Separable effects of the approximate number system, symbolic number knowledge, and number ordering ability on early arithmetic development.

There is evidence that early variations in the development of an approximate number system (ANS) and symbolic number understanding are both influences on the later development of formal arithmetic skills. We report a large-scale (N = 552) longitudinal study of the predictors of arithmetic spanning a critical developmental period (the first 3 years of formal education). Variations in early knowledge of symbolic representations of number and the ordinal associations between them are direct predictors of later arithmetic skills. The development of number ordering ability is in turn predicted by earlier variations in arithmetic, the ANS (numerosity judgments), and rapid automatized naming (RAN). These findings have important implications for theories of numerical and arithmetical development and potentially for the teaching of these skills.

The Production Effect Improves Memory in 7- to 10-Year-Old Children.

The production effect-whereby reading words aloud improves memory for those words relative to reading them silently-was investigated in two experiments with 7- to 10-year-old children residing in Brisbane, Australia. Experiment 1 (n = 41) involved familiar printed words, with words read aloud or silently appearing either in mixed- or blocked-list formats in a within-subject design. Recognition for words read aloud was better than for those read silently, an effect consistent across both list formats. These results were confirmed in Experiment 2 (n = 40) using longer lists of printed novel nonwords. Final analyses indicated that the production effect was comparable for words and nonwords. Findings are discussed in relation to the distinctiveness account and the use of production as a mnemonic in children.

Data on numerosity discrimination, inhibition and arithmetic during the early school years.

Participants consisted of 496 children (mean age = 6 years; 9 months) recruited from 11 schools in Brisbane, Australia. Children were assessed on the addition and subtraction subtests of the Test of Basic Arithmetic and Number Skills (TOBANS), an adapted version of the Head-Toes-Knees-Shoulders task to measure inhibition, numerosity discrimination using eight subtests varying ratio (2:3 or 5:6) and congruency, and non-verbal cognitive ability using an adapted version of Raven's Coloured Progressive Matrices. Information on children's demographics (gender, English as an additional language, and learning difficulty status) is also provided. All assessments were administered during the second year of formal schooling (i.e. Grade 1). Findings regarding the impact of inhibition on the relation between numerosity discrimination and arithmetic are reported elsewhere [1].

Stage 2 Registered Report: There is no appreciable relationship between strength of hand preference and language ability in 6- to 7-year-old children.

Background: Weak or inconsistent hand preference has been postulated to be a risk factor for developmental language delay. Following on from our Registered Stage 1 report this study assessed the extent to which variations in language skills are associated with the strength of hand preference. Methods: Data are drawn from a large sample ( N = 569) of 6- to 7-year-old children unselected for ability, assessed at two time points, 6 months apart. Hand preference was assessed using the Quantitative Hand Preference (QHP) task and five uni-manual motor tasks. Language skills (expressive and receptive vocabulary, receptive grammar, and morphological awareness) were assessed with standardized measures. Results: We found QHP scores did not distinguish children with weaker language skills from those with stronger language skills and the correlation between QHP scores and language ability was negligible in this study. Hand preference on the QHP task was significantly stronger among right-handed than left-handed children and left-handed children were typically inconsistent in the hand used across different tasks.  Conclusions: The findings presented here fail to provide any support for the theory that weak cerebral lateralisation (as assessed here by the QHP task) places children at risk of language difficulties . Stage 1 report:  https://doi.org/10.12688/wellcomeopenres.15077.1.

The relationship between numerosity discrimination and arithmetic skill reflects the approximate number system and cannot be explained by inhibitory control.

Numerosity discrimination tasks (judging which of two random dotarrays contains the larger number) have been widely used as a measure of the efficiency of an approximate number system (ANS) and are a correlate of early arithmetic skills. Recently, it has been suggested that the relationship between numerosity discrimination and arithmeticis explained by inhibition rather than the ANS. We assessed this hypothesis in astudy of 496 children (mean age = 81.23 months) using numerosity discrimination tasks that manipulated the congruency between surface area and numerosity. Numerosity discrimination for incongruent arrays (which are postulated to require inhibition due to a conflict between judgments based on surface area rather than numerosity) was more difficult than that for congruent arrays. However, all numerosity discrimination tasks showed substantial correlations with each other and correlated with arithmetic. A latent variable path model showed that a general numerosity judgment factorcorrelated witharithmetic even after controlling for a measure of response inhibition. In contrast, numerosity discrimination for incongruent arrays showed no unique relationship with arithmetic ability. Our results do not support the view that the relationship between numerosity discrimination and arithmetic is largely attributable to inhibition; rather, theyare consistent withthe view that numerosity discrimination tasks tap the operation of an ANS.

Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Stage 1 Registered Report: The relationship between handedness and language ability in children.

Weak or inconsistent hand preference may be a risk factor for developmental language delay.  This study will test the extent to which variations in language skills are associated with the strength of hand preference. Data are drawn from a large sample (n = 569) of 6- to 7-year-old children unselected for ability, assessed at two time points, 6 months apart. Hand preference is assessed using the Quantitative Hand Preference task (QHP) and five uni-manual motor tasks. Language skills (expressive and receptive vocabulary, receptive grammar, and morphological awareness) are assessed with standardized measures. If weak cerebral lateralisation (as assessed by the QHP task) is a risk factor for language difficulties, it should be possible to detect such effects in the large representative sample of children examined here.

Learning correspondences between magnitudes, symbols and words: Evidence for a triple code model of arithmetic development.

According to the Triple Code Model, early arithmetic development depends on learning the mappings between non-verbal representations of magnitude (quantity) and symbolic verbal (number words) and visual (Arabic numerals) representations of number. We examined this hypothesis in a sample of 166 4- to 7-year old children. Children completed 4 paired-associate learning tasks and a broad range of measures assessing early numerical (symbolic and non-symbolic magnitude comparison, digit writing, arithmetic) and reading skills (letter-sound knowledge, phoneme awareness, rapid automatized naming, word reading). A path model showed that paired-associate learning tasks involving mapping magnitudes onto verbal or visual stimuli predicted arithmetic performance over and above other well-established predictors. This relationship was specific to arithmetic and, consistent with the Triple Code Model, highlights that mapping between non-symbolic magnitude representations and the corresponding symbolic forms (verbal and visual) is important to the development of arithmetic skills.

Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.

Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.

Emojis: Insights, Affordances, and Possibilities for Psychological Science.

We live in a digital society that provides a range of opportunities for virtual interaction. Consequently, emojis have become popular for clarifying online communication. This presents an exciting opportunity for psychologists, as these prolific online behaviours can be used to help reveal something unique about contemporary human behaviour.

The cognitive foundations of early arithmetic skills: It is counting and number judgment, but not finger gnosis, that count.

Following on from ideas developed by Gerstmann, a body of work has suggested that impairments in finger gnosis may be causally related to children's difficulties in learning arithmetic. We report a study with a large sample of typically developing children (N=197) in which we assessed finger gnosis and arithmetic along with a range of other relevant cognitive predictors of arithmetic skills (vocabulary, counting, and symbolic and nonsymbolic magnitude judgments). Contrary to some earlier claims, we found no meaningful association between finger gnosis and arithmetic skills. Counting and symbolic magnitude comparison were, however, powerful predictors of arithmetic skills, replicating a number of earlier findings. Our findings seriously question theories that posit either a simple association or a causal connection between finger gnosis and the development of arithmetic skills.

Is It a Name or a Fact? Disambiguation of Reference Via Exclusivity and Pragmatic Reasoning.

Adults reason by exclusivity to identify the meanings of novel words. However, it is debated whether, like children, they extend this strategy to disambiguate other referential expressions (e.g., facts about objects). To further inform this debate, this study tested 41 adults on four conditions of a disambiguation task: label/label, fact/fact, label/fact, and fact/label (Scofield & Behrend, ). Participants also provided a verbal explanation for their referent selections to tease apart the underlying processes. Results indicated that adults successfully discerned the target object in the label/label and label/fact condition, yet not the remaining two conditions. Verbal reports indicated that the strategy utilized to disambiguate differed depending upon communicative context. These findings confirm that the tendency to reason by exclusivity becomes restricted to word-learning situations with growing linguistic and communicative experience.

Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men.

BACKGROUND: Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions. METHODS: A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One rectal tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS: Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS: Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.

Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men.

BACKGROUND: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. METHODS: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. RESULTS: SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). CONCLUSIONS: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. CLINICAL TRIALS REGISTRATION: NCT00775294.

Brief report: are children with autism proficient word learners?

Many approaches to word learning argue for the importance of joint attention and other social-pragmatic abilities. This study explored word learning in children with autism (CWA), by examining it in ostensive and non-ostensive contexts, tested through both comprehension and elicited production. Novel nouns were taught to 17 CWA and 13 children with moderate learning difficulties (MLD) using an adapted version of Tomasello and Barton's (Developmental Psychology, 30: 639-650, 1994) search paradigm. In elicited production for words learnt within an ostensive context, CWA performed at a significantly higher level than MLD children. This is contrary to prior findings and suggests that word learning abilities in CWA have been underestimated.