Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1.

RhoA and its effectors, the transcriptional coactivators myocardin-related transcription factor (MRTF) and serum response factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding (PAB) model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor (TNF)-α or transforming growth factor (TGF)-ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling, and MRTF, indicative of a positive feedback cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Of importance, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. As the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.NEW & NOTEWORTHY We show that expression of the RhoA regulator GEF-H1 is upregulated in tubular cells exposed to fibrogenic cytokines and in animal models of kidney and heart fibrosis. We identify a pathway wherein GEF-H1/RhoA-dependent MRTF activation through its noncanonical partner Sp1 upregulates GEF-H1. Our data reveal the existence of a positive feedback cycle that enhances Rho signaling through control of both GEF-H1 activation and expression. This feedback loop may play an important role in organ fibrosis.

ADHD, chronotype, and circadian preference in a multi-site sample of college students.

Attention-deficit/hyperactivity disorder and an evening chronotype are both common among college students, and there is growing interest in understanding the possible link between attention-deficit/hyperactivity disorder and circadian function. However, mixed findings have been reported, and many of the existing studies have used small samples that were unable to examine chronotype across attention-deficit/hyperactivity disorder presentations. Participants were 4751 students (73% female; 80% White), aged 18-29 years (M = 19.28, SD = 1.50), from five universities who completed measures assessing attention-deficit/hyperactivity disorder, depressive and anxiety symptoms, as well as the Morningness-Eveningness Questionnaire to assess chronotype (categorical) and circadian preference (dimensional). Participants with either attention-deficit/hyperactivity disorder predominantly inattentive presentation or attention-deficit/hyperactivity disorder combined presentation had higher rates of being an evening type (47.2% and 41.5%, respectively) than participants without elevated attention-deficit/hyperactivity disorder (28.5%), and participants with attention-deficit/hyperactivity disorder predominantly inattentive presentation also had higher rates of being an evening type than participants with attention-deficit/hyperactivity disorder predominantly hyperactive-impulsive presentation (30.7%). Dimensional analyses indicated that attention-deficit/hyperactivity disorder inattentive symptoms were more strongly associated than hyperactive-impulsive symptoms with eveningness preference. Finally, greater eveningness preference strengthened the association between attention-deficit/hyperactivity disorder inattention and depressive symptoms but not anxiety symptoms. This is the largest study to document that college students with elevated attention-deficit/hyperactivity disorder symptoms are more likely to be evening types than other college students, and inattentive symptoms in particular are associated with later circadian preference.

Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.

The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.

Is reduced social competence a mechanism linking elevated autism spectrum symptoms with increased risk for social anxiety?

OBJECTIVES: Approximately 50% of children with autism spectrum disorder (ASD) develop comorbid social anxiety disorder, and this comorbidity predicts poorer treatment outcomes than either syndrome alone. ASD and social anxiety are both associated with reduced social competence as evidenced by difficulties implementing fundamental social skills for successful social interactions, but it remains unclear whether reduced social competence reflects a mechanism that explains the increased risk for social anxiety associated with elevated autism spectrum symptoms. DESIGN/METHODS: To address this gap in the literature, the current study combined multi-informant measures (child, parent and teacher report) with a sample of 194 children with and without psychiatric disorders (ages 8-13; 68 girls; 69% White/Non-Hispanic). Autism spectrum traits, social competence and social anxiety symptoms were measured continuously. RESULTS: Bias-corrected, bootstrapped conditional effects modelling indicated that elevated parent-reported autism spectrum symptoms predicted reduced teacher-perceived social competence (ß = -.21) and elevated child self-reported social anxiety (ß = .17); reduced social competence accounted for 20% of the autism/social anxiety link (indirect pathway ß = .04, ER = .20), and reduced social competence also predicted higher social anxiety independent of autism symptoms (ß = -.16; all 95% CIs exclude 0.0, indicating significant effects). Exploratory analyses suggested that these findings were driven primarily by autism spectrum social communication difficulties rather than restricted/repetitive behaviours/interests. CONCLUSIONS: The current findings are consistent with prior work implicating reduced social competence as a risk factor for the development of social anxiety among children with ASD, and extend prior work by demonstrating that this link is robust to control for mono-informant/mono-measure bias, age, sex, SES, majority/minoritized race/ethnicity status, clinical comorbidities, and item overlap across measures.

Evaluating the Simple View of Reading for Children With Attention-Deficit/Hyperactivity Disorder.

The 'simple view of reading' is an influential model of reading comprehension which asserts that children's reading comprehension performance can be explained entirely by their decoding and language comprehension skills. Children with ADHD often exhibit difficulty across all three of these reading domains on standardized achievement tests, yet it is unclear whether the simple view of reading is sufficient to explain reading comprehension performance for these children. The current study was the first to use multiple indicators and latent estimates to examine the veracity of key predictions from the simple view of reading in a clinically-evaluated sample of 250 children with and without ADHD (ages 8-13, Mage=10.29, SD=1.47; 93 girls; 70% White/Non-Hispanic). Results of the full-sample structural equation model revealed that decoding and language comprehension explained all (R2=.99) of the variance in reading comprehension for children with and without ADHD. Further, multigroup modeling (ADHD, Non-ADHD) indicated that there was no difference in the quantity of variance explained for children with ADHD versus clinically-evaluated children without ADHD, and that the quantity of explained variance did not differ from 100% for either group. Sensitivity analyses indicated that these effects were generally robust to control for monomethod bias, time sampling error, and IQ. These findings are consistent with 'simple view' predictions that decoding and language comprehension are both necessary and together sufficient for explaining children's reading comprehension skills. The findings extend prior work by indicating that the 'simple view' holds for both children with ADHD and clinically-evaluated children without ADHD.

Is There a Functional Relation Between Set Shifting and Hyperactivity in Children with Attention-Deficit/Hyperactivity Disorder (ADHD)?

OBJECTIVE: Replicated evidence indicates that children with attention-deficit/hyperactivity disorder (ADHD) show disproportionate increases in hyperactivity/physical movement when their underdeveloped executive functions are taxed. However, our understanding of hyperactivity's relation with set shifting is limited, which is surprising given set shifting's importance as the third core executive function alongside working memory and inhibition. The aim of this study was to experimentally examine the effect of imposing set shifting and inhibition demands on objectively measured activity level in children with and without ADHD. METHOD: The current study used a validated experimental manipulation to differentially evoke set shifting, inhibition, and general cognitive demands in a carefully phenotyped sample of children aged 8-13 years with ADHD (n = 43) and without ADHD (n = 34). Activity level was sampled during each task using multiple, high-precision actigraphs; total hyperactivity scores (THS) were calculated. RESULTS: Results of the 2 × 5 Bayesian ANOVA for hyperactivity revealed strong support for a main effect of task (BF10 = 1.79 × 1018, p < .001, ω2 = .20), such that children upregulated their physical movement in response to general cognitive demands and set shifting demands specifically, but not in response to increased inhibition demands. Importantly, however, this manipulation did not disproportionally increase hyperactivity in ADHD as demonstrated by significant evidence against the task × group interaction (BF01 = 18.21, p = .48, ω2 = .002). CONCLUSIONS: Inhibition demands do not cause children to upregulate their physical activity. Set shifting produces reliable increases in children's physical movement/hyperactivity over and above the effects of general cognitive demands but cannot specifically explain hyperactivity in children with ADHD.

Lichtenstein Versus Total Extraperitoneal Patch Plasty Versus Transabdominal Patch Plasty Technique for Primary Unilateral Inguinal Hernia Repair: A Registry-based, Propensity Score-matched Comparison of 57,906 Patients.

OBJECTIVE: Outcome comparison of the Lichtenstein, total extraperitoneal patch plasty (TEP), and transabdominal patch plasty (TAPP) techniques for primary unilateral inguinal hernia repair. BACKGROUND: For comparison of these techniques the number of cases included in meta-analyses of randomized controlled trials is limited. There is therefore an urgent need for more comparative data. METHODS: In total, 57,906 patients with a primary unilateral inguinal hernia and 1-year follow up from the Herniamed Registry were selected between September 1, 2009 and February 1, 2015. Using propensity score matching, 12,564 matched pairs were formed for comparison of Lichtenstein versus TEP, 16,375 for Lichtenstein versus TAPP, and 14,426 for TEP versus TAPP. RESULTS: Comparison of Lichtenstein versus TEP revealed disadvantages for the Lichtenstein operation with regard to the postoperative complications (3.4% vs 1.7%; P < 0.001), complication-related reoperations (1.1% vs 0.8%; P = 0.008), pain at rest (5.2% vs 4.3%; P = 0.003), and pain on exertion (10.6% vs 7.7%; P < 0.001). TEP had disadvantages in terms of the intraoperative complications (0.9% vs 1.2%; P = 0.035). Likewise, comparison of Lichtenstein versus TAPP showed disadvantages for the Lichtenstein operation with regard to the postoperative complications (3.8% vs 3.3%; P = 0.029), complication-related reoperations (1.2% vs 0.9%; P = 0.019), pain at rest (5% vs 4.5%; P = 0.029), and on exertion (10.2% vs 7.8%; P < 0.001). CONCLUSIONS: TEP and TAPP were found to have advantages over the Lichtenstein operation.

Factor Structure and Criterion Validity of the Five Cs Model of Positive Youth Development in a Multi-University Sample of College Students.

There is growing recognition that clinical and developmental outcomes will be optimized by interventions that harness strengths in addition to ameliorating deficits. Although empirically-supported methods for identifying strengths are available for children and adolescents, this framework has yet to be applied to emerging adulthood. This study evaluates the nature of the Five Cs model of Positive Youth Development (PYD) - character, confidence, competence, connection, and caring - in a sample of emerging adults from six universities (N = 4654; 70% female; 81% White). Historically, PYD has been modeled as either separate correlated factors or a second-order factor structure. More recently, the bifactor model has been recommended to determine the degree to which PYD is unidimensional versus multidimensional. The present study examined the multidimensionality of PYD by comparing the model fit of a one-factor, five-correlated factor model, and second-order factor structure with a bifactor model and found support for the bifactor model with evidence of invariance across sex. Criterion validity was also assessed using three criterion measures particularly relevant for adjustment during emerging adulthood: anxiety, depressive symptoms, and emotion regulation difficulties. PYD and the residual Cs tended to correlate negatively with indicators of maladaptive development. Future directions including applications of the PYD framework as a measure of thriving across emerging adulthood are discussed.

Working memory and organizational skills problems in ADHD.

BACKGROUND: This study tested model-driven predictions regarding working memory's role in the organizational problems associated with ADHD. METHOD: Children aged 8-13 (M = 10.33, SD = 1.42) with and without ADHD (N = 103; 39 girls; 73% Caucasian/Non-Hispanic) were assessed on multiple, counterbalanced working memory tasks. Parents and teachers completed norm-referenced measures of organizational problems (Children's Organizational Skills Scale; COSS). RESULTS: Results confirmed large magnitude working memory deficits (d = 1.24) and organizational problems in ADHD (d = 0.85). Bias-corrected, bootstrapped conditional effects models linked impaired working memory with greater parent- and teacher-reported inattention, hyperactivity/impulsivity, and organizational problems. Working memory predicted organization problems across all parent and teacher COSS subscales (R2  = .19-.23). Approximately 38%-57% of working memory's effect on organization problems was conveyed by working memory's association with inattentive behavior. Unique effects of working memory remained significant for both parent- and teacher-reported task planning, as well as for teacher-reported memory/materials management and overall organization problems. Attention problems uniquely predicted worse organizational skills. Hyperactivity was unrelated to parent-reported organizational skills, but predicted better teacher-reported task planning. CONCLUSIONS: Children with ADHD exhibit multisetting, broad-based organizational impairment. These impaired organizational skills are attributable in part to performance deficits secondary to working memory dysfunction, both directly and indirectly via working memory's role in regulating attention. Impaired working memory in ADHD renders it extraordinarily difficult for these children to consistently anticipate, plan, enact, and maintain goal-directed actions.

Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling.

The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk(-/-) HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk(-/-) HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk.

Twisted amide electrophiles enable cyclic peptide sequencing.

There is an ever-increasing interest in synthetic methods that not only enable peptide macrocyclization, but also facilitate downstream application of the synthesized molecules. We have found that aziridine amides are stereoelectronically attenuated in a macrocyclic environment such that non-specific interactions with biological nucleophiles are reduced or even shut down. The electrophilic reactivity, revealed at high pH, enables peptide sequencing by mass spectrometry, which will further broaden the utility of aziridine amide-containing libraries of macrocycles.

The emergence of co-occurring adolescent polysubstance use and depressive symptoms: A latent growth modeling approach.

This study tests competing models of the relation between depression and polysubstance use over the course of adolescence. Participants included a nationwide sample of adolescents (N = 3,604), ages 12 to 17 at study Wave 1, assessed annually for 3 years. Models were tested using cohort-sequential latent growth curve modeling to determine whether depressive symptoms at baseline predicted concurrent and age-related changes in drug use, whether drug use at baseline predicted concurrent and age-related changes in depressive symptoms, and whether initial levels of depression predicted changes in substance use significantly better than vice versa. The results suggest a transactional model such that early polysubstance use promotes early depressive symptoms, which in turn convey elevated risk for increasing polysubstance use over time, which in turn conveys additional risk for future depressive symptoms, even after accounting for gender, ethnicity, and household income. In contrast, early drug use did not portend risk for future depressive symptoms. These findings suggest a complicated pattern of interrelations over time and indicate that many current models of co-occurring polysubstance use and depressive symptoms may not fully account for these associations. Instead, the results suggest a developmental cascade, in which symptoms of one disorder promote symptoms of the other across intrapersonal domains.

Improving the efficacy and effectiveness of evidence-based psychosocial interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent, chronic, and impairing mental health disorder of childhood. Decades of empirical research has established a strong evidence-based intervention armamentarium for ADHD; however, limitations exist in regards to efficacy and effectiveness of these interventions. We provide an overview of select evidence-based interventions for children and adolescents, highlighting potential approaches to further improving the efficacy and effectiveness of these interventions. We conclude with broader recommendations for interventions, including considerations to moderators and under-explored intervention target areas as well as avenues to improve access and availability of evidence-based interventions through leveraging underutilized workforces and leveraging technology.

[Formula: see text] Neurocognition in children with cognitive disengagement syndrome: accurate but slow.

Cognitive disengagement syndrome (CDS), previously termed sluggish cognitive tempo (SCT), is characterized by excessive daydreaming, mental confusion, and slowed behavior or thinking. Prior research has found inconsistent relations between CDS and neurocognition, though most studies have used small or ADHD-defined samples, non-optimal measures of CDS, and/or examined limited neurocognitive domains. Accordingly, this study examined the association of parent- and teacher-reported CDS symptoms using a comprehensive neurocognitive battery in a sample of 263 children (aged 8-12) selected with a range of CDS symptomatology. Parents and teachers provided ratings of CDS and ADHD inattentive (ADHD-IN) symptoms. Path analyses were conducted to examine CDS and ADHD-IN as unique predictors of neurocognitive functioning after covarying for age, sex, and family income. CDS symptoms were uniquely associated with slower performance across a range of cognitive domains, including verbal inhibition, rapid naming/reading, planning, divided attention, and set shifting. In contrast, ADHD-IN symptoms were uniquely associated with poorer performance on a Go/NoGo task (inhibition/distractibility), visual scanning and discrimination, and interference control. Findings from the current study, amongst the first to recruit children based on levels of CDS symptomatology, provide the strongest evidence to date that the neurocognitive phenotype of CDS is characterized by slowed cognitive processing, and add to its validity as a separate syndrome from ADHD. If replicated, these findings have implications for assessment, treatment, and school accommodations for CDS. Neuroimaging studies exploring the neurobiological basis of CDS are also needed.

The role of working memory and organizational skills in academic functioning for children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) exhibit difficulties with organizational skills such as task planning, managing materials, and organizing activities that have downstream consequences on academic functioning. At the same time, deficits in working memory have been linked with both the organizational skills difficulties and academic underachievement and underperformance observed in children with ADHD and have been hypothesized to account for the link between organizational and academic functioning. However, the extent to which working memory and organizational skills independently versus jointly contribute to ADHD-related academic difficulties remains unclear. METHOD: The present study is the first to examine the unique and shared roles of working memory and organizational skills for explaining ADHD-related underachievement and underperformance in a clinically evaluated sample of 309 children with and without ADHD (Mage = 10.34, SD = 1.42; 123 girls; 69.6% White Not Hispanic or Latino). RESULTS: Bias-corrected, bootstrapped latent path analyses revealed that working memory and organizational skills together accounted for 100% of the academic achievement (d = -1.09) and 80.6% of the academic performance (d = -0.58) difficulties exhibited by children with ADHD. Working memory (d = -0.95 to -0.26), organizational skills (d = -0.30 to -0.11), and shared variance across working memory and organizational skills (d = -0.13 to -0.06) each independently predicted ADHD-related difficulties in both academic achievement and performance outcomes. CONCLUSIONS: These findings are consistent with models suggesting that working memory has downstream consequences for functional impairments in ADHD, as well as evidence that organizational skills and working memory are each important predictors of ADHD-related academic functioning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Working memory and math skills in children with and without ADHD.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) frequently demonstrate deficits in working memory and in multiple domains of math skills, including underdeveloped problem-solving and computation skills. The Baddeley model of working memory posits a multicomponent system, including a domain-general central executive and two domain-specific subsystems-phonological short-term memory and visuospatial short-term memory. Extant literature indicates a strong link between neurocognitive deficits in working/short-term memory and math skills; however, the extent to which each component of working/short-term memory may account for this relation is unclear. METHOD: The present study was the first to use bifactor (S·I-1) modeling to examine relations between each working/short-term memory subcomponent (i.e., central executive, phonological short-term memory, and visuospatial short-term memory), ADHD symptoms, and math skills in a clinically evaluated sample of 186 children ages 8-13 (Myears = 10.40, SD = 1.49; 62 girls; 69% White/non-Hispanic). RESULTS: Structural equation modeling indicated that all three working/short-term memory components exert a significant and approximately equal effect on latent math skills (ß = .29-.50, all p < .05) and together explain 56% of the variance in children's math achievement (R² = .56). Exploratory analyses indicated that teacher-reported ADHD inattentive symptoms provided a small but significant contribution to predicting latent math skills (ΔR² = .07) and accounted for 24% of the central executive/math association. CONCLUSIONS: These findings suggest that math difficulties in children with ADHD and clinically evaluated children without ADHD are associated, in large part, with their neurocognitive vulnerabilities in working/short-term memory and, to a lesser extent, overt ADHD symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Social functioning in children with ADHD: an examination of inhibition, self-control, and working memory as potential mediators.

Children with attention-deficit/hyperactivity disorder (ADHD) experience a host of social problems, in addition to significant impairments in behavioral inhibition, working memory, and self-control. Behavioral inhibition and working memory difficulties have been linked with social functioning deficits, but to date, most studies have examined these neurocognitive problems either in isolation or as an aggregate measure in relation to social problems, and none has considered the role of self-control. Thus, it remains unclear whether all of these executive functions are linked with social problems or if the link can be more parsimoniously explained by construct overlap. Fifty-eight children with ADHD and 63 typically developing (TD) children completed tests assessing self-control, behavioral inhibition, and working memory; parents and teachers rated children's social functioning. Examination of potential indirect effects with the bootstrapping procedure indicated that working memory mediated the relation between group membership (ADHD, TD) and child social functioning based on teacher but not parent ratings. Behavioral inhibition and self-control did not have direct relations with either parent- or teacher-rated social functioning. These findings point to important differences regarding how executive functioning difficulties manifest at school compared to home, as well as the specific executive function components that predict ADHD-related social difficulties.

Working memory and inhibitory control deficits in children with ADHD: an experimental evaluation of competing model predictions.

Introduction: Children with ADHD demonstrate difficulties on many different neuropsychological tests. However, it remains unclear whether this pattern reflects a large number of distinct deficits or a small number of deficit(s) that broadly impact test performance. The current study is among the first experiments to systematically manipulate demands on both working memory and inhibition, with implications for competing conceptual models of ADHD pathogenesis. Method: A clinically evaluated, carefully phenotyped sample of 110 children with ADHD, anxiety disorders, or co-occurring ADHD+anxiety (Mage=10.35, 44 girls; 69% White Not Hispanic/Latino) completed a counterbalanced, double dissociation experiment, with two tasks each per inhibition (low vs. high) x working memory (low vs. high) condition. Results: Bayesian and frequentist models converged in indicating that both manipulations successfully increased demands on their target executive function (BF10>5.33x108, p<.001). Importantly, occupying children's limited capacity working memory system produced slower response times and reduced accuracy on inhibition tasks (BF10>317.42, p<.001, d=0.67-1.53). It also appeared to differentially reduce inhibition (and non-inhibition) accuracy for children with ADHD relative to children with anxiety (BF10=2.03, p=.02, d=0.50). In contrast, there was strong evidence against models that view working memory deficits as secondary outcomes of underlying inhibition deficits in ADHD (BF01=18.52, p=.85). Discussion: This pattern indicates that working memory broadly affects children's ability to inhibit prepotent tendencies and maintain fast/accurate performance, and may explain the errors that children with ADHD make on inhibition tests. These findings are broadly consistent with models describing working memory as a causal mechanism that gives rise to secondary impairments. In contrast, these findings provide evidence against models that view disinhibition as a cause of working memory difficulties or view working memory as a non-causal correlate or epiphenomenon in ADHD.

Does Anxiety Systematically Bias Estimates of Executive Functioning Deficits in Pediatric Attention-Deficit/Hyperactivity Disorder?

Growing evidence suggests that childhood ADHD is associated with larger impairments in working memory relative to inhibition. However, most studies have not considered the role of co-occurring anxiety on these estimates - a potentially significant confound given prior evidence that anxiety may increase working memory difficulties but decrease inhibition difficulties for these children. The current study extends prior work to examine the extent to which co-occurring anxiety may be systematically affecting recent estimates of the magnitude of working memory/inhibitory control deficits in ADHD. The carefully-phenotyped sample included 197 children with ADHD and 142 children without ADHD between the ages of 8 and 13 years (N = 339; Mage = 10.31, SD = 1.39; 144 female participants). Results demonstrated that ADHD diagnosis predicted small impairments in inhibitory control (d = 0.31) and large impairments in working memory (d = 0.99). However, child trait anxiety assessed dimensionally across multiple informants (child, parent, teacher) did not uniquely predict either executive function, nor did it moderate estimates of ADHD-related working memory/inhibition deficits. When evaluating anxiety categorically and controlling for ADHD, anxiety diagnosis predicted slightly better working memory (d = 0.19) but not inhibitory control for clinically evaluated children generally. Findings from the current study indicate that trait anxiety, measured dimensionally or categorically, does not differentially affect estimates of executive dysfunction in pediatric ADHD. Further, results suggest that trait anxiety is generally not associated with executive dysfunction above and beyond the impact of co-occurring ADHD. Future research is needed to further assess the role of anxiety in ADHD behavioral symptomatology, neurocognitive functioning, and mechanisms underlying these relations.

Nuclear Import and Export of YAP and TAZ.

Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they also play key roles in tumorigenesis and metastasis formation. Their activity is primarily regulated by their localization, that is, Hippo pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details of such prevailing retention models have been elucidated, much less is known about their actual nuclear traffic: import and export. Although their size is not far from the cutoff for passive diffusion through the nuclear pore complex (NPC), and they do not contain any classic nuclear localization (NLS) or nuclear export signal (NES), evidence has been accumulating that their shuttling involves mediated and thus regulatable/targetable processes. The aim of this review is to summarize emerging information/concepts about their nucleocytoplasmic shuttling, encompassing the relevant structural requirements (NLS, NES), nuclear transport receptors (NTRs, karyophererins), and NPC components, along with the potential transport mechanisms and their regulation. While dissecting retention vs. transport is often challenging, the emerging picture suggests that YAP/TAZ shuttles across the NPC via multiple, non-exclusive, mediated mechanisms, constituting a novel and intriguing facet of YAP/TAZ biology.