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IntroductionSocietal perceptions and lack of understanding of autism spectrum disorder can be stigmatizing for autistic individuals and their families. This may be particularly the case for individuals who meet criteria for profound autism. Despite the considerable service needs of this marginalized group, there is little data on the prevalence of profound autism, nor on the experiences of those with profound autism and their families.MethodsThe current study leveraged a mixed-methods approach to address these gaps. First, the prevalence of profound autism was examined in six samples-three from the United States and three from Western Europe. Second, inductive thematic analysis was used to code interviews from 20 caregivers of profoundly autistic adults.ResultsThe prevalence of profound autism varied widely across the six samples-from 11% to 48%. There were also notable differences between samples in prevalence by gender, race, and ethnicity. Two overarching themes were identified via inductive thematic analysis: Community Perceptions of Autism and Family Support Needs and Advocacy Challenges. Though caregivers were not directly asked about stigmatization during interviews, 85% of caregivers reported at least one instance of perceived stigma.DiscussionFuture research should continue to examine the unique needs and stigmatization experiences of profoundly autistic individuals and their families across the life course.

The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor β (TGFβ) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGFβ receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGFβ signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGFβ signalling may be a novel strategy in treating mild traumatic brain injury.

Young adults with autism spectrum disorder (ASD) experience limited social connectedness, difficulty living independently, and other poor outcomes at high rates. Vocational activities, including employment and postsecondary education, are associated with increased positive outcomes and subjective well-being in typical adults. This study identified vocational activity trajectory groups in adults with ASD, examined change in these trajectories from ages 18 to 28, and compared levels of parent- and self-report subjective well-being across trajectory groups. One hundred fifty-one adults with ASD were drawn from an ongoing longitudinal study. Data on psychosocial outcomes and vocational activities were compiled from parent-report demographic forms. Vocational activities were scored using the vocational index (VDI). There was no significant effect of age on the slope of vocational trajectories (p = 0.787). Participants in the Independent Activities group had significantly higher parent-report happiness factor scores than participants in the No Activities group (F [3, 107] = 3.56, p = 0.017) and significantly higher self-report happiness factor scores than participants in the Volunteer Activities group (F [2, 35] = 6.46, p = 0.004). The Independent Activities group was also significantly more likely to have at least one social contact (X2 [3, 118] = 10.54, p = 0.014), however, there was no difference in trajectories groups in the likelihood of living independently (X2 [3, 120] = 1.71, p = 0.634). The results of this study indicate vocational activities in young adults with ASD are stable across time. In the current sample, participation in independent vocational activities was associated with increased levels of subjective well-being.

ObjectiveDaily living skills (DLS) are a predictor of positive outcomes in youths with autism spectrum disorder (ASD), yet little is known about trajectories of DLS in adults with ASD. This study investigated the impact of high school exit on participants' trajectories of daily living skills age equivalent (DLS-AE) scores from ages 2 to 26 and the relationship between DLS-AE trajectories and employment and education outcomes.MethodParticipants were 98 adults with ASD drawn from an ongoing longitudinal study. The Vineland Adaptive Behavior Scales were administered 8 times from ages 2 to 26. Employment and education data were compiled from parent report demographic forms.ResultsDLS-AE trajectories modestly increased with age before exiting school, at which point DLS-AE trajectories plateaued, then declined. A significant (p < .01) decrease occurred in the slope of DLS-AE trajectories following school exit. High DLS-AE scores predicted participation in postsecondary education (χ25 [n = 73] = 27.83, p < .001). Autism symptom severity predicted participation in employment (χ25 [n = 58] = 27.54, p < .001).ConclusionThese findings provide evidence that DLS decline in adults with ASD, specifically after school exit, and highlight the importance of DLS in normative adult outcomes. Future work should examine the trajectories of DLS in middle and later adulthood and consider intervention targets for bolstering DLS following school exit.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

Over 200 years ago, Alessandro Volta published his observations of a steady voltage when a piece of electrolyte-soaked cardboard was sandwiched between two dissimilar metals. This observation initiated a century of argument as to the origin of voltaic electricity (contact vs chemical) and catalyzed practical advances, such as the first demonstration of water electrolysis by William Nicholson and Anthony Carlisle within a few months of Volta's announcement. A deep dive into the literature demonstrates that practitioners at the time were disadvantaged in their quest for a detailed understanding of the pile. For instance, the idea of salt dissociation into charged ions and the discovery of the electron did not come to light until nearly an entire century after the pile made its first debut. A thorough survey of the literature also indicates that original piles, which were composed of silver or copper as the cathode and zinc as the anode, operated by the dissolution of zinc at the anode and the reduction of some species at the cathode. A cathodic reaction commonly implicated is the hydrogen evolution reaction (HER). Here, we demonstrate that the oxygen reduction reaction (ORR) contributes to the cathodic half-reaction from pH 0 to 14, suggesting that the true mechanism of the voltaic pile depends on the mixed potential set by the HER/ORR and zinc oxidation. While the main point of this article is to implicate dissolved oxygen, we end the article with suggestions for experimental modifications to promote hands-on learning.

A substantial body of empirical research outside of the marketing education literature indicates that students adopt "surface," "deep," or "strategic" learning approaches based on their learning environment, among other factors. Using the Revised Approaches to Studying Inventory and the Course Experience Questionnaire, this exploratory research examines upper-level marketing majors' learning approaches, their perceptions of the overall academic quality of their program of study, and the relationships between those two sets of indicators. Findings from 345 senior-level marketing students indicate the heaviest use of the strategic approach, followed by the deep approach, and then the surface approach. Results also suggest that strategic and deep learning approaches are associated with higher perceptions of the quality of the academic program. Surface learning is the least preferred approach and negatively associated with the perception of academic program quality and satisfaction with academic achievement. Recommendations are offered for reaching strategic learners.

Settling‐driven gravitational instabilities (SDGIs) can form at the base of buoyant particle‐laden suspensions, modulating particle sedimentation in various settings such as meteorological and volcanic clouds, fluvial plumes, magma chambers, submarine hydrothermal plumes, or industrial emissions. These instabilities result in the formation of rapidly descending currents called 'fingers' within which fine particles settle faster collectively than individually. This study investigates SDGI triggering conditions underneath volcanic ash clouds through analogue experiments considering sedimentation from aqueous particle suspensions. We confirm that the conditions for which SDGIs develop are controlled by two dimensionless numbers: Bf (ratio of the characteristic finger velocity to the individual particle settling velocity); and Bi (ratio of timescale for individual particle settling to that for collective settling controlled by inertial drag). SDGIs are triggered for values of Bf and Bi > 1 for which particles are fully coupled with the flow within fingers. Using these parameters, we produce a regime diagram for the 2010 eruption of Eyjafjallajökull (Iceland) that describes particle settling as a function of particle concentration and size. More studies are needed to produce a general regime diagram accounting for the evolution of SDGIs properties with eruption and atmospheric parameters. Nonetheless, our study confirms that fingers affect sedimentation from volcanic clouds with high ash volume fractions above 10−6 vol.%. Our validation of criteria predicting the onset of fingers due to SDGIs constitutes a step forward toward the incorporation of these collective settling processes in volcanic ash transport and dispersion models. Plain Language Summary: Fine particles can fall more rapidly than individually when settling collectively within vertical currents that are usually termed 'fingers'. Fingers have been observed to form in different natural environments, such as the base of volcanic ash clouds, where they can result from the destabilization of the cloud base and affect the deposition of volcanic ash to the ground. We conducted laboratory experiments simulating particle settling in water to understand the conditions that trigger instabilities and the formation of fingers. We confirm that high particle concentrations of fine particles promote the occurrence of instabilities. In general, instabilities occur when particles remain coupled with the fluid, which is the case when the ratio of the finger velocity to the individual particle velocity is greater than one, as parameterized by two dimensionless numbers. Using these parameters, we created a regime diagram describing particle settling during the 2010 Eyjafjallajökull eruption. More research is needed to create a comprehensive diagram considering other factors like eruption parameters. Key Points: Settling‐driven gravitational instabilities can produce fingers under buoyant particle suspensions, impacting particle sedimentationConditions for the onset of instabilities in laboratory experiments are predicted by ratios of the terminal settling and finger velocitiesRegime diagrams predicting the formation of instabilities below volcanic ash clouds can be obtained [ABSTRACT FROM AUTHOR]

Stimulus equivalence training has been relatively under represented in the research literature for training individuals with autism spectrum disorder (ASD) in early letter-sound correspondence. The primary purpose of the current study was to compare the effectiveness of two different topographies of intraverbals on the emergence of untrained relations between letters and their phonemic sounds for two elementary aged children with ASD. Given frequent difficulties answering WH-questions for children with ASD, assessment and training using questions or statements was compared using a test-train-test sequence. Relations that required auditory-visual match to sample tasks emerged for both participants; however, emergence of untrained intraverbal relations differed based on the topography of assessment and training used. Limitations and future directions are discussed.