Variable cardiac responses in rhesus macaque monkeys after discrete mediodorsal thalamus manipulations.

The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit-the central automatic network-responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion.

Sex, Gender, and Sexual Orientation in Psychological Research: Exploring Data Trends & Researcher Opinions.

Psychology researchers have historically neglected variables related to sex, gender, and sexual orientation, leading to the erasure of sex, gender, and sexual orientation in research, which limits the generalizability of psychological findings. We argue that these important variables need to be considered more consistently by researchers across psychology subdisciplines. In Study 1 we found that 15.1% of a large MTurk sample (i.e., 8500+) identified as a sexual or gender minority (SGM; e.g., lesbian, gay, bisexual, transgender, queer [LGBTQ+]). In addition, data from Study 1 showed that our youngest cohort (i.e., aged 18-25 years) reported significantly higher rates of LGBTQ+ identification (22.7%) than our oldest cohort (i.e., 65-84 years; 1.3%), suggesting that endorsement of these idnetities is increasing. Next, in Study 2 we found that psychology researchers (N = 135) tended to rate expansive sex, gender, and sexual orientation demographic variables as important in general, but were much less likely to report actually using these variables in their own studies. Moreover, younger faculty and faculty who identified as women rated these variables as more important than their colleagues. Based on our findings, we conclude that psychology researchers should use expansive sex, gender, and sexual orientation items in their studies, report these demographic variables consistently, and analyze their data by these important variables when possible. Because a substantial and growing proportion of individuals identify as LGBTQ+, and because SGM identity is related to additional life stressors, it is imperative to better understand these individuals. Various resources are offered and challenges are discussed.

ADHD and Psychological Need Fulfillment in College Students.

OBJECTIVE: Self-determination theory suggests that the satisfaction and frustration of basic psychological needs-autonomy, competence, relatedness-are uniquely associated with overall well-being. Undergraduates with attention-deficit/hyperactivity disorder (ADHD) experience more academic-related impairment and are less likely to graduate. Thus, well-being is important to understand and aim to improve in these students. METHOD: Students at four universities (N = 2,197) completed a survey and reported previous diagnoses, ADHD symptoms, and psychological need satisfaction and frustration. Group differences were explored via t-tests; associations were explored via structural equation modeling. RESULTS: The ADHD group reported lower satisfaction and higher frustration across all psychological needs. Inattention and hyperactivity/impulsivity were uniquely associated with aspects of need fulfillment beyond the impact of comorbid symptoms. Sex differences emerged such that women with ADHD had the lowest overall need satisfaction. CONCLUSIONS: Addressing need fulfillment, both satisfaction and frustration, in interventions with undergraduates with clinical/subclinical levels of ADHD may optimize treatment effectiveness.

Promoting academic success in college students with ADHD and LD: A systematic literature review to identify intervention targets.

Objective: College students with attention-deficit/hyperactivity disorder (ADHD) and/or a learning disorder (LD) are at higher risk for not attaining a bachelor's degree. The purpose is to identify the predictors of academic success in college for students with ADHD and/or LD using a systematic review of the literature. Method: Academic Search Premier, Education Full Text, Education Source, Education Resources Information Center, Teacher Reference Center, PsycINFO, PsycArticles, and Primary Search and relevant journals were searched using PRISMA guidelines. Studies were screened based on the following inclusion criteria: college students with ADHD and/or LD, student characteristics as predictors, and GPA and/or retention as outcomes. Results: Twenty-one studies were included (20 quantitative studies and 1 randomized control trial). Academic regulation, academic self-efficacy, emotional regulation, ADHD symptoms, and academic and social integration predicted college success. Conclusion: Incorporating these components into interventions with students with ADHD and/or LD may enhance their success in college.

Social performance-based interventions promote gains in social knowledge in the absence of explicit training for youth with autism spectrum disorder.

Youth with autism spectrum disorder (ASD) experience deficits in social knowledge. It has long been theorized that these youth must learn these skills explicitly, and social skills interventions (SSIs) have followed suit. Recently, performance-based SSIs have emerged, which promote in vivo opportunities for social engagement without explicit instruction. Effects of performance-based SSIs on social knowledge have not been examined. This study employs two discrete samples (one lab-based, one community-based) of youth with ASD to examine the effects of performance-based interventions on social knowledge. Results largely support the efficacy and effectiveness of improving social knowledge by performance-based interventions without explicit teaching. This indicates that youth with ASD may be able to learn these aspects of social cognition implicitly, rather than exclusively explicitly. The results of the current study also suggest that SSI content, dosage, and intensity may relate to these outcomes, which are important considerations in clinical practice and future studies.

Childhood Executive Functioning Predicts Young Adult Outcomes in 22q11.2 Deletion Syndrome.

OBJECTIVE: While individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for a variety of functional impairments and psychiatric disorders, including psychosis, not all individuals with 22q11DS experience negative outcomes. Efforts to further understand which childhood variables best predict adult functional outcomes are needed, especially those that investigate childhood executive functioning abilities. METHODS: This longitudinal study followed 63 individuals with 22q11DS and 43 control participants over 9 years. Childhood executive functioning ability was assessed using both rater-based and performance-based measures and tested as predictors of young adult outcomes. RESULTS: Childhood global executive functioning abilities and parent report of child executive functioning abilities were the most consistent predictors of young adult outcomes. The study group moderated the relationship between child executive functioning and young adult outcomes for several outcomes such that the relationships were stronger in the 22q11DS sample. CONCLUSION: Rater-based and performance-based measures of childhood executive functioning abilities predicted young adult outcomes in individuals with and without 22q11DS. Executive functioning could be a valuable target for treatment in children with 22q11DS for improving not only childhood functioning but also adult outcomes. (JINS, 2018, 24, 905-916).

The molecular mechanism of intestinal levodopa absorption and its possible implications for the treatment of Parkinson's disease.

Levodopa (L-DOPA) is the naturally occurring precursor amino acid for dopamine and the main therapeutic agent for neurologic disorders due to dopamine depletion, such as Parkinson's disease. l-DOPA absorption in small intestine has been suggested to be mediated by the large neutral amino acids transport machinery, but the identity of the involved transporters is unknown. Clinically, coadministration of l-DOPA and dietary amino acids is avoided to decrease competition for transport in intestine and at the blood-brain barrier. l-DOPA is routinely coadministered with levodopa metabolism inhibitors (dopa-decarboxylase and cathechol-O-methyl transferase inhibitors) that share structural similarity with levodopa. In this systematic study involving Xenopus laevis oocytes and Madin-Darby canine kidney epithelia expression systems and ex vivo preparations from wild-type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) b(0,+)AT-rBAT (SLC7A9-SLC3A1) as the luminal intestinal l-DOPA transporter. The major luminal cotransporter (symporter) B(0)AT1 (SLC6A19) was not involved in levodopa transport. L-Leucine and L-arginine competed with levodopa across the luminal enterocyte membrane as expected for b(0,+)AT-rBAT substrates, whereas dopa-decarboxylase and cathechol-O-methyl transferase inhibitors had no effect. The presence of amino acids in the basolateral compartment mimicking the postprandial phase increased transepithelial levodopa transport by stimulating basolateral efflux via the antiporter LAT2-4F2 (SLC7A8-SLC3A2). Additionally, the aromatic amino acid uniporter TAT1 (SLC16A10) was shown to play a major role in l-DOPA efflux from intestinal enterocytes. These results identify the molecular mechanisms mediating small intestinal levodopa absorption and suggest strategies for optimization of delivery and absorption of this important prodrug.

T-type amino acid transporter TAT1 (Slc16a10) is essential for extracellular aromatic amino acid homeostasis control.

The uniporter TAT1 (Slc16a10) mediates the facilitated diffusion of aromatic amino acids (AAAs) across basolateral membranes of kidney, small intestine and liver epithelial cells, and across the plasma membrane of non-epithelial cells like skeletal myocytes. Its role for body AA homeostasis has now been investigated using newly generated TAT1 (Slc16a10) defective mice (tat1(-/-)). These mice grow and reproduce normally, show no gross phenotype and no obvious neurological defect. Histological analysis did not reveal abnormalities and there is no compensatory change in any tested AA transporter mRNA. TAT1 null mice, however, display increased plasma, muscle and kidney AAA concentration under both normal and high protein diet, although this concentration remains normal in the liver. A major aromatic aminoaciduria and a smaller urinary loss of all substrates additionally transported by l-type AA antiporter Lat2-4F2hc (Slc7a8) were revealed under a high protein diet. This suggests an epithelial transport defect as also shown by the accumulation of intravenously injected (123)I-2-I-l-Phe in kidney and l-[(3)H]Phe in ex vivo everted gut sac enterocytes. Taken together, these data indicate that the uniporter TAT1 is required to equilibrate the concentration of AAAs across specific membranes. For instance, it enables hepatocytes to function as a sink that controls the extracellular AAAs concentration. Additionally, it facilitates the release of AAAs across the basolateral membrane of small intestine and proximal kidney tubule epithelial cells, thereby allowing the efflux of other neutral AAs presumably via Lat2-4F2hc.

Defective intestinal amino acid absorption in Ace2 null mice.

Mutations in the main intestinal and kidney luminal neutral amino acid transporter B(0)AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor L-tryptophan. Since Ace2 is necessary for intestinal B(0)AT1 expression, we tested the impact of intestinal B(0)AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na(+)-dependent uptake of B(0)AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na(+)-dependent transport of L-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more L-tryptophan than other B(0)AT1 substrates reach the ileum in wild-type mice, which is in line with its known lower apparent affinity. In ace2 null mice, the absorption defect was confirmed by a severalfold increase of L-tryptophan and of other neutral amino acids reaching the ileum lumen. Furthermore, plasma and muscle levels of glycine and L-tryptophan were significantly decreased in ace2 null mice, with other neutral amino acids displaying a similar trend. A low-protein/low-niacin diet challenge led to differential changes in plasma amino acid levels in both wild-type and ace2 null mice, but only in ace2 null mice to a stop in weight gain. Despite the combination of low-niacin with a low-protein diet, plasma niacin concentrations remained normal in ace2 null mice and no pellagra symptoms, such as photosensitive skin rash or ataxia, were observed. In summary, mice lacking Ace2-dependent intestinal amino acid transport display no total niacin deficiency nor clear pellagra symptoms, even under a low-protein and low-niacin diet, despite gross amino acid homeostasis alterations.

Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response.

Activin is an important orchestrator of wound repair, but its potential role in skin carcinogenesis has not been addressed. Here we show using different types of genetically modified mice that enhanced levels of activin in the skin promote skin tumour formation and their malignant progression through induction of a pro-tumourigenic microenvironment. This includes accumulation of tumour-promoting Langerhans cells and regulatory T cells in the epidermis. Furthermore, activin inhibits proliferation of tumour-suppressive epidermal γδ T cells, resulting in their progressive loss during tumour promotion. An increase in activin expression was also found in human cutaneous basal and squamous cell carcinomas when compared with control tissue. These findings highlight the parallels between wound healing and cancer, and suggest inhibition of activin action as a promising strategy for the treatment of cancers overexpressing this factor.

Kidney amino acid transport.

Near complete reabsorption of filtered amino acids is a main specialized transport function of the kidney proximal tubule. This evolutionary conserved task is carried out by a subset of luminal and basolateral transporters that together form the transcellular amino acid transport machinery similar to that of small intestine. A number of other amino acid transporters expressed in the basolateral membrane of proximal kidney tubule cells subserve either specialized metabolic functions, such as the production of ammonium, or are part of the cellular housekeeping equipment. A new finding is that the luminal Na(+)-dependent neutral amino acid transporters of the SLC6 family require an associated protein for their surface expression as shown for the Hartnup transporter B(0)AT1 (SLC6A19) and suggested for the L: -proline transporter SIT1 (IMINO(B), SLC6A20) and for B(0)AT3 (XT2, SLC6A18). This accessory subunit called collectrin (TMEM27) is homologous to the transmembrane anchor region of the renin-angiotensin system enzyme ACE2 that we have shown to function in small intestine as associated subunit of the luminal SLC6 transporters B(0)AT1 and SIT1. Some mutations of B(0)AT1 differentially interact with these accessory subunits, providing an explanation for differential intestinal phenotypes among Hartnup patients. The basolateral efflux of numerous amino acids from kidney tubular cells is mediated by heteromeric amino acid transporters that function as obligatory exchangers. Thus, other transporters within the same membrane need to mediate the net efflux of exchange substrates, controlling thereby the net basolateral amino transport and thus the intracellular amino acid concentration.

Recycling of aromatic amino acids via TAT1 allows efflux of neutral amino acids via LAT2-4F2hc exchanger.

The rate of amino acid efflux from individual cells needs to be adapted to cellular demands and plays a central role for the control of extracellular amino acid homeostasis. A particular example of such an outward amino acid transport is the basolateral efflux from transporting epithelial cells located in the small intestine and kidney proximal tubule. Because LAT2-4F2hc (Slc7a8-Slc3a2), the best known basolateral neutral amino acid transporter of these epithelial cells, functions as an obligatory exchanger, we tested whether TAT1 (Slc16a10), the aromatic amino-acid facilitated diffusion transporter, might allow amino acid efflux via this exchanger by recycling its influx substrates. In this study, we show by immunofluorescence that TAT1 and LAT2 indeed colocalize in the early kidney proximal tubule. Using the Xenopus laevis oocytes expression system, we show that L-glutamine is released from oocytes into an amino-acid-free medium only when both transporters are coexpressed. High-performance liquid chromatography analysis reveals that several other neutral amino acids are released as well. The transport function of both TAT1 and LAT2-4F2hc is necessary for this efflux, as coexpression of functionally inactive but surface-expressed mutants is ineffective. Based on negative results of coimmunoprecipitation and crosslinking experiments, the physical interaction of these transporters does not appear to be required. Furthermore, replacement of TAT1 or LAT2-4F2hc by the facilitated diffusion transporter LAT4 or the obligatory exchanger LAT1, respectively, supports similar functional cooperation. Taken together, the results suggest that the aromatic amino acid diffusion pathway TAT1 can control neutral amino acid efflux via neighboring exchanger LAT2-4F2hc, by recycling its aromatic influx substrates.

Essential role for collectrin in renal amino acid transport.

Angiotensin -converting enzyme 2 (ACE2) is a regulator of the renin angiotensin system involved in acute lung failure, cardiovascular functions and severe acute respiratory syndrome (SARS) infections in mammals. A gene encoding a homologue to ACE2, termed collectrin (Tmem27), has been identified in immediate proximity to the ace2 locus. The in vivo function of collectrin was unclear. Here we report that targeted disruption of collectrin in mice results in a severe defect in renal amino acid uptake owing to downregulation of apical amino acid transporters in the kidney. Collectrin associates with multiple apical transporters and defines a novel group of renal amino acid transporters. Expression of collectrin in Xenopus oocytes and Madin-Darby canine kidney (MDCK) cells enhances amino acid transport by the transporter B(0)AT1. These data identify collectrin as a key regulator of renal amino acid uptake.

Basolateral aromatic amino acid transporter TAT1 (Slc16a10) functions as an efflux pathway.

Basolateral efflux is a necessary step in transepithelial (re)absorption of amino acids from small intestine and kidney proximal tubule. The best characterized basolateral amino acid transporters are y+LAT1-4F2hc and LAT2-4F2hc that function as obligatory exchangers and thus, do not contribute to net amino acid (re)absorption. The aromatic amino acid transporter TAT1 was shown previously to localize basolaterally in rat's small intestine and to mediate the efflux of L-Trp in the absence of exchange substrate, upon expression in Xenopus oocytes. We compared here the amino acid influx and efflux via mouse TAT1 in Xenopus oocytes. The results show that mTAT1 functions as facilitated diffusion pathway for aromatic amino acids and that its properties are symmetrical in terms of selectivity and apparent affinity. We show by real-time RT-PCR that its mRNA is highly expressed in mouse small intestine mucosa, kidney, liver, and skeletal muscle as well as present in all other tested tissues. We show that mTAT1 is not N-glycosylated and that it localizes to the mouse kidney proximal tubule. This expression is characterized by an axial gradient similar to that of the luminal neutral amino acid transporter B0AT1 and shows the same basolateral localization as 4F2hc. mTAT1 also localizes to the basolateral membrane of small intestine enterocytes and to the sinusoidal side of perivenous hepatocytes. In summary, we show that TAT1 is a basolateral epithelial transporter and that it can function as a net efflux pathway for aromatic amino acids. We propose that it, thereby, may supply parallel exchangers with recycling uptake substrates that could drive the efflux of other amino acids.

Novel renal amino acid transporters.

Reabsorption of amino acids, similar to that of glucose, is a major task of the proximal kidney tubule. Various amino acids are actively transported across the luminal brush border membrane into proximal tubule epithelial cells, most of which by cotransport. An important player is the newly identified cotransporter (symporter) B0AT1 (SLC6A19), which imports a broad range of neutral amino acids together with Na+ across the luminal membrane and which is defective in Hartnup disorder. In contrast, cationic amino acids and cystine are taken up in exchange for recycled neutral amino acids by the heterodimeric cystinuria transporter. The basolateral release of some neutral amino acids into the extracellular space is mediated by unidirectional efflux transporters, analogous to GLUT2, that have not yet been definitively identified. Additionally, cationic amino acids and some other neutral amino acids leave the cell basolaterally via heterodimeric obligatory exchangers.

SPECT and PET amino acid tracer influx via system L (h4F2hc-hLAT1) and its transstimulation.

UNLABELLED: System L amino acid transport is increased in various types of cancer. The tracer 123I-2-iodotyrosine (2IT), which is accumulated via system L, could thus serve to allow visualization of cancer in vivo. Here, we studied the transport of 125I-2IT by h4F2hc-hLAT1, the major transporter subserving system L in growing cells, using the Xenopus laevis oocyte expression system. We compared the apparent affinity of 125I-2IT with that of tyrosine, tested the influence of intracellular methionine availability on the influx rate of this substrate, and then compared the transport of 2IT with that of the other tracers-iodo-alpha-methyltyrosine (IMT), fluoroethyltyrosine (FET), and 2-fluorotyrosine (2FT)-by measuring their transstimulating effect on phenylalanine efflux. METHODS: Transport experiments were performed with Xenopus laevis oocytes expressing h4F2hc-hLAT1 (the functional transporter) and oocytes expressing only h4F2hc (negative control). The values obtained for the functional transporter were corrected for endogenous background transport by subtracting the values for the negative controls. RESULTS: The apparent affinity for 125I-2IT and 3H-tyrosine was 29.3 +/- 9.3 micromol/L and 21.2 +/- 4.2 micromol/L, respectively. The influx rate of 125I-2IT was, similarly to that of 3H-phenylalanine, transstimulated by a factor of > or =3 when the oocytes were preinjected with methionine or phenylalanine. The proportion of preinjected 3H-phenylalanine that effluxed within 90 s in the presence of an extracellular 2IT concentration of 0.1 mmol/L was 4.1% +/- 0.5%, compared with 3.3% +/- 0.4% for extracellular IMT, 1.3% +/- 0.3% for FET, 9.3% +/- 0.8% for 2FT, and 9.1% +/- 0.5% for phenylalanine. CONCLUSION: 2IT has a high affinity for h4F2hc-hLAT1, comparable to that of natural tyrosine, and its influx rate is transstimulated by intracellular amino acids. The 2IT influx rate is comparable to that of IMT but lower than that of phenylalanine. In contrast to FET, which is only poorly transported, 2FT displays a high influx rate equal to that of phenylalanine.