Animacy-induced conflict in sentence production and comprehension from late childhood to adolescence.

Some animacy configurations elicit parallel semantic interference in adult production and comprehension; for example, phrases with similar animate nouns like the man that the girl is hugging are more difficult than phrases like the doll that the girl is hugging. Yet little is known about how this interference manifests in development, particularly, beyond early childhood. Because frontal brain maturation and cognitive control improvements are known to occur across late childhood and adolescence, we investigated (a) how animacy-induced difficulty in production and comprehension vary with age throughout this period and (b) whether control processes reflected in the backward digit span (BDS) test uniquely explained these differences besides other language measures. In separate tasks, participants (8- to 15-year-old children; N = 91) heard auditory descriptions of depicted characters, produced characters' descriptions, and completed BDS, vocabulary, and reading experience tests. Results indicated that, as in adults, animacy modulated performance in production and comprehension across all ages. The animacy modulation interacted with age in production but not in comprehension, suggesting age-related animacy differences in production but relatively stable differences in comprehension despite processing speed improvements. Importantly, these age-related production differences were also modulated by the BDS scores; only participants with higher BDS scores displayed age-related animacy differences. Together, these results indicate that comprehension and production develop at different rates and that the development of BDS performance interacts with age-dependent changes in sentence planning from late childhood to adolescence. More generally, the study highlights tasks' disparities to be explained by cognitive and developmental models of language.

Does the maturation of early sleep patterns predict language ability at school entry? A Born in Bradford study.

Children's vocabulary ability at school entry is highly variable and predictive of later language and literacy outcomes. Sleep is potentially useful in understanding and explaining that variability, with sleep patterns being predictive of global trajectories of language acquisition. Here, we looked to replicate and extend these findings. Data from 354 children (without English as an additional language) in the Born in Bradford study were analysed, describing the mean intercepts and linear trends in parent-reported day-time and night-time sleep duration over five time points between 6 and 36 months-of-age. The mean difference between night-time and day-time sleep was predictive of receptive vocabulary at age five, with more night-time sleep relative to day-time sleep predicting better language. An exploratory analysis suggested that socioeconomic status was predictive of vocabulary outcomes, with sleep patterns partially mediating this relationship. We suggest that the consolidation of sleep patterns acts as a driver of early language development.

Advances toward Curing HIV-1 Infection in Tissue Reservoirs.

A disease of more than 39.6 million people worldwide, HIV-1 infection has no curative therapy. To date, one man has achieved a sterile cure, with millions more hoping to avoid the potential pitfalls of lifelong antiretroviral therapy and other HIV-related disorders, including neurocognitive decline. Recent developments in immunotherapies and gene therapies provide renewed hope in advancing efforts toward a sterilizing or functional cure. On the horizon is research concentrated in multiple separate but potentially complementary domains: vaccine research, viral transcript editing, T-cell effector response targeting including checkpoint inhibitors, and gene editing. Here, we review the concept of targeting the HIV-1 tissue reservoirs, with an emphasis on the central nervous system, and describe relevant new work in functional cure research and strategies for HIV-1 eradication.

Timing storytime to maximize children's ability to retain new vocabulary.

Shared storybook reading is a key aid to vocabulary acquisition during childhood. However, word learning research has tended to use unnaturalistic (explicit) training regimes. Using a storybook paradigm, we examined whether children (particularly those with weaker vocabularies) are more likely to retain new words if they learn them closer to sleep. Parents read their children (5- to 7-year-olds; N = 237) an alien adventure story that contained 12 novel words with illustrations at one of two training times: at bedtime or 3-5 h before bedtime. Using online tasks, parents tested their children's ability to recall the new words (production) and associate them with pictures (comprehension) immediately after hearing the story and again the following morning. As hypothesized, we replicated two findings. First, children showed overnight improvements in their ability to produce and comprehend new words when tested again the next day. Second, children with better existing vocabulary knowledge showed larger overnight gains in new word comprehension. Counter to expectations, overnight gains in comprehension were larger if the story was read 3-5 h before bedtime rather than at bedtime. These ecologically valid findings are consistent with theories that characterize word learning as a prolonged process supported by mechanisms such as consolidation and retrieval practice, with existing vocabulary knowledge acting as an important source of variability in retention. The findings provide preliminary evidence that encountering new words in stories later in the day (but not too close to sleep) may help to harness vocabulary growth and may be more beneficial than leaving shared storybook reading just for bedtime.

Sleep-dependent consolidation in children with comprehension and vocabulary weaknesses: it'll be alright on the night?

BACKGROUND: Vocabulary is crucial for an array of life outcomes and is frequently impaired in developmental disorders. Notably, 'poor comprehenders' (children with reading comprehension deficits but intact word reading) often have vocabulary deficits, but underlying mechanisms remain unclear. Prior research suggests intact encoding but difficulties consolidating new word knowledge. We test the hypothesis that poor comprehenders' sleep-associated vocabulary consolidation is compromised by their impoverished lexical-semantic knowledge. METHODS: Memory for new words was tracked across wake and sleep to assess encoding and consolidation in 8-to-12-year-old good and poor comprehenders. Each child participated in two sets of sessions, one beginning in the morning (AM-encoding) and the other in the evening (PM-encoding). In each case, they were taught 12 words and were trained on a spatial memory task. Memory was assessed immediately, 12- and 24-hr later via stem-completion, picture-naming, and definition tasks to probe different aspects of word knowledge. Long-term retention was assessed 1-2 months later. RESULTS: Recall of word-forms improved over sleep and postsleep wake, as measured in both stem-completion and picture-naming tasks. Counter to hypotheses, deficits for poor comprehenders were not observed in consolidation but instead were seen across measures and throughout testing, suggesting a deficit from encoding. Variability in vocabulary knowledge across the whole sample predicted sleep-associated consolidation, but only when words were learned early in the day and not when sleep followed soon after learning. CONCLUSIONS: Poor comprehenders showed weaker memory for new words than good comprehenders, but sleep-associated consolidation benefits were comparable between groups. Sleeping soon after learning had long-lasting benefits for memory and may be especially beneficial for children with weaker vocabulary. These results provide new insights into the breadth of poor comprehenders' vocabulary weaknesses, and ways in which learning might be better timed to remediate vocabulary difficulties.

Atypicalities in sleep and semantic consolidation in autism.

Sleep is known to support the neocortical consolidation of declarative memory, including the acquisition of new language. Autism spectrum disorder (ASD) is often characterized by both sleep and language learning difficulties, but few studies have explored a potential connection between the two. Here, 54 children with and without ASD (matched on age, nonverbal ability and vocabulary) were taught nine rare animal names (e.g., pipa). Memory was assessed via definitions, naming and speeded semantic decision tasks immediately after learning (pre-sleep), the next day (post-sleep, with a night of polysomnography between pre- and post-sleep tests) and roughly 1 month later (follow-up). Both groups showed comparable performance at pre-test and similar levels of overnight change on all tasks; but at follow-up children with ASD showed significantly greater forgetting of the unique features of the new animals (e.g., pipa is a flat frog). Children with ASD had significantly lower central non-rapid eye movement (NREM) sigma power. Associations between spindle properties and overnight changes in speeded semantic decisions differed by group. For the TD group, spindle duration predicted overnight changes in responses to novel animals but not familiar animals, reinforcing a role for sleep in the stabilization of new semantic knowledge. For the ASD group, sigma power and spindle duration were associated with improvements in responses to novel and particularly familiar animals, perhaps reflecting more general sleep-associated improvements in task performance. Plausibly, microstructural sleep atypicalities in children with ASD and differences in how information is prioritized for consolidation may lead to cumulative consolidation difficulties, compromising the quality of newly formed semantic representations in long-term memory.

Offline consolidation supersedes prior knowledge benefits in children's (but not adults') word learning.

Prior linguistic knowledge is proposed to support the acquisition and consolidation of new words. Adults typically have larger vocabularies to support word learning than children, but the developing brain shows enhanced neural processes that are associated with offline memory consolidation. This study investigated contributions of prior knowledge to initial word acquisition and consolidation at different points in development, by teaching children and adults novel words (e.g., ballow) that varied in the number of English word-form "neighbours" (e.g., wallow, bellow). Memory for the novel word-forms was tested immediately after training, the next day and 1 week later, to assess the time-course of prior knowledge contributions. Children aged 7-9 years (Experiments 1, 3) and adults (Experiment 2) recalled words with neighbours better than words without neighbours when tested immediately after training. However, a period of offline consolidation improved overall recall and reduced the influence of word-form neighbours on longer term memory. These offline consolidation benefits were larger in children than adults, supporting theories that children have a greater propensity for consolidating phonologically distinctive language information. Local knowledge of just a single word-form neighbour was enough to enhance learning, and this led to the individual differences in word recall that were related to adults' global vocabulary ability. The results support the proposal that the relative contributions of different learning mechanisms change across the lifespan, and highlight the importance of testing theoretical models of word learning in the context of development.

Human endogenous retrovirus-K (HML-2): a comprehensive review.

The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered "junk DNA" and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.

Consolidation of vocabulary is associated with sleep in typically developing children, but not in children with dyslexia.

Sleep is known to play an active role in consolidating new vocabulary in adults; however, the mechanisms by which sleep promotes vocabulary consolidation in childhood are less well understood. Furthermore, there has been no investigation into whether previously reported differences in sleep architecture might account for variability in vocabulary consolidation in children with dyslexia. Twenty-three children with dyslexia and 29 age-matched typically developing peers were exposed to 16 novel spoken words. Typically developing children showed overnight improvements in novel word recall; the size of the improvement correlated positively with slow wave activity, similar to previous findings with adults. Children with dyslexia showed poorer recall of the novel words overall, but nevertheless showed overnight improvements similar to age-matched peers. However, comparisons with younger children matched on initial levels of novel word recall pointed to reduced consolidation in dyslexics after 1 week. Crucially, there were no significant correlations between overnight consolidation and sleep parameters in the dyslexic group. This suggests a reduced role of sleep in vocabulary consolidation in dyslexia, possibly as a consequence of lower levels of learning prior to sleep, and highlights how models of sleep-associated memory consolidation can be usefully informed by data from typical and atypical development.

The effect of coloured overlays and lenses on reading: a systematic review of the literature.

PURPOSE: There are many anecdotal claims and research reports that coloured lenses and overlays improve reading performance. Here we present the results of a systematic review of this literature and examine the quality of the evidence. METHODS: We systematically reviewed the literature concerning the effect of coloured lenses or overlays on reading performance by searching the PsychInfo, Medline and Embase databases. This revealed 51 published items (containing 54 data sets). Given that different systems are in use for issuing coloured overlays or lenses, we reviewed the evidence under four separate system headings (Intuitive, Irlen, Harris/Chromagen and Other), classifying each published item using the Cochrane Risk of Bias tool. RESULTS: Although the different colour systems have been subjected to different amounts of scientific scrutiny, the results do not differ according to the system type, or whether the sample under investigation was classified as having visual stress (or a similarly defined condition), reading difficulty, or both. The majority of studies are subject to 'high' or 'uncertain' risk of bias in one or more key aspects of study design or outcome, with studies at lower risk from bias providing less support for the benefit of coloured lenses/overlays on reading ability. While many studies report improvements with coloured lenses, the effect size is generally small and/or similar to the improvement found with a placebo condition. We discuss the strengths and shortcomings of the published literature and, whilst acknowledging the difficulties associated with conducting trials of this type, offer some suggestions about how future trials might be conducted. CONCLUSIONS: Consistent with previous reviews and advice from several professional bodies, we conclude that the use of coloured lenses or overlays to ameliorate reading difficulties cannot be endorsed and that any benefits reported by individuals in clinical settings are likely to be the result of placebo, practice or Hawthorne effects.

Learning and consolidation of new spoken words in autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by rich heterogeneity in vocabulary knowledge and word knowledge that is not well accounted for by current cognitive theories. This study examines whether individual differences in vocabulary knowledge in ASD might be partly explained by a difficulty with consolidating newly learned spoken words and/or integrating them with existing knowledge. Nineteen boys with ASD and 19 typically developing (TD) boys matched on age and vocabulary knowledge showed similar improvements in recognition and recall of novel words (e.g. 'biscal') 24 hours after training, suggesting an intact ability to consolidate explicit knowledge of new spoken word forms. TD children showed competition effects for existing neighbors (e.g. 'biscuit') after 24 hours, suggesting that the new words had been integrated with existing knowledge over time. In contrast, children with ASD showed immediate competition effects that were not significant after 24 hours, suggesting a qualitative difference in the time course of lexical integration. These results are considered from the perspective of the dual-memory systems framework.

Continence advice by telehealth for young people.

Children and young people operate in an advanced technological world where new, exciting opportunities exist for remote interactions. To engage with these service users, we set up a nurse-led telehealth facility that enabled young people with spina bifida to access specialist continence service from home. This article describes efforts to embed this innovation into practice and offer insight to some of the challenges we faced in the process. It offers practical guidance on setting up similar services.

Reliability of the serial reaction time task: If at first you don't succeed, try, try, try again.

Procedural memory is involved in the acquisition and control of skills and habits that underlie rule and procedural learning, including the acquisition of grammar and phonology. The serial reaction time task (SRTT), commonly used to assess procedural learning, has been shown to have poor stability (test-retest reliability). We investigated factors that may affect the stability of the SRTT in adults. Experiment 1 examined whether the similarity of sequences learned in two sessions would impact stability: test-retest correlations were low regardless of sequence similarity (r < .31). Experiment 2 added a third session to examine whether individual differences in learning would stabilise with further training. There was a small (but nonsignificant) improvement in stability for later sessions (Sessions 1 and 2: r = .42; Sessions 2 and 3: r = .60). Stability of procedural learning on the SRTT remained suboptimal in all conditions, posing a serious obstacle to the use of this task as a sensitive predictor of individual differences and ultimately theoretical advance.

Training semantic long-term memory retrieval transfers to executive function and reading fluency.

The retrieval of information from long-term memory is a fundamental cognitive ability, crucial for most aspects of successful human functioning. Whether and how long-term memory retrieval (LTMR) can be improved with training has clear societal importance but also theoretical value for furthering our understanding of underlying mechanisms. Here, we provide electrophysiological evidence for the plasticity of semantic LTMR. Thirty-five university students were randomly assigned to adaptive semantic LTMR training (using a Posner task) or to a non-adaptive version of the training. Before and after training they were assessed on measures of semantic LTMR, working memory, central executive function (interference control, switching), reading fluency, and fluid intelligence. Adaptive LTMR training (relative to non-adaptive training) led to significant improvements in semantic LTMR. The intervention group (in contrast to the control group) also showed a significant reduction in the mean amplitude of the N400 ERP component and 700-1000 ms measured during a semantic LTMR task, suggesting that changes in retrieval occurred at an early/automatic point and retrieval processing in semantic processing. Moreover, transfer effects were observed for switching, working memory and reading fluency, but not for interference control or fluid intelligence. These results point to the plasticity of semantic LTMR, and suggest that improvement in this ability can transfer to other domains for which LTMR is key.

HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes.

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.

Antisense Oligonucleotides for Rapid Translation of Gene Therapy in Glioblastoma.

PURPOSE: The limited efficacy of current treatments for malignant brain tumors necessitates novel therapeutic strategies. This study aimed to assess the potential of antisense oligonucleotides (ASOs) as adjuvant therapy for high-grade gliomas, focusing on their CNS penetration and clinical translation prospects. METHODS: A comprehensive review of the existing literature was conducted to evaluate the implications of ASOs in neuro-oncology. Studies that investigated ASO therapy's efficacy, CNS penetration, and safety profile were analyzed to assess its potential as a therapeutic intervention for high-grade gliomas. RESULTS: ASOs present a promising avenue for enhancing targeted gene therapies in malignant gliomas. Their potent CNS penetration, in vivo durability, and efficient transduction offer advantages over conventional treatments. Preliminary in vivo and in vitro studies suggest ASOs as a viable adjuvant therapy for high-grade gliomas, warranting further exploration in clinical trials. CONCLUSIONS: ASOs hold significant promise as adjuvant therapy for high-grade gliomas, offering improved CNS penetration and durability compared with existing treatments. While preliminary studies are encouraging, additional research is needed to establish the safety and efficacy of ASO therapy in clinical settings. Further investigation and clinical trials are warranted to validate ASOs as a transformative approach in neuro-oncology.

Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation.

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.

Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/ß-catenin signaling in astrocytes: relevance to HIV neuropathogenesis.

Wnt/ß-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/ß-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/ß-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/ß-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/ß-catenin signaling as demonstrated by its inhibition of active ß-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/ß-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit ß-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter ß-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of ß-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with ß-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of ß-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV long terminal repeat. These findings highlight a bidirectional interference between Tat and Wnt/ß-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/ß-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.

Role of ß-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.

The Wnt/ß-catenin pathway is involved in diverse cell functions governing development and disease. ß-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/ß-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active ß-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down ß-catenin or TCF/LEF members in primary astrocytes and astrocytomas transiently transfected with an HIV long terminal repeat (LTR)-luciferase reporter that contained an integrated copy of the HIV LTR-luciferase construct. Knockdown of either ß-catenin or TCF-4 induced LTR activity by 2- to 3-fold under both the episomal and integrated conditions. This knockdown also increased presence of serine 2-phosphorylated RNA polymerase II (Pol II) on the HIV LTR as well as enhanced its processivity. Knockdown of ß-catenin/TCF-4 also impacted tethering of other transcription factors on the HIV promoter. Specifically, knockdown of TCF-4 enhanced binding of C/EBPß, C/EBPδ, and NF-κB to the HIV LTR, while ß-catenin knockdown increased binding of C/EBPß and C/EBPδ but had no effect on NF-κB. Approximately 150 genes in astrocytes were impacted by ß-catenin knockdown, including genes involved in inflammation/immunity, uptake/transport, vesicular transport/exocytosis, apoptosis/cellular stress, and cytoskeleton/trafficking. These findings indicate that modulation of the ß-catenin/TCF-4 axis impacts the basal level of HIV transcription in astrocytes, which may drive low level/persistent HIV in astrocytes that can contribute to ongoing neuroinflammation, and this axis also has profound effects on astrocyte biology.

Identification of novel T cell factor 4 (TCF-4) binding sites on the HIV long terminal repeat which associate with TCF-4, ß-catenin, and SMAR1 to repress HIV transcription.

Molecular regulation of HIV transcription is a multifaceted process dictated in part by the abundance of cellular transcription factors that induce or repress HIV promoter activity. ß-Catenin partners with members of the T cell factor (TCF)/LEF transcription factors to regulate gene expression. The interaction between ß-catenin and TCF-4 is linked to inhibition of HIV replication in multiple cell types, including lymphocytes and astrocytes. Here, we evaluated the molecular mechanism by which ß-catenin/TCF-4 repress HIV replication. We identified for the first time multiple TCF-4 binding sites at -336, -143, +66, and +186 relative to the transcription initiation site on the HIV long terminal repeat (LTR). Two of the sites (-143 and +66) were present in approximately 1/3 of 500 HIV-1 isolates examined. Although all four sites could bind to TCF-4, the strongest association occurred at -143. Deletion and/or mutation of -143, in conjunction with ß-catenin or TCF-4 knockdown in cells stably expressing an LTR reporter construct, enhanced basal HIV promoter activity by 5-fold but had no effect on Tat-mediated transactivation of the HIV LTR. We also found that TCF-4, ß-catenin, and the nuclear matrix binding protein SMAR1 tether at the -143-nucleotide (nt) site on the HIV LTR to inhibit HIV promoter activity. Collectively, these data indicate that TCF-4 and ß-catenin at -143 associate with SMAR1, which likely pulls the HIV DNA segment into the nuclear matrix and away from transcriptional machinery, leading to repression of basal HIV LTR transcription. These studies point to novel avenues for regulation of HIV replication by manipulation of ß-catenin signaling within cells.