Z to H2A.W in constitutive heterochromatin, resulting in significant effects on the definition and distribution of chromatin states in and outside of constitutive heterochromatin. We thus propose that dynamic exchanges of histone variants control the organization of histone modifications into chromatin states, acting as molecular landmarks.

Changing the incentive structure of social media platforms to halt the spread of misinformation.

The powerful allure of social media platforms has been attributed to the human need for social rewards. Here, we demonstrate that the spread of misinformation on such platforms is facilitated by existing social 'carrots' (e.g., 'likes') and 'sticks' (e.g., 'dislikes') that are dissociated from the veracity of the information shared. Testing 951 participants over six experiments, we show that a slight change to the incentive structure of social media platforms, such that social rewards and punishments are contingent on information veracity, produces a considerable increase in the discernment of shared information. Namely, an increase in the proportion of true information shared relative to the proportion of false information shared. Computational modeling (i.e., drift-diffusion models) revealed the underlying mechanism of this effect is associated with an increase in the weight participants assign to evidence consistent with discerning behavior. The results offer evidence for an intervention that could be adopted to reduce misinformation spread, which in turn could reduce violence, vaccine hesitancy and political polarization, without reducing engagement.

In recent years, the amount of untrue information, or 'misinformation', shared online has increased rapidly. This can have profound effects on society and has been linked to violence, political extremism, and resistance to climate action. One reason for the spread of misinformation is the lack of incentives for users to share true content and avoid sharing false content. People tend to select actions that they believe will lead to positive feedback ('carrots') and try to avoid actions that lead to negative feedback ('sticks'). On most social media sites, these carrots and sticks come in the form of 'like' and 'dislike' reactions, respectively. Stories that users think will attract 'likes' are most likely to be shared with other users. However, because the number of likes a post receives is not representative of how accurate it is, users share information even if they suspect it may not be accurate. As a result, misinformation can spread rapidly. Measures aimed at slowing the spread of misinformation have been introduced to some social media sites, such as removing a few virulent spreaders of falsities and flagging misleading content. However, measures that change the incentive structure of sites so that positive and negative feedback is based on the trustworthiness of the information have not yet been explored. To test this approach, Globig et al. set up a simulated social media site that included 'trust' and 'distrust' buttons, as well as the usual 'like' and 'dislike' options. The site featured up to one hundred news stories, half of which were untrue. More than 900 participants viewed the news posts and could react using the new buttons as well as repost the stories. The experiment showed that participants used the 'trust' and 'distrust' buttons to differentiate between true and false posts more than the other options. As a result, to receive more 'trust' responses and less 'distrust' responses from other users, participants were more likely to repost true stories than false ones. This led to a large reduction in the amount of misinformation being spread. Computational modeling revealed that the participants were paying more attention to how reliable a news story appeared to be when deciding whether to repost it. Globig et al. showed that adding buttons to highlight the trustworthiness of posts on social media sites reduces the spread of misinformation, without reducing user engagement. This measure could be easily incorporated into existing social media sites and could have a positive impact on issues that are often fuelled by misinformation, such as vaccine hesitancy and resistance to climate action.

DDM1-mediated gene body DNA methylation is associated with inducible activation of defense-related genes in Arabidopsis.

BACKGROUND: Plants memorize previous pathogen attacks and are "primed" to produce a faster and stronger defense response, which is critical for defense against pathogens. In plants, cytosines in transposons and gene bodies are reported to be frequently methylated. Demethylation of transposons can affect disease resistance by regulating the transcription of nearby genes during defense response, but the role of gene body methylation (GBM) in defense responses remains unclear. RESULTS: Here, we find that loss of the chromatin remodeler decrease in DNA methylation 1 (ddm1) synergistically enhances resistance to a biotrophic pathogen under mild chemical priming. DDM1 mediates gene body methylation at a subset of stress-responsive genes with distinct chromatin properties from conventional gene body methylated genes. Decreased gene body methylation in loss of ddm1 mutant is associated with hyperactivation of these gene body methylated genes. Knockout of glyoxysomal protein kinase 1 (gpk1), a hypomethylated gene in ddm1 loss-of-function mutant, impairs priming of defense response to pathogen infection in Arabidopsis. We also find that DDM1-mediated gene body methylation is prone to epigenetic variation among natural Arabidopsis populations, and GPK1 expression is hyperactivated in natural variants with demethylated GPK1. CONCLUSIONS: Based on our collective results, we propose that DDM1-mediated GBM provides a possible regulatory axis for plants to modulate the inducibility of the immune response.

Losing control without your smartphone: Anxiety affects the dynamic choice process of impulsive decision-making and purchase.

Different interacting contexts influence the decision-making process, as revealed by the computational modeling. Through four studies, we investigated how smartphone addiction and anxiety influenced impulsive behaviors, along with the underlying psychological mechanisms and dynamic decision-making processes. In the first and second studies, we found no significant correlation between smartphone addiction and impulsive behavior. However, in the third study, we found that smartphone separation increased impulsive decision-making and purchases, and state anxiety, but not trait anxiety, mediated this effect. We explored the dynamic decision-making process using a multi-attribute drift diffusion model (DDM). The results showed that anxiety triggered by smartphone separation changed the trade-offs between decision weights for the fundamental components of the dynamic choice process. In the fourth study, we investigated why smartphone addiction led to increased anxiety and found that extended-self was a mediating factor. Our findings show that smartphone addiction was not correlated with impulsive behaviors, but was correlated with state anxiety in the context of smartphone separation. Further, this study shows how emotional states triggered by different interacting contexts affect the dynamic decision-making process and consumer behaviors.

Extensive de novo activity stabilizes epigenetic inheritance of CG methylation in Arabidopsis transposons.

Cytosine methylation within CG dinucleotides (mCG) can be epigenetically inherited over many generations. Such inheritance is thought to be mediated by a semiconservative mechanism that produces binary present/absent methylation patterns. However, we show here that, in Arabidopsis thaliana h1ddm1 mutants, intermediate heterochromatic mCG is stably inherited across many generations and is quantitatively associated with transposon expression. We develop a mathematical model that estimates the rates of semiconservative maintenance failure and de novo methylation at each transposon, demonstrating that mCG can be stably inherited at any level via a dynamic balance of these activities. We find that DRM2-the core methyltransferase of the RNA-directed DNA methylation pathway-catalyzes most of the heterochromatic de novo mCG, with de novo rates orders of magnitude higher than previously thought, whereas chromomethylases make smaller contributions. Our results demonstrate that stable epigenetic inheritance of mCG in plant heterochromatin is enabled by extensive de novo methylation.

DDM1-Mediated TE Silencing in Plants.

Epigenetic modifications are indispensable for regulating gene bodies and TE silencing. DECREASE IN DNA METHYLATION 1 (DDM1) is a chromatin remodeller involved in histone modifications and DNA methylation. Apart from maintaining the epigenome, DDM1 also maintains key plant traits such as flowering time and heterosis. The role of DDM1 in epigenetic regulation is best characterised in plants, especially arabidopsis, rice, maize and tomato. The epigenetic changes induced by DDM1 establish the stable inheritance of many plant traits for at least eight generations, yet DDM1 does not methylate protein-coding genes. The DDM1 TE silencing mechanism is distinct and has evolved independently of other silencing pathways. Unlike the RNA-directed DNA Methylation (RdDM) pathway, DDM1 does not depend on siRNAs to enforce the heterochromatic state of TEs. Here, we review DDM1 TE silencing activity in the RdDM and non-RdDM contexts. The DDM1 TE silencing machinery is strongly associated with the histone linker H1 and histone H2A.W. While the linker histone H1 excludes the RdDM factors from methylating the heterochromatin, the histone H2A.W variant prevents TE mobility. The DDM1-H2A.W strategy alone silences nearly all the mobile TEs in the arabidopsis genome. Thus, the DDM1-directed TE silencing essentially preserves heterochromatic features and abolishes mobile threats to genome stability.

Multivariate decoding methods reveal how speaking two dialects affects executive functions.

How speaking two languages affects executive functions has been a long-standing debate and the mechanisms underlying the observed cognitive advantages of bilingualism remain unspecified. Here, using multivariate pattern classification methods, we decoded spatial patterns of neural signals associated with Flanker task performance in mono-dialectal and bi-dialectal speakers of Chinese. While univariate approach to even-related potentials (ERPs) showed no between-group difference, decoding accuracy of ERPs was reduced in bi-dialectal as compared to mono-dialectal speakers in both congruent-neutral and incongruent-neutral classifications. There was no effect of bidialectalism, however, on decoding accuracy of alpha-band oscillations, an electrophysiological index implicated in inhibition. Behavioural data analysed using the Drift Diffusion Model (DDM) showed facilitating effects of bidialectalism on non-decision times but no effect on drift rates. These findings demonstrate that using two dialects on a daily basis enhances general attentional deployment rather than affecting specific component of executive functions such as inhibitory control. Given that the two dialects of Chinese differed almost exclusively in phonology, the bidialectalism effect was most likely motivated by resolving phonological competition at lexical processing level.

Human dentin materials for minimally invasive bone regeneration: Animal studies and clinical cases.

OBJECTIVES: Bone, platelet concentrate, and tooth-derived dentin/cementum have been used as autologous materials in regenerative medicine Dentin materials were first recycled in 2002 for bone regeneration in humans, although bone autografts were noted in the 19th century, and auto-platelet concentrates were developed in 1998. Dentin/cementum-based material therapy has been applied as an innovative technique for minimally invasive bone surgery, while bone autografts are associated with donor site morbidity. METHODS: In October 2021, PubMed, Google Scholar, Scopus, and the Cochrane Library databases from 1980 to 2020 were screened. RESULTS: The demineralized dentin/cementum matrix (DDM) had better performance in bone induction and bone regeneration than mineralized dentin. CONCLUSIONS: Unlike cell culture therapy, DDM is a matrix-based therapy that includes growth factors. A matrix-based system is a realistic and acceptable treatment, even in developing countries. The aim of this review was to summarize the evidence related to both animal studies and human clinical cases using human dentin materials with a patch of cementum, especially DDM.

Updating perceptual expectations as certainty diminishes.

Forming expectations about what we are likely to perceive often facilitates perception. We forge such expectations on the basis of strong statistical relationships between events in our environment. However, due to our ever-changing world these relationships often subsequently degrade or even disappear, yet it is unclear how these altered statistics influence perceptual expectations. We examined this question across two studies by training participants in perfect relationships between actions (index or little finger abductions) and outcomes (clockwise or counter-clockwise gratings), before degrading the predictive relationship in a test phase - such that 'expected' events followed actions on 50-75% of trials and 'unexpected' events ensued on the remainder. Perceptual decisions about outcomes were faster and less error prone on expected than unexpected trials when predictive relationships remained high and reduced as the relationship diminished. Drift diffusion modelling indicated that these effects are explained by shifting the starting point in the evidence accumulation process as well as biasing the rate of evidence accumulation - with the former reflecting biases from statistics within the training session and the latter those of the test session. These findings demonstrate how perceptual expectations are updated as statistical certainty diminishes, with interacting influences speculatively dependent upon learning consolidation. We discuss how underlying mechanisms optimise the interaction between learning and perception - allowing our experiences to reflect a nuanced, ever-changing environment.