Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats.

Air pollutant exposures have been linked to systemic disease; however, the underlying mechanisms between responses of the target tissue and systemic effects are poorly understood. A prototypic inducer of stress, ozone causes respiratory and systemic multiorgan effects through activation of a neuroendocrine stress response. The goal of this study was to assess transcriptomic signatures of multiple tissues and serum metabolomics to understand how neuroendocrine and adrenal-derived stress hormones contribute to multiorgan health outcomes. Male Wistar Kyoto rats (12-13 weeks old) were exposed to filtered air or 0.8 ppm ozone for 4-hours, and blood/tissues were collected immediately post-exposure. Each tissue had distinct expression profiles at baseline. Ozone changed 1,640 genes in lung, 274 in hypothalamus, 2,516 in adrenals, 1,333 in liver, 1,242 in adipose, and 5,102 in muscle (adjusted p-value < 0.1, absolute fold-change > 50%). Serum metabolomic analysis identified 863 metabolites, of which 447 were significantly altered in ozone-exposed rats (adjusted p-value < 0.1, absolute fold change > 20%). A total of 6 genes were differentially expressed in all 6 tissues. Glucocorticoid signaling, hypoxia, and GPCR signaling were commonly changed, but ozone induced tissue-specific changes in oxidative stress, immune processes, and metabolic pathways. Genes upregulated by TNF-mediated NFkB signaling were differentially expressed in all ozone-exposed tissues, but those defining inflammatory response were tissue-specific. Upstream predictor analysis identified common mediators of effects including glucocorticoids, although the specific genes responsible for these predictors varied by tissue. Metabolomic analysis showed major changes in lipids, amino acids, and metabolites linked to the gut microbiome, concordant with transcriptional changes identified through pathway analysis within liver, muscle, and adipose tissues. The distribution of receptors and transcriptional mechanisms underlying the ozone-induced stress response are tissue-specific and involve induction of unique gene networks and metabolic phenotypes, but the shared initiating triggers converge into shared pathway-level responses. This multi-tissue transcriptomic analysis, combined with circulating metabolomic assessment, allows characterization of the systemic inhaled pollutant-induced stress response.

Staying and Returning dynamics of young children's attention.

In this paper, we decompose selective sustained attending behavior into components of continuous attention maintenance and attentional transitions and study how each of these components develops in young children. Our results in two experiments suggest that changes in children's ability to return attention to a target locus after distraction ("Returning") play a crucial role in the development of selective sustained attention between the ages of 3.5-6 years, perhaps to a greater extent than changes in the ability to continuously maintain attention on the target ("Staying"). We further distinguish Returning from the behavior of transitioning attention away from task (i.e., becoming distracted) and investigate the relative contributions of bottom-up and top-down factors on these different types of attentional transitions. Overall, these results (a) suggest the importance of understanding the cognitive process of transitioning attention for understanding selective sustained attention and its development, (b) provide an empirical paradigm within which to study this process, and (c) begin to characterize basic features of this process, namely its development and its relative dependence on top-down and bottom-up influences on attention. RESEARCH HIGHLIGHTS: Young children exhibited an endogenously ability, Returning, to preferentially transition attention to task-relevant information over task-irrelevant information. Selective sustained attention and its development were decomposed into Returning and Staying, or task-selective attention maintenance, using novel eye-tracking-based measures. Returning improved between the ages of 3.5-6 years, to a greater extent than Staying. Improvements in Returning supported improvements in selective sustained attention between these ages.

Intratracheal instillation of respirable particulate matter elicits neuroendocrine activation.

OBJECTIVE: Inhalation of ozone activates central sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal stress axes. While airway neural networks are known to communicate noxious stimuli to higher brain centers, it is not known to what extent responses generated from pulmonary airways contribute to neuroendocrine activation. MATERIALS AND METHODS: Unlike inhalational exposures that involve the entire respiratory tract, we employed intratracheal (IT) instillations to expose only pulmonary airways to either soluble metal-rich residual oil fly ash (ROFA) or compressor-generated diesel exhaust particles (C-DEP). Male Wistar-Kyoto rats (12-13 weeks) were IT instilled with either saline, C-DEP or ROFA (5 mg/kg) and necropsied at 4 or 24 hr to assess temporal effects. RESULTS: IT-instillation of particulate matter (PM) induced hyperglycemia as early as 30-min and glucose intolerance when measured at 2 hr post-exposure. We observed PM- and time-specific effects on markers of pulmonary injury/inflammation (ROFA>C-DEP; 24 hr>4hr) as corroborated by increases in lavage fluid injury markers, neutrophils (ROFA>C-DEP), and lymphocytes (ROFA). Increases in lavage fluid pro-inflammatory cytokines differed between C-DEP and ROFA in that C-DEP caused larger increases in TNF-α whereas ROFA caused larger increases in IL-6. No increases in circulating cytokines occurred. At 4 hr, PM impacts on neuroendocrine activation were observed through depletion of circulating leukocytes, increases in adrenaline (ROFA), and decreases in thyroid-stimulating-hormone, T3, prolactin, luteinizing-hormone, and testosterone. C-DEP and ROFA both increased lung expression of genes involved in acute stress and inflammatory processes. Moreover, small increases occurred in hypothalamic Fkbp5, a glucocorticoid-sensitive gene. CONCLUSION: Respiratory alterations differed between C-DEP and ROFA, with ROFA inducing greater overall lung injury/inflammation; however, both PM induced a similar degree of neuroendocrine activation. These findings demonstrate neuroendocrine activation after pulmonary-only PM exposure, and suggest the involvement of pituitary- and adrenal-derived hormones.

Longitudinal investigation of executive function development employing task-based, teacher reports, and fNIRS multimethodology in 4- to 5-year-old children.

Increased focus on resting-state functional connectivity (rsFC) and the use and accessibility of functional near-infrared spectroscopy (fNIRS) have advanced knowledge on the interconnected nature of neural substrates underlying executive function (EF) development in adults and clinical populations. Less is known about the relationship between rsFC and developmental changes in EF during preschool years in typically developing children, a gap the present study addresses employing task-based assessment, teacher reports, and fNIRS multimethodology. This preregistered study contributes to our understanding of the neural basis of EF development longitudinally with 41 children ages 4-5. Changes in prefrontal cortex (PFC) rsFC utilizing fNIRS, EF measured with a common task-based assessment (Day-Night task), and teacher reports of behavior (BRIEF-P) were monitored over multiple timepoints: Initial Assessment, 72 h follow-up, 1 Month Follow-up, and 4 Month Follow-up. Measures of rsFC were strongly correlated 72 h apart, providing evidence of high rsFC measurement reliability using fNIRS with preschool-aged children. PFC rsFC was positively correlated with performance on task-based and report-based EF assessments. Children's PFC functional connectivity at rest uniquely predicted later EF, controlling for verbal IQ, age, and sex. Functional connectivity at rest using fNIRS may potentially show the rapid changes in EF development in young children, not only neurophysiologically, but also as a correlate of task-based EF performance and ecologically-relevant teacher reports of EF in a classroom context.

Peripheral metabolic effects of ozone exposure in healthy and diabetic rats on normal or high-cholesterol diet.

Epidemiological studies show that individuals with underlying diabetes and diet-associated ailments are more susceptible than healthy individuals to adverse health effects of air pollution. Exposure to air pollutants can induce metabolic stress and increase cardiometabolic disease risk. Using male Wistar and Wistar-derived Goto-Kakizaki (GK) rats, which exhibit a non-obese type-2 diabetes phenotype, we investigated whether two key metabolic stressors, type-2 diabetes and a high-cholesterol atherogenic diet, exacerbate ozone-induced metabolic effects. Rats were fed a normal control diet (ND) or high-cholesterol diet (HCD) for 12 weeks and then exposed to filtered air or 1.0-ppm ozone (6 h/day) for 1 or 2 days. Metabolic responses were analyzed at the end of each day and after an 18-h recovery period following the 2-day exposure. In GK rats, baseline hyperglycemia and glucose intolerance were exacerbated by HCD vs. ND and by ozone vs. air. HCD also resulted in higher insulin in ozone-exposed GK rats and circulating lipase, aspartate transaminase, and alanine transaminase in all groups (Wistar>GK). Histopathological effects induced by HCD in the liver, which included macrovesicular vacuolation and hepatocellular necrosis, were more severe in Wistar vs. GK rats. Liver gene expression in Wistar and GK rats fed ND showed numerous strain differences, including evidence of increased lipid metabolizing activity and ozone-induced alterations in glucose and lipid transporters, specifically in GK rats. Collectively, these findings indicate that peripheral metabolic alterations induced by diabetes and high-cholesterol diet can enhance susceptibility to the metabolic effects of inhaled pollutants.

Diets enriched with coconut, fish, or olive oil modify peripheral metabolic effects of ozone in rats.

Dietary factors may modulate metabolic effects of air pollutant exposures. We hypothesized that diets enriched with coconut oil (CO), fish oil (FO), or olive oil (OO) would alter ozone-induced metabolic responses. Male Wistar-Kyoto rats (1-month-old) were fed normal diet (ND), or CO-, FO-, or OO-enriched diets. After eight weeks, animals were exposed to air or 0.8 ppm ozone, 4 h/day for 2 days. Relative to ND, CO- and OO-enriched diet increased body fat, serum triglycerides, cholesterols, and leptin, while all supplements increased liver lipid staining (OO > FO > CO). FO increased n-3, OO increased n-6/n-9, and all supplements increased saturated fatty-acids. Ozone increased total cholesterol, low-density lipoprotein, branched-chain amino acids (BCAA), induced hyperglycemia, glucose intolerance, and changed gene expression involved in energy metabolism in adipose and muscle tissue in rats fed ND. Ozone-induced glucose intolerance was exacerbated by OO-enriched diet. Ozone increased leptin in CO- and FO-enriched groups; however, BCAA increases were blunted by FO and OO. Ozone-induced inhibition of liver cholesterol biosynthesis genes in ND-fed rats was not evident in enriched dietary groups; however, genes involved in energy metabolism and glucose transport were increased in rats fed FO and OO-enriched diet. FO- and OO-enriched diets blunted ozone-induced inhibition of genes involved in adipose tissue glucose uptake and cholesterol synthesis, but exacerbated genes involved in adipose lipolysis. Ozone-induced decreases in muscle energy metabolism genes were similar in all dietary groups. In conclusion, CO-, FO-, and OO-enriched diets modified ozone-induced metabolic changes in a diet-specific manner, which could contribute to altered peripheral energy homeostasis.

Experience-Driven Semantic Differentiation: Effects of a Naturalistic Experience on Within- and Across-Domain Differentiation in Children.

Organized semantic networks reflecting distinctions within and across domains of knowledge are critical for higher-level cognition. Thus, understanding how semantic structure changes with experience is a fundamental question in developmental science. This study probed changes in semantic structure in 4-6 year-old children (N = 29) as a result of participating in an enrichment program at a local botanical garden. This study presents the first direct evidence that (a) the accumulation of experience with items in a domain promoted increases in both within- and across-domain semantic differentiation, and that (b) this experience-driven semantic differentiation generalized to nonexperienced items. These findings have implications for understanding the role of experience in building semantic networks, and for conceptualizing the contribution of enrichment experiences to academic success.

Lumping and splitting: Developmental changes in the structure of children's semantic networks.

Organized semantic representations encoding across- and within-domain distinctions are a hallmark of mature cognition, and understanding how they change with experience and learning is a key endeavor in developmental science. Existing computational modeling studies provide a mechanistic framework for understanding how structured semantic representations emerge as a result of development and learning. However, their predictions remain largely untested in young children, with the existing evidence providing only indirect tests of these predictions. Across two experiments, we provide the first direct examination of a key prediction derived from these computational models-that early in development, broad across-domain distinctions should generally be more strongly represented relative to finer-grained within-domain distinctions. The results support this hypothesis, being consistent with the exploitation of patterns of covariation among entities as a mechanism supporting the acquisition of structured semantic representations.

A hidden Markov model for analyzing eye-tracking of moving objects : Case study in a sustained attention paradigm.

Eye-tracking provides an opportunity to generate and analyze high-density data relevant to understanding cognition. However, while events in the real world are often dynamic, eye-tracking paradigms are typically limited to assessing gaze toward static objects. In this study, we propose a generative framework, based on a hidden Markov model (HMM), for using eye-tracking data to analyze behavior in the context of multiple moving objects of interest. We apply this framework to analyze data from a recent visual object tracking task paradigm, TrackIt, for studying selective sustained attention in children. Within this paradigm, we present two validation experiments to show that the HMM provides a viable approach to studying eye-tracking data with moving stimuli, and to illustrate the benefits of the HMM approach over some more naive possible approaches. The first experiment utilizes a novel 'supervised' variant of TrackIt, while the second compares directly with judgments made by human coders using data from the original TrackIt task. Our results suggest that the HMM-based method provides a robust analysis of eye-tracking data with moving stimuli, both for adults and for children as young as 3.5-6 years old.

Preventing and identifying hospital-acquired delirium.

Hospital-acquired delirium often goes unnoticed because the signs and symptoms resemble those of dementia and depression, making diagnosis difficult. This article explores the differences between delirium, dementia, and depression and discusses the role of nursing in patient assessment and education.

PARP-3 and APLF function together to accelerate nonhomologous end-joining.

PARP-3 is a member of the ADP-ribosyl transferase superfamily of unknown function. We show that PARP-3 is stimulated by DNA double-strand breaks (DSBs) in vitro and functions in the same pathway as the poly (ADP-ribose)-binding protein APLF to accelerate chromosomal DNA DSB repair. We implicate PARP-3 in the accumulation of APLF at DSBs and demonstrate that APLF promotes the retention of XRCC4/DNA ligase IV complex in chromatin, suggesting that PARP-3 and APLF accelerate DNA ligation during nonhomologous end-joining (NHEJ). Consistent with this, we show that class switch recombination in Aplf(-/-) B cells is biased toward microhomology-mediated end-joining, a pathway that operates in the absence of XRCC4/DNA ligase IV, and that the requirement for PARP-3 and APLF for NHEJ is circumvented by overexpression of XRCC4/DNA ligase IV. These data identify molecular roles for PARP-3 and APLF in chromosomal DNA double-strand break repair reactions.

Rapid, experience-related changes in the organization of children's semantic knowledge.

The organization of knowledge according to relations between concepts is crucially important for many cognitive processes, and its emergence during childhood is a key focus of cognitive development research. Prior evidence about the role of learning and experience in the development of knowledge organization primarily comes from studies investigating differences between preexisting, naturally occurring groups (e.g., children from rural vs. urban settings, children who own a pet vs. children who do not) and a handful of studies on the effects of researcher-developed educational interventions. However, we know little about whether knowledge organization can be relatively rapidly molded by shorter-term real-world learning experiences (e.g., on a timescale of days vs. years or months). The current study investigated whether naturalistic learning experiences can drive rapid measurable changes in knowledge organization in children by investigating the effects of a week-long zoo summer camp (compared with a control school-based camp) on the degree to which 4- to 9-year-old children's knowledge about animals was organized according to taxonomic relations. Although there were no differences in taxonomic organization between the zoo camp and the school-based camp at pretest, only children who participated in the zoo camp showed increases in taxonomic organization at posttest. Moreover, analyses of changes in taxonomic organization in zoo camp children suggested that these changes were primarily driven by improvements in the degree to which children differentiated between taxonomic categories. These findings provide novel evidence that naturalistic experiences can drive rapid changes in knowledge organization.

Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation.

Ozone-induced systemic effects are modulated through activation of the neuro-hormonal stress response pathway. Adrenal demedullation (DEMED) or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effects of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM) prior to their exposure to air or ozone (1ppm), 4h/day for 1 or 2days. Ozone exposure significantly changed the expression of over 2300 genes in lungs of SHAM rats, and these changes were markedly reduced in DEMED and ADREX rats. SHAM surgery but not DEMED or ADREX resulted in activation of multiple ozone-responsive pathways, including glucocorticoid, acute phase response, NRF2, and PI3K-AKT. Predicted targets from sequencing data showed a similarity between transcriptional changes induced by ozone and adrenergic and steroidal modulation of effects in SHAM but not ADREX rats. Ozone-induced increases in lung Il6 in SHAM rats coincided with neutrophilic inflammation, but were diminished in DEMED and ADREX rats. Although ozone exposure in SHAM rats did not significantly alter mRNA expression of Ifnγ and Il-4, the IL-4 protein and ratio of IL-4 to IFNγ (IL-4/IFNγ) proteins increased suggesting a tendency for a Th2 response. This did not occur in ADREX and DEMED rats. We demonstrate that ozone-induced lung injury and neutrophilic inflammation require the presence of circulating epinephrine and corticosterone, which transcriptionally regulates signaling mechanisms involved in this response.

Developmental changes in semantic knowledge organization.

Semantic knowledge is a crucial aspect of higher cognition. Theoretical accounts of semantic knowledge posit that relations between concepts provide organizational structure that converts information known about individual entities into an interconnected network in which concepts can be linked by many types of relations (e.g., taxonomic, thematic). The goal of the current research was to address several methodological shortcomings of prior studies on the development of semantic organization, by using a variant of the spatial arrangement method (SpAM) to collect graded judgments of relatedness for a set of entities that can be cross-classified into either taxonomic or thematic groups. In Experiment 1, we used the cross-classify SpAM (CC-SpAM) to obtain graded relatedness judgments and derive a representation of developmental changes in the organization of semantic knowledge. In Experiment 2, we validated the findings of Experiment 1 by using a more traditional pairwise similarity judgment paradigm. Across both experiments, we found that an early recognition of links between entities that are both taxonomically and thematically related preceded an increasing recognition of links based on a single type of relation. The utility of CC-SpAM for evaluating theoretical accounts of semantic development is discussed.

Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice.

Environmental exposures occurring early in life may have an important influence on cancer risk later in life. Here, we investigated carryover effects of dichloroacetic acid (DCA), a small molecule analog of pyruvate with metabolic programming properties, on age-related incidence of liver cancer. The study followed a stop-exposure/promotion design in which 4-week-old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0 or 3.5g/l) for 10 weeks followed by dH2O or PB (n = 20-30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared with controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (≥85% tumor incidence and number) to those seen after continuous lifetime exposure. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce persistent liver cytotoxicity or preneoplastic changes on histopathology or alter DNA sequence variant profiles within liver tumors compared with controls. Distinct changes in liver messenger RNA and micro RNA profiles associated with prior DCA treatment were not apparent at 98 weeks. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects related to cellular metabolism.

Conceptual influences on induction: A case for a late onset.

This research examines the mechanism of early induction, the development of induction, and the ways attentional and conceptual factors contribute to induction across development. Different theoretical views offer different answers to these questions. Six experiments with 4- and 5-year-olds, 7-year-olds and adults (N=208) test these competing theories by teaching categories for which category membership and perceptual similarity are in conflict, and varying orthogonally conceptual and attentional factors that may potentially affect inductive inference. The results suggest that early induction is similarity-based; conceptual information plays a negligible role in early induction, but its role increases gradually, with the 7-year-olds being a transitional group. And finally, there is substantial contribution of attention to the development of induction: only adults, but not children, could perform category-based induction without attentional support. Therefore, category-based induction exhibits protracted development, with attentional factors contributing early in development and conceptual factors contributing later in development. These results are discussed in relation to existing theories of development of inductive inference and broader theoretical views on cognitive development.

Development of category-based induction and semantic knowledge.

Category-based induction is a hallmark of mature cognition; however, little is known about its origins. This study evaluated the hypothesis that category-based induction is related to semantic development. Computational studies suggest that early on there is little differentiation among concepts, but learning and development lead to increased differentiation based on taxonomic relatedness. This study reports findings from a new task aimed to (a) examine this putative increase in semantic differentiation and (b) test whether individual differences in semantic differentiation are related to category-based induction in 4- to 7-year-old children (N = 85). The results provide the first empirical evidence of an age-related increase in differentiation of representations of animal concepts and suggest that category-based induction is related to increased semantic differentiation.

Endogenously and exogenously driven selective sustained attention: Contributions to learning in kindergarten children.

Selective sustained attention is vital for higher order cognition. Although endogenous and exogenous factors influence selective sustained attention, assessment of the degree to which these factors influence performance and learning is often challenging. We report findings from the Track-It task, a paradigm that aims to assess the contribution of endogenous and exogenous factors to selective sustained attention within the same task. Behavioral accuracy and eye-tracking data on the Track-It task were correlated with performance on an explicit learning task. Behavioral accuracy and fixations to distractors during the Track-It task did not predict learning when exogenous factors supported selective sustained attention. In contrast, when endogenous factors supported selective sustained attention, fixations to distractors were negatively correlated with learning. Similarly, when endogenous factors supported selective sustained attention, higher behavioral accuracy was correlated with greater learning. These findings suggest that endogenously and exogenously driven selective sustained attention, as measured through different conditions of the Track-It task, may support different kinds of learning.

Visual environment, attention allocation, and learning in young children: when too much of a good thing may be bad.

A large body of evidence supports the importance of focused attention for encoding and task performance. Yet young children with immature regulation of focused attention are often placed in elementary-school classrooms containing many displays that are not relevant to ongoing instruction. We investigated whether such displays can affect children's ability to maintain focused attention during instruction and to learn the lesson content. We placed kindergarten children in a laboratory classroom for six introductory science lessons, and we experimentally manipulated the visual environment in the classroom. Children were more distracted by the visual environment, spent more time off task, and demonstrated smaller learning gains when the walls were highly decorated than when the decorations were removed.

Making History in 1 h: How Sex, Aging, Technology, and Elevation Affect the Cycling Hour Record.

PURPOSE: The purpose of this article was to analyze more than a century of cycling hour records (CHR) to examine the effects of sex, age, and altitude on cycling performance. Our hypotheses were that men's performance (distance) would exceed those of women by more than 10% but would decline at similar rates with aging and that altitude would have a small benefit, which might reach a maximum. METHODS: Data were cultivated from the Facebook World Hour Record Discussion Group's crowd-sourced database of more than 600-known-hour records and verified through extensive online research and/or personal communication. Regression and statistical modeling were produced using STATA v15.0. R2 values were used to ascertain model quality, with four distinct models being produced for comparisons. Alpha was set at 0.05 significance for all tests. RESULTS: R2 values ranged from 65% to 74.9%. Women's distances were 10.8% shorter ( P < 0.001) than those of men, but the difference was narrower than either the historical elite women's difference of 14.2% or the 2022 record difference of 13.3%. Age-related decline modeling indicates performance declines significantly past age 40 yr at a rate of 1.08% per year. Altitude had a significant ( P < 0.001) marginal improvement up to 1000 m before declining. The marginal benefits of altitude were small, but this is consistent with the finding benefits reach a maximum at a moderate altitude with "benefits" becoming ambiguous starting at ~1000 m. Technological advancement was estimated to be a small but significant ( P < 0.001) improvement of ~0.18% per year. CONCLUSIONS: Across decades of CHR data in well-trained endurance cyclists, men are only ~11% faster, and this difference remains stable until at least age 80 yr. CHR attempts greater than 500 m likely offer at best a small advantage. Despite small year-on-year improvements, the CHR has likely improved more than 10 km because of technological advancements.