Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

After articulating 12 concepts for the reasoning component of citizen-level science literacy and restating these as assessable student learning outcomes (SLOs), we developed a valid and reliable assessment instrument for addressing the outcomes with a brief 25-item science literacy concept inventory (SLCI). In this paper, we report the results that we obtained from assessing the citizen-level science literacy of 17,382 undergraduate students, 149 graduate students, and 181 professors. We address only findings at or above the 99.9% confidence level. We found that general education (GE) science courses do not significantly advance understanding of science as a way of knowing. However, the understanding of science’s way of knowing does increase through academic ranks, indicating that the extended overall academic experience better accounts for increasing such thinking capacity than do science courses alone. Higher mean institutional SLCI scores correlate closely with increased institutional selectivity, as measured by the institutions’ higher mean SAT and ACT scores. Socioeconomic factors of a) first-generation student, b) English as a native language, and c) interest in commitment to a science major are unequally distributed across ethnic groups. These factors proved powerful in accounting for the variations in SLCI scores across ethnicities and genders.

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We have found evidence for a bolide impacting Earth in the mid-Devonian ( approximately 380 million years ago), including high concentrations of shocked quartz, Ni, Cr, As, V, and Co anomalies; a large negative carbon isotope shift (-9 per mil); and microspherules and microcrysts at Jebel Mech Irdane in the Anti Atlas desert near Rissani, Morocco. This impact is important because it is coincident with a major global extinction event (Kacák/otomari event), suggesting a possible cause-and-effect relation between the impact and the extinction. The result may represent the extinction of as many as 40% of all living marine animal genera.