Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide ...isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.
The novel catechol-BODIPY dyad, 8-(3,4-dihydroxyphenyl)-2,6-bis(ethoxycarbonyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (FerriBRIGHT) was rationally designed with the aid of ...computational methods. FerriBRIGHT could be prepared by standard one-pot synthesis of BODIPY fluorophores from 3,4-bis(benzyloxy)benzaldehyde (1) and 3,5-dimethyl-4-(ethoxycarbonyl)pyrrole (3); however, isolating the dipyrrin intermediate 8-3,4-bis(benzyloxy)phenyl-2,6-bis(ethoxycarbonyl)-1,3,5,7-tetramethyl-4,4-diaza-s-indacene (7) prior to reaction with excess BF(3).OEt(2) led to marked improvements in the isolated overall yield of the desired compound. In addition to these improvements in fluorophore synthesis, microwave-assisted palladium-catalyzed hydrogenolysis of benzyl ethers was used to reduce reaction times and catalyst loading in preparation of the desired compound. When FerriBRIGHT is exposed to excess FeCl(3), CuCl(2), Co(NH(3))(5)ClCl(2), 2,3-dichloro-5,6-dicyanobenzoquinone, or ceric ammonium nitrate in methanol, a significant enhancement of fluorescence is observed. FerriBRIGHT-Q, the product resulting from the oxidation of the pendant catechol to the corresponding quinone, was found to be the emissive species. FerriBRIGHT-Q was synthesized independently, isolated, and fully characterized to allow for direct comparison with the spectroscopic data acquired in solution. Biologically relevant reactive oxygen species, such as H(2)O(2), (*)OH, (1)O(2), O(2)(*-), and bleach (NaOCl), failed to cause any changes in the emission intensity of FerriBRIGHT. In accordance with the quantum mechanical calculations, the quantum yield of fluorescence for FerriBRIGHT (Phi(fl) approximately 0) and FerriBRIGHT-Q (Phi(fl) = 0.026, lambda(ex)/lambda(em) = 490 nm/510 nm) suggests that photoinduced electron transfer between the catechol and the BODIPY dye is attenuated upon oxidation, which results in fluorescence enhancement. Binding studies of FerriBRIGHT with Ga(NO(3))(3), a redox-inactive analogue of Fe(III), provided conditional binding constant log beta(12)' = 13.3 +/- 0.2 for a Ga(FerriBRIGHT)(2)(-) complex. A 2.8-fold enhancement of fluorescence intensity upon addition of Ga(III) to FerriBRIGHT suggests the possibility of metal ion sensing with this new class of compounds.
Adolescents with autism often experience pronounced difficulties with social communication, and novel interventions designed to improve core abilities are greatly needed. This study examines if ...providing immediate video feedback, an extension of video self-modeling, can aid adolescents with autism to self-identify strengths and irregularities from their social interactions. Using multiple baseline design across four participants, individuals engaged in naturalistic conversations wearing video recording glasses. During the intervention, videos were reviewed immediately and participants recognized when they were not following typical social-communicative convention. Based on observational data coded from videos, all four participants modified their behavior during subsequent conversations. Although adolescents with autism may hypothetically know to behave, viewing themselves on video may provide practical cues to support social insight and behavioral change.
People with autism spectrum disorder (ASD) often have difficulty comprehending social situations in the complex, dynamic contexts encountered in the real world. To study the social brain under ...conditions which approximate naturalistic situations, we measured brain activity with FUNCTIONAL MAGNETIC RESONANCE IMAGING: while participants watched a full-length episode of the sitcom The Office. Having quantified the degree of social awkwardness at each moment of the episode, as judged by an independent sample of controls, we found that both individuals with ASD and control participants showed reliable activation of several brain regions commonly associated with social perception and cognition (e.g. those comprising the 'mentalizing network') during the more awkward moments. However, individuals with ASD showed less activity than controls in a region near right temporo-parietal junction (RTPJ) extending into the posterior end of the right superior temporal sulcus (RSTS). Further analyses suggested that, despite the free-form nature of the experimental design, this group difference was specific to this RTPJ/RSTS area of the mentalizing network; other regions of interest showed similar activity across groups with respect to both location and magnitude. These findings add support to a body of evidence suggesting that RTPJ/RSTS plays a special role in social processes across modalities and may function atypically in individuals with ASD navigating the social world.
Epigenome-wide association studies seek to identify DNA methylation sites associated with clinical outcomes. Difference in observed methylation between specific cell-subtypes is often of interest; ...however, available samples often comprise a mixture of cells. To date, cell-subtype estimates have been obtained from mixed-cell DNA data using linear regression models, but the accuracy of such estimates has not been critically assessed. We evaluated linear regression performance for cell-subtype specific methylation estimation using a 450K methylation array dataset of both mixed-cell and cell-subtype sorted samples from six healthy males. CpGs associated with each cell-subtype were first identified using t-tests between groups of cell-subtype sorted samples. Subsequent reduced panels of reliably accurate CpGs were identified from mixed-cell samples using an accuracy heuristic (D). Performance was assessed by comparing cell-subtype specific estimates from mixed-cells with corresponding cell-sorted mean using the mean absolute error (MAE) and the Coefficient of Determination (R2). At the cell-subtype level, methylation levels at 3272 CpGs could be estimated to within a MAE of 5% of the expected value. The cell-subtypes with the highest accuracy were CD56+ NK (R2 = 0.56) and CD8+T (R2 = 0.48), where 23% of sites were accurately estimated. Hierarchical clustering and pathways enrichment analysis confirmed the biological relevance of the panels. Our results suggest that linear regression for cell-subtype specific methylation estimation is accurate only for some cell-subtypes at a small fraction of cell-associated sites but may be applicable to EWASs of disease traits with a blood-based pathology. Although sample size was a limitation in this study, we suggest that alternative statistical methods will provide the greatest performance improvements.
Naturalistic imaging paradigms, in which participants view complex videos in the scanner, are increasingly used in human cognitive neuroscience. Videos evoke temporally synchronized brain responses ...that are similar across subjects as well as within subjects, but the reproducibility of these brain responses across different data acquisition sites has not yet been quantified. Here, we characterize the consistency of brain responses across independent samples of participants viewing the same videos in functional magnetic resonance imaging (fMRI) scanners at different sites (Indiana University and Caltech). We compared brain responses collected at these different sites for two carefully matched datasets with identical scanner models, acquisition, and preprocessing details, along with a third unmatched dataset in which these details varied. Our overall conclusion is that for matched and unmatched datasets alike, video‐evoked brain responses have high consistency across these different sites, both when compared across groups and across pairs of individuals. As one might expect, differences between sites were larger for unmatched datasets than matched datasets. Residual differences between datasets could in part reflect participant‐level variability rather than scanner‐ or data‐ related effects. Altogether our results indicate promise for the development and, critically, generalization of video fMRI studies of individual differences in healthy and clinical populations alike.
We found that when independent samples of participants watched the same videos in functional magnetic resonance imaging scanners at different sites, brain responses across most of the cortex were highly consistent across the two sites. As predicted, the highest across‐site consistency was observed when acquisition and processing details were carefully matched, but consistency remained high even when acquisition and processing details differed.
In this paper, we propose a multi-hop index modulation-aided orthogonal frequency-division multiplexing (IM-aided OFDM) system, which employs decode-and-forward (DF) relaying techniques to enable the ...transmission of information from source to destination via the use of multiple relays. Through the use of such a cooperative transmission system, the broadcasting coverage can be enlarged and the energy efficiency enhanced accordingly. To reduce the system complexity and provide a unified analysis without the need to employ a dual-mode transmission protocol, we also present a tailored version of the conventional subcarrier activation method, which we have modified to mitigate the zero-active subcarrier dilemma. We provide a detailed comparison of the data transmission rates of both the standard method and the tailored method presented here and give proof that the method we propose has a transmission rate, which matches or exceeds the original method. We investigate the performance of the method by analyzing and presenting the average outage probability, block error rate and network capacity in closed forms. All of the analyses presented are verified through the use of numerical simulations. The results provided in this paper present the promising vision of the IM-aided OFDM in both multi-hop networks and in their potential use in the next generation networks.
Where one looks within their environment constrains one’s visual experiences, directly affects cognitive, emotional, and social processing 1–4, influences learning opportunities 5, and ultimately ...shapes one’s developmental path. While there is a high degree of similarity across individuals with regard to which features of a scene are fixated 6–8, large individual differences are also present, especially in disorders of development 9–13, and clarifying the origins of these differences is essential to understand the processes by which individuals develop within the complex environments in which they exist and interact. Toward this end, a recent paper 14 found that “social visual engagement”—namely, gaze to eyes and mouths of faces—is strongly influenced by genetic factors. However, whether genetic factors influence gaze to complex visual scenes more broadly, impacting how both social and non-social scene content are fixated, as well as general visual exploration strategies, has yet to be determined. Using a behavioral genetic approach and eye tracking data from a large sample of 11-year-old human twins (233 same-sex twin pairs; 51% monozygotic, 49% dizygotic), we demonstrate that genetic factors do indeed contribute strongly to eye movement patterns, influencing both one’s general tendency for visual exploration of scene content, as well as the precise moment-to-moment spatiotemporal pattern of fixations during viewing of complex social and non-social scenes alike. This study adds to a now growing set of results that together illustrate how genetics may broadly influence the process by which individuals actively shape and create their own visual experiences.
•We recorded eye movements in a large sample of identical and fraternal twins•We find eye movements to complex social and nonsocial scenes are heritable•The influence of genes manifests even in the precise temporal order of fixations•This demonstrates that genes can shape the active selection of visual experiences
Kennedy et al. show that spatiotemporal patterns of gaze to naturalistic complex scenes—both social and non-social—are heritable. These results suggest a mechanism whereby genes can influence the visual experiences individuals actively create for themselves over development.
The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO2 and nitrogen deposition driven gains in carbon stocks are partially offset by ...climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years. This uncertainty is driven by plant productivity, allocation, and turnover response to atmospheric CO2 (and to a smaller extent to LULCC), and the response of soil to LULCC (and to a lesser extent climate). Overall, differences in turnover explain ~70% of model spread in both vegetation and soil carbon changes. Further analysis of internal plant and soil (individual pools) cycling is needed to reduce uncertainty in the controlling processes behind the global land carbon sink.
Background
Top‐down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal‐directed action in everyday life. In this twin study, we ...examined the relation between performance on a response inhibition eye‐tracking paradigm and parent‐rated ADHD traits in a population‐based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors.
Methods
A total of 640 twins (320 pairs, 50% monozygotic) aged 9–14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed‐effects models and genetic and environmental influences with multivariate twin models.
Results
Premature anticipatory eye movements were positively associated with inattentive traits (β = .17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2 = 0.40, 95% CI: 0.22, 0.56; h2 = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r = .19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits.
Conclusions
This study indicates that there is a specific, genetically influenced, relation between top‐down eye movement control and the inattentive traits typical of ADHD.
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