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We conducted a rat exposure study to assess the impacts of dose and co-exposure with other rare earth elements (REEs) on the toxicokinetics of praseodymium (Pr) and cerium (Ce). We first determined the kinetic profiles of elemental Pr and Ce in blood, urine and feces along with tissue levels at sacrifice on the seventh day following intravenous injection of PrCl 3 or CeCl 3 at 0.3 or 1 mg/kg bw (of the chloride salts) in adult male Sprague–Dawley rats (n = 5 per group). In blood, Pr and Ce half-lives for the initial phase (t1/2 α ) increased with increasing doses, while their half-lives for the terminal phase (t1/2 β ) were similar at both doses. In urine, a minor excretion route, no significant effect of the dose on the cumulative excretion was apparent. In feces, a major excretion route, the fraction of the Pr dose recovered was significantly lower at the 1 mg/kg bw dose compared to the 0.3 mg/kg bw dose, while no significant dose effect was apparent for Ce. In the liver and spleen, which are the main sites of REEs accumulation, there was a significant effect of the dose only for Ce retention in the spleen ( i.e. , increased retention of Ce in spleen at higher dose). Results were compared with those of a previous toxicokinetic study with a similar design but an exposure to a quaternary mixture of CeCl 3 , PrCl 3 , NdCl 3 and YCl 3 , each administered at 0.3 mg/kg bw or 1 mg/kg bw. A mixture effect was apparent for the initial elimination phase (t1/2 α ) of Pr and Ce from blood and for the fecal excretion of Ce at the 1 mg/kg bw. In urine and liver, there was no evident overall mixture effect; in the spleen, there was a higher retention of Pr and Ce in rats exposed to the mixture at the 0.3 mg/kg bw, but not at the 1 mg/kg bw dose. Overall, this study showed that the dose and mixture exposure are two important factors to consider as determinants of the toxicokinetics of REEs.

There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose–response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment.

Risk assessments are increasingly reliant on information from in vitro assays. The in vitro micronucleus test (MNvit) is a genotoxicity test that detects chromosomal abnormalities, including chromosome breakage (clastogenicity) and/or whole chromosome loss (aneugenicity). In this study, MNvit datasets for 292 chemicals, generated by the US EPA’s ToxCast program, were evaluated using a decision tree-based pipeline for hazard identification. Chemicals were tested with 19 concentrations ( n  = 1) up to 200 µM, in the presence and absence of Aroclor 1254-induced rat liver S9. To identify clastogenic chemicals, %MN values at each concentration were compared to a distribution of batch-specific solvent controls; this was followed by cytotoxicity assessment and benchmark concentration (BMC) analyses. The approach classified 157 substances as positives, 25 as negatives, and 110 as inconclusive. Using the approach described in Bryce et al. (Environ Mol Mutagen 52:280–286, 2011), we identified 15 (5%) aneugens. IVIVE (in vitro to in vivo extrapolation) was employed to convert BMCs into administered equivalent doses (AEDs). Where possible, AEDs were compared to points of departure (PODs) for traditional genotoxicity endpoints; AEDs were generally lower than PODs based on in vivo endpoints. To facilitate interpretation of in vitro MN assay concentration–response data for risk assessment, exposure estimates were utilized to calculate bioactivity exposure ratio (BER) values. BERs for 50 clastogens and two aneugens had AEDs that approached exposure estimates (i.e., BER < 100); these chemicals might be considered priorities for additional testing. This work provides a framework for the use of high-throughput in vitro genotoxicity testing for priority setting and chemical risk assessment.

Background/Objectives: Self-care has great potential to benefit consumers and health systems, but its mainstream adoption is hindered by a systemic lack of consumer health literacy (HL). Published data on consumer awareness of self-care and HL are limited for regions in Asia, and are needed to develop interventions to enhance HL and self-care for diverse populations in this region. The aim of this research was to describe and analyze patterns of HL and awareness of self-care among consumers in Asia. Methods: We conducted a mixed-methods study comprising qualitative focus group discussions (FGDs; 64 participants) followed by a quantitative online survey (1200 participants) among consumers in four Asian countries (India, Philippines, Malaysia, and Republic of Korea). We examined five dimensions of HL and self-care relevant to consumers: actively managing health; confidence/skills to find and access health information; confidence/skills to appraise information; support from social circle; and support from healthcare providers. From the quantitative survey, responses for 16 questions covering the five dimensions were used to calculate the Consumer Health Literacy Quotient (CHLQ; normalized range 0–100), an index we developed to assess HL in the context of personal wellness and self-treatable conditions. Latent class analysis (LCA) was applied to identify distinctive patterns of consumer HL within the sample. Results: The mean CHLQ was 75 out of 100 (SD ± 12.9), indicating ‘moderate’ levels of consumer HL across the countries. LCA identified five distinct consumer HL profiles, differing in their average CHLQ (overall score) and along the CHLQ dimensions. Consistent with CHLQ results, the profiles differed in their response patterns for common self-manageable ailments. Conclusions: This study identified distinct patterns of HL and awareness of self-care among consumers in four Asian countries through combined use of the CHLQ and quantitative profiling. This offers a promising approach for understanding self-care-related HL among consumers in Asia. Our findings on patterns of strengths and weakness in specific dimensions of HL and self-care in diverse populations can inform research, communications, and targeted interventions to empower consumers and foster self-care.

In vitro toxicology has used immortalized cancer cell lines as model human systems for decades. However, these cell lines pose problems in designing toxicity testing programs as they inherently do not represent normal human biology. There is also a huge number of such cell lines to choose from, derived from human cancer cells from nearly every tissue. We explored the idea of using available basal gene expression data (NCI-60 cell line panel and Human GTEx tissue data) to determine if there was sufficient variability in cell line gene expression to group cell lines by relevance to specific human tissues. The transcriptomic analysis suggests that the variability in gene expression in cancer cell lines and in normal human tissue is minimal. The overall basal gene expression of cancer cells lines even overlapped normal human tissue gene expression. While some human tissues (e.g., lung) have basal expression profiles that do not appear to be like any cancer cell line, including cancers that may be derived from the same tissue, most human tissues show basal expression profiles comparable to several cancer cell lines. These results are important to address the genomic baseline and variability of cancer cell lines used for new approach methods of toxicity testing.

This study investigates how norepinephrine (NE) and acetylcholine (ACh) in the prefrontal cortex (PFC) modulate inhibitory control, a critical executive function. Using fluorescent sensors, we tracked prefrontal NE/ACh dynamics in mice during inhibitory control tasks and found strong NE-ACh coherence at 0.4–0.8 Hz. Inhibiting locus coeruleus (LC) neurons projecting to the basal forebrain (BF) induced greater impairments in inhibitory control than targeting those projecting to the PFC, despite partial overlap. This inhibition disrupted NE-ACh phase synchrony between successful and failed trials, indicating its importance. Conversely, silencing cholinergic neurons projecting to the LC did not affect task performance or phase synchrony. Neuropixels recordings revealed that disrupting LC-BF projections impaired PFC neuronal encoding and altered population firing patterns linked to inhibitory control. These findings suggest that the LC and cholinergic systems jointly modulate inhibitory control by influencing NE-ACh synchrony and its effect on PFC activity, underscoring their role in cognitive control. The role of norepinephrine (NE) and acetylcholine (ACh) signaling in the cognitive control of impulsivity remains unclear. Here, the authors reveal that impulse control depends on phase synchrony between NE and ACh dynamics in the prefrontal cortex.

Human mesenchymal stem cells (hMSC) are a population of multipotent cells that can differentiate into osteoblasts, chondrocytes, adipocytes, and other cells. The exact mechanism governing the differentiation of hMSC into osteoblasts remains largely unknown. Here, we analyzed protein expression profiles of undifferentiated as well as osteogenic induced hMSC using 2-D gel electrophoresis (2-DE), mass spectrometry (MS), and peptide mass fingerprinting (PMF) to investigate the early gene expression in osteoblast differentiation. We have generated proteome maps of undifferentiated hMSC and osteogenic induced hMSC on day 3 and day 7. 2-DE revealed 102 spots with at least 2.0-fold changes in expression and 52 differently expressed proteins were successfully identified by MALDI-TOF-MS. These proteins were classified into 7 functional categories: metabolism, signal transduction, transcription, calcium-binding protein, protein degradation, protein folding and others. The expression of some identified proteins was confirmed by further RT-PCR analyses. This study clarifies the global proteome during osteoblast differentiation. Our results will play an important role in better elucidating the underlying molecular mechanism in hMSC differentiation into osteoblasts.

Inhibitory control is a critical executive function that allows animals to suppress their impulsive behavior in order to achieve certain goals or avoid punishment. We investigated norepinephrine (NE) and acetylcholine (ACh) dynamics and population neuronal activity in the prefrontal cortex (PFC) during inhibitory control. Using fluorescent sensors to measure extracellular levels of NE and ACh, we simultaneously recorded prefrontal NE and ACh dynamics in mice performing inhibitory control tasks. The prefrontal NE and ACh signals exhibited strong coherence at 0.4-0.8 Hz. Although inhibition of locus coeruleus (LC) neurons projecting to the PFC impaired inhibitory control, inhibiting LC neurons projecting to the basal forebrain (BF) caused a more profound impairment, despite an approximately 30% overlap between LC neurons projecting to the PFC and BF, as revealed by our tracing studies. The inhibition of LC neurons projecting to the BF did not diminish the difference in prefrontal NE/ACh signals between successful and failed trials; instead, it abolished the difference in NE-ACh phase synchrony between successful and failed trials, indicating that NE-ACh phase synchrony is a task-relevant neuromodulatory feature. Chemogenetic inhibition of cholinergic neurons that project to the LC region did not impair inhibitory control, nor did it abolish the difference in NE-ACh phase synchrony between successful or failed trials, further confirming the relevance of NE-ACh phase synchrony to inhibitory control. To understand the possible effect of NE-ACh synchrony on prefrontal population activity, we employed Neuropixels to record from the PFC during inhibitory control. The inhibition of LC neurons projecting to the BF not only reduced the number of prefrontal neurons encoding inhibitory control, but also disrupted population firing patterns representing inhibitory control, as revealed by a demixed principal component (dPCA) analysis. Taken together, these findings suggest that the LC modulates inhibitory control through its collective effect with cholinergic systems on population activity in the prefrontal cortex. Our results further indicate that NE-ACh phase synchrony is a critical neuromodulatory feature with important implications for cognitive control.

Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and Tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine (NE) reuptake inhibition can worsen memory deficits in the ADLP mouse model. However, the effects of long-term LC stimulation in Tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear. To evaluate the impact of long-term locus coeruleus stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunohistochemical analysis. The radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunohistochemistry was employed to examine Tau phosphorylation, neurodegeneration, and neuroinflammation. Long-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased AEP expression, Tau hyperphosphorylation, and astrocyte activation. Long-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Elevated norepinephrine levels resulting from long-term LC stimulation may increase AEP expression, contributing to Tau hyperphosphorylation in the LC.