Critical Time Window Research Articles

Deciphering temporal gene expression dynamics during epilepsy development using a rat model of focal neocortical epilepsy.

Epilepsy involves significant changes in neural cells during epileptogenesis. Although the molecular mechanism of epileptogenesis remains obscure, changes in gene regulation play a crucial role in the evolution of epilepsy. This study aimed to compare changes in a subset of specific genes during epilepsy development, focusing on the period after the first spontaneous seizure, to identify critical time windows for targeting different regulators. Using a rat model of acquired focal neocortical epilepsy induced by tetanus toxin, we characterized gene expression at acute, subacute, and chronic stages (48-72 h, 2 weeks, and 30 days after first spontaneous seizure, respectively), focusing on genes' potential contribution to epilepsy progression. We observed dynamic changes in the expression of these genes throughout the period after the first spontaneous seizure. Astrocytic reactions primarily occur early, before epilepsy is well established. Changes in Mtor (mammalian target of rapamycin) and Rest (repressor element 1 silencing transcription factor) signaling pathways are highly dynamic and correlated with the progression of epilepsy development. Ccl2 (chemokine C-C-motif ligand) is upregulated at the chronic stage, indicating activation of the neuroinflammatory pathway. Finally, Gabra5 (γ-aminobutyric acidergic signaling) is downregulated at the late stage after epilepsy is established. Surprisingly, changes in the expression of specific genes are linked to the time since the first seizure, rather than seizure frequency or duration. These results suggest that the regulation of specific genes is essentially stage-dependent during the development of epilepsy, highlighting the importance of targeting specific genes at appropriate stages of epilepsy development.

The excessive tonic inhibition of the peri-infarct cortex depresses low gamma rhythm power during post-stroke recovery.

The cortex immediately surrounding a brain ischemic lesion, the peri-infarct cortex, harbors a large part of the potential to recover lost functions. However, our understanding of the neurophysiological conditions in which synaptic plasticity operates, remains limited. Here we hypothesized that the chronic imbalance between excitation and inhibition of the peri-infarct cortex prevents the normalization of the gamma rhythm, a waveband of neural oscillations thought to orchestrate action potential trafficking. Probing the local field potential activity of the forelimb primary sensory cortex (S1FL) located in the peri-infarct cortex of male adult mice, we found a constant, deep reduction of low-gamma oscillation power (L-gamma; 30-50 Hz) precisely during the critical time window for recovery (1 to 3 weeks after stroke). The collapse of L-gamma power negatively corelated with behavioral progress in affected forelimb use. Mapping astrocyte reactivity and GABA-like immunoreactivity in the peri-infarct cortex revealed a parallel high signal, which gradually increased when approaching the lesion. Increasing tonic inhibition with local infusion of GABA or by blocking its recapture reduced L-gamma oscillation power in a magnitude similar to stroke. Conversely, the negative allosteric modulation of tonic GABA conductance using L655,708 or the gliopeptide ODN rescued the L-gamma power of the peri-infarct cortex. Altogether the present data point-out that the chronic excess of ambient GABA in the peri-infarct cortex limits the generation of L-gamma oscillations in the repairing cortex and suggests that rehabilitative interventions aimed at normalizing low-gamma power within the critical period of stroke recovery could optimize the restitution of lost functions.Significance Statement After a stroke, the recovery of lost motor function depends on the reorganization of surviving neural networks. However, the excitation/inhibition balance in the repairing area is suboptimal as it leans excessively towards inhibition. In this work, using an in vivo approach, we demonstrate here that this imbalance, occurring during the critical window for recovery, leads to the collapse of gamma oscillations, a crucial cerebral rhythm for organizing neural communication. This study reinforces the concept of timely therapeutic interventions aimed at correcting the pathological oscillatory regimen of stroke recovery to enhance plasticity.

Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo

BackgroundThe first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.ResultsPseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77–82%; lncRNA 15–17%; pseudogenes 4–5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.ConclusionsHuman lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

Timing of intravenous immunoglobulin treatment and outcome in Guillain-Barré syndrome: Is time nerve?

Despite treatment, a considerable proportion of patients with Guillain-Barré syndrome (GBS) experience poor recovery, highlighting a therapeutic need. There is a lack of evidence that treatment timing affects recovery. This study aims to investigate the effects of intravenous immunoglobulin (IVIg) timing on disability and speed of recovery in GBS. We performed a retrospective study of 136 IVIg-treated GBS patients admitted to two Korean centers between 2010 and 2021. We analyzed the effect of time to IVIg on the GBS disability scale (GBS-DS) and the degree of improvement from nadir (∆GBS-DS) at 1, 3, 6, and 12 months, as well as the time to regain the ability to walk or run unaided. Time to IVIg was treated either as a continuous variable or categorized into 1-week intervals to explore critical time windows. Known prognostic factors, the modified Erasmus GBS Outcome Scores on admission and pre-treatment serum albumin levels were adjusted as covariates. Shorter time to IVIg was independently associated with better GBS-DS, greater ∆GBS-DS, and shorter time to walk or run unaided at all time points. The therapeutic effect of IVIg was notably diminished when administered beyond the first 2 weeks of onset. Our study highlights the timing of IVIg as a modifiable prognostic factor in GBS. The earlier IVIg is initiated, the better the outcomes, with the ideal time window being within the first 2 weeks. These findings underscore the importance of prompt diagnosis and early intervention to optimize recovery in GBS patients.

Reversal of neurodevelopmental impairment and cognitive enhancement by pharmacological intervention with the polyphenol polydatin in a Down syndrome model

Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. ID in DS is largely attributable to neurogenesis and dendritogenesis alterations taking place in the prenatal/neonatal period, the most critical time window for brain development. There are currently no treatments for ID in DS. Considering the timeline of brain development, treatment aimed at improving the neurological phenotypes of DS should be initiated as early as possible and use safe agents. The goal of this study was to establish whether it is possible to improve DS-linked neurodevelopmental defects through early treatment with polydatin, a natural polyphenol. We used the Ts65Dn mouse model of DS and focused on the hippocampus, a brain region fundamental for long-term memory. We found that in Ts65Dn mice of both sexes treated with polydatin from postnatal (P) day 3 to P15 there was full restoration of neurogenesis, neuron number, and dendritic development. These effects were accompanied by normalization of Cyclin D1 and DSCAM levels, which may account for the rescue of neurogenesis and dendritogenesis, respectively. Importantly, in Ts65Dn mice treated with polydatin from P3 to adolescence (∼P50) there was full restoration of hippocampus-dependent memory, indicating a pro-cognitive outcome of treatment. No adverse effects were observed on the body and brain weight. The efficacy and safety of polydatin in a model of DS prospect the possibility of its use during early life stages for amelioration of DS-linked neurodevelopmental alterations.

Open-field exploration immediately before the retention test impairs retrieval and spaced fear extinction of contextual fear memory

According to the behavioral tagging theory, various stages of fear memory, such as contextual fear conditioning, memory retrieval, and fear extinction, can be facilitated by the exploration of a novel open field (OF). A critical time window of efficacy exists for this process. Novel exploration closely adjacent to weak learning may interfere with the setting of the learning tag, leading to a negative effect. In this mouse study, we consistently showed that exposure to a novel or familiar OF immediately prior to the retention test impaired the retrieval of long-term contextual fear memory. However, OF exposure had no effect on the retrieval of recent or remote cued fear memory or short-term contextual fear memory or the reconsolidation of contextual fear memory. In addition, OF exposure impaired spaced but not massed extinction of contextual fear memory. These results suggest that interfering stimulus may result in the transient forgetting of fear memory; however, temporary loss of fear may lead to retention failure of fear extinction. The results of this study are an important complement to the behavioral tagging theory and may provide new guidance for the treatment of post-traumatic stress disorder.

Identification of candidate genes and pathways involved in the establishment of sexual size dimorphism in the olive flounder (Paralichthys olivaceus) using RNA-seq

Olive flounder (Paralichthys olivaceus) is a valuable mariculture fish that shows female-biased sexual size dimorphism (SSD), yet the molecular mechanisms responsible for this phenomenon remain poorly understood. In this study, the growth differences between females and males were compared, and comparative transcriptome analyses of brains/pituitaries, livers, muscles, and gonads from 13-month-old females and males were performed. The critical time window for SSD was from 13- to 14-month-old, with females reaching significantly larger sizes than males. Muscle cell size and plasma growth hormone (GH), insulin-like growth factor 1 and 2 (IGF1, IGF2), 11-ketotestosterone (11-KT), and 17β-estradiol (E2) levels had no significant differences between the sexes of 13- and 14-month-old flounders. Furthermore, the RNA-seq data revealed differential expression in the genes encoding the receptors for these hormones, suggesting that regulation may occur at the receptor level, potentially leading to SSD during the critical window. RNA-seq analysis identified 88, 645, 414, and 15,833 differentially expressed genes between females and males in brains/pituitaries, livers, muscles, and gonads, respectively. KEGG (Kyoto Encyclopedia of Genes and Genomes) and GSEA-based KEGG analyses revealed that some pathways associated with growth and development, including “prolactin signaling pathway” in brains/pituitaries, “cell cycle”, “oocyte meiosis”, and “DNA replication” in livers, “focal adhesion”, “ECM-receptor interaction”, “protein digestion and absorption”, “arginine and proline metabolism”, and “cysteine and methionine metabolism” in muscles, and “Hippo signaling pathway” and “JAK-STAT signaling pathway” in gonads may be involved in the establishment of sexual growth differences. Notably, females had lower steroid hormone synthesis abilities than males in brains/pituitaries, livers, and gonads, indicating the importance of sex steroid hormones in the establishment of SSD. Moreover, genes including frizzled3 (fzd3) and prolactin (prl) in brains/pituitaries, and growth hormone receptor (ghr), estrogen receptor (esr1), insulin-like growth factor binding protein-3 (igfbp3), bone morphogenetic protein 8A-like (bmp8a), leptin receptor (lepr), and lipoprotein lipase-like (lpl) in livers emerge as potential candidates for the establishment of SSD. In conclusion, this study may help clarify the molecular mechanisms involved in SSD-related growth traits in flounder and provide basic data for genetic breeding of flounder.

Histological observations and transcriptome analyses reveal the dynamic changes in the gonads of the blotched snakehead (Channa maculata) during sex differentiation and gametogenesis

BackgroundBlotched snakehead (Channa maculata) displays significant sexual dimorphism, with males exhibiting faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. Nonetheless, the intricate processes governing the development of bipotential gonads into either testis or ovary in C. maculata remain inadequately elucidated. Therefore, it is necessary to determine the critical time window of sex differentiation in C. maculata, providing a theoretical basis for sex control in production practices.MethodsThe body length and weight of male and female C. maculata were measured at different developmental stages to reveal when sexual dimorphism in growth initially appears. Histological observations and spatiotemporal comparative transcriptome analyses were performed on ovaries and testes across various developmental stages to determine the crucial time windows for sex differentiation in each sex and the sex-related genes. Additionally, qPCR and MG2C were utilized to validate and locate sex-related genes, and levels of E2 and T were quantified to understand sex steroid synthesis.ResultsSexual dimorphism in growth became evident starting from 90 dpf. Histological observations revealed that morphological sex differentiation in females and males occurred between 20 and 25 dpf or earlier and 30–35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in testes and ovaries after 30 dpf. The periods of 40–60 dpf and 60–90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in male sex differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and development. Numerous biological pathways linked to sex differentiation and gametogenesis were also identified. Additionally, E2 and T exhibited sexual dimorphism during sex differentiation and gonadal development. Based on these results, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a–Dmrt1–Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development.ConclusionsThis study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, establishing a scientific foundation for sex control in this species.

Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ± 0.4% for the free drug vs. 5.6 ± 0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ± 11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ± 16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention.

Childhood Helicobacter pylori infection: Impacts of environmental exposures and parental stress

BackgroundHelicobacter pylori infection (HPI) is extremely common in the world, particularly in less developed areas, but the primary causes of childhood HPI are unspecified. ObjectivesTo determine the influences of exposure to home environmental factors (HEFs), outdoor air pollutants (OAPs), and parental stress (PS), as well as their interactions on children’s HPI. MethodsWe implemented a retrospective cohort study with 8689 preschoolers from nine districts at Changsha, China, was conducted using questionnaires to collect data of health and HEFs. Temperature and OAPs data were collected from ten and eight monitoring stations, individually. Temperature and OAPs exposures were calculated for all home addresses using the inversed distance weighted (IDW) model. Multiple logistic regression analysis was carried out to determine the separate and combined impacts of HEFs, OAPs, and PS on HPI. ResultsChildren’s HPI was significantly associated with exposure to moisture-specific indoor allergens in one-year preceding conception, gestation, and first year, smoke-specific air pollution throughout life, and plant-specific allergens in previous year. Outdoor exposures to CO in the 7th-9th month before conception, as well as PM2.5 in the second trimester and previous year, were associated with HPI, with ORs (95 % CIs) of 1.22 (1.05–1.41), 1.23 (1.03–1.46), and 1.33 (1.14–1.55). Parents’ socioeconomic and psychological stress indicators were positively related to HPI. High socioeconomic indicators and psychological stresses increased the roles of indoor renovation and moisture indicators as well as outdoor SO2, PM2.5 and O3 on children’s HPI over their entire lives. Parental psychological stress interacts with indoor renovation-specific air pollution, moisture- and plant-specific allergens, as well as outdoor traffic-related air pollution on HPI, during a critical time window in early life. ConclusionsIndoor and outdoor air pollutants, as well as allergens, separately and interactively exert important effects on childhood HPI, lending support to the “(pre-) fetal origin of HPI” hypothesis.

Impact of temperature and relative humidity variability on children’s allergic diseases and critical time window identification

BackgroundThe effects of temperature and relative humidity on different types of children’s allergic diseases have not been comprehensively evaluated so far. This study aims to assess the impact of temperature and relative humidity variability on children’s allergic diseases and to identify the critical time window.MethodsWe collected outpatient data on allergen testing in children between July 2020 and January 2022 from the Affiliated Children’s Hospital of Nanjing Medical University. We defined the 1st, 10th, 90th, and 99th percentiles as extreme cold, moderate cold, moderate hot, and extreme hot for temperature, and as low, moderate high, and extreme high for relative humidity, respectively. A distributed lag nonlinear model (DLNM) combined with a binomial regression model was used to assess the possible nonlinear relationship at different periods. Subgroup analysis by gender and age was conducted.ResultsWe found that extreme and moderate cold temperatures were positively associated with skin allergies and total allergies (28 days: OR = 4.69, 95% CI: 2.88, 7.63; OR = 3.36, 95% CI: 2.39, 4.73) and (28 days: OR = 3.76, CI: 2.43, 5.81; OR = 2.71, 95% CI: 2.00, 3.68), respectively. Moderate and extreme hot temperatures were negatively associated with food allergies (28 days: OR = 0.13, 95% CI: 0.04, 0.41 and OR = 0.04; 95% CI: 0.01, 0.27). Low relative humidity was negatively associated with respiratory allergies, skin allergies, and total allergic diseases (28 days: OR = 0.26, 95% CI: 0.10, 0.71; OR = 0.29, 95% CI: 0.15, 0.55; and OR = 0.42, 95% CI: 0.26, 0.68). Meanwhile, extreme high relative humidity was negatively associated with respiratory allergies, and positively associated with skin allergies, food allergies, and total allergies (28 days: OR = 0.16, 95%CI: 0.07, 0.37; OR = 3.60, 95% CI: 2.52, 5.14; OR = 15.61, 95% CI: 3.23, 75.56; and OR = 2.33, 95% CI: 1.73, 3.15). A stronger relationship between temperature, relative humidity, and allergic diseases was observed in children under 5 years, specifically girls.ConclusionsOur study provides evidence that temperature and relative humidity variability may be associated with allergic diseases, however, the directionality of the relationship differs by allergic type.

Asbestos Surveillance Program Aachen (ASPA): Cancer mortality among asbestos exposed power industry workers

BackgroundThe time between initial asbestos exposure and asbestos-related disease can span several decades. The Asbestos Surveillance Program aims to detect early asbestos-related diseases in a cohort of 8,565 power industry workers formerly exposed to asbestos. Research questionHow does asbestos exposure patterns affect cancer mortality and the duration of latency until death? MethodsA mortality follow-up was conducted with available vital status for 8,476 participants (99 %) and available death certificates for 89.9 % of deceased participants. Standardised mortality ratios (SMR) were calculated for asbestos-related cancers. The SMR of mesothelioma and lung cancer were stratified by exposure duration, cumulative asbestos exposure and smoking. The effect of age at first exposure, cumulative asbestos exposure and smoking on the duration of latency until death was examined using multiple linear regression analysis. ResultsThe mortality risk of mesothelioma (n = 104) increased with cumulative asbestos exposure but not with exposure duration; the highest mortality (SMR: 23.20; 95 % CI: 17.62–29.99) was observed in participants who performed activities with short extremely high exposures (steam turbine revisions). Lung cancer mortality (n = 215) was not increased (SMR: 1.03; 95 % CI: 0.89–1.17). Median latency until death was 46 (15–63) years for mesothelioma and 44 (15–70) years for lung cancer and deaths occurred between age 64 and 82 years. Latency until death was not influenced by age at first exposure, cumulative exposure, or smoking. ConclusionCumulative dose seems to be more appropriate than exposure duration for estimating the risk of mesothelioma death. Additionally, exposure with high cumulative doses in short time should be considered. Since only lung cancer mortality, not incidence, was recorded in this study, lung cancer risk associated with asbestos exposure could not be assessed and the lung cancer mortality was lower than expected probably due to screening effects and improved treatments. The critical time window of death from asbestos-related cancer is between the seventh and ninth decade of life. Future studies should further explore the concept of latency, especially since large ranges are reported throughout the literature.

Development of systemic and mucosal immune responses against gut microbiota in early life and implications for the onset of allergies.

The early microbial colonization of human mucosal surfaces is essential for the development of the host immune system. Already during pregnancy, the unborn child is prepared for the postnatal influx of commensals and pathogens via maternal antibodies, and after birth this protection is continued with antibodies in breast milk. During this critical window of time, which extends from pregnancy to the first year of life, each encounter with a microorganism can influence children's immune response and can have a lifelong impact on their life. For example, there are numerous links between the development of allergies and an altered gut microbiome. However, the exact mechanisms behind microbial influences, also extending to how viruses influence host-microbe interactions, are incompletely understood. In this review, we address the impact of infants' first microbial encounters, how the immune system develops to interact with gut microbiota, and summarize how an altered immune response could be implied in allergies.

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β1-42 (Aβ1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Butyrate metabolism in rumen epithelium affected by host and diet regime through regulating microbiota in a goat model

The rumen is an important organ that enables ruminants to digest nutrients. However, the biological mechanism by which the microbiota and its derived fatty acids regulate rumen development is still unclear. In this study, 18 female Haimen goats were selected and slaughtered at d 30, 60, and 90 of age. Multi-omics analyses (rumen microbial sequencing, host transcriptome sequencing, and rumen epithelial metabolomics) were performed to investigate host–microbe interactions from preweaning to postweaning in a goat model. With increasing age, and after the introduction of solid feed, the increased abundances of Prevotella and Roseburia (P < 0.05) showed positive correlations with volatile fatty acid (VFA) levels and morphological parameters (P < 0.05). Epithelial transcriptomic analysis showed that the expression levels of hub genes, including 3-hydroxy-3-methylglutaryl-CoA synthase isoform 2 (HMGCS2), enoyl-CoA hydratase, short chain 1 (ECHS1), and peroxisome proliferator activated receptor gamma (PPARG), were positively associated with animal phenotype (P < 0.05). These hub genes were mainly correlated to VFA metabolism, oxidative phosphorylation, and the mechanistic target of rapamycin kinase (mTOR) and peroxisome proliferator activated receptor (PPAR) signaling pathways (P < 0.05). Moreover, the primary metabolites in the epithelium changed from glucose preweaning to (R)-3-hydroxybutyric acid (BHBA) and acetoacetic acid (ACAC) postweaning (P < 0.05). Diet and butyrate were the major factors shaping epithelial metabolomics in young ruminants (P < 0.05). Multi-omics analysis showed that the rumen microbiota and VFAs were mainly associated with the epithelial transcriptome, and that alterations in gene expression influenced host metabolism. The “butanoate metabolism” pathway, which transcriptomic and metabolomic analyses identified as being upregulated with age, produces ketones that regulate the “oxidative phosphorylation” pathway, which could provide energy for the development of rumen papillae. Our findings reveal the changes that occur in the rumen microbiota, host transcriptome, and metabolome with age, and validate the role of microbiota-derived VFAs in manipulating host gene expression and subsequent metabolism. This study provides insight into the molecular mechanisms of host–microbe interactions in goats and supplies a theoretical basis and guidance for precise nutritional regulation during the critical time window for rumen development of young ruminants.

When to Go Against the Flow: Examining Patterns of Performance Over Multiday Migration Events in the Hawaiian Stream Fish, 'O'opu Nōpili (Sicyopterus stimpsoni).

Many animals migrate across regions of their geographic range as part of extended events, with groups of individuals proceeding through areas of travel on several successive days. Early migrating individuals may have an advantage over late migrating individuals by gaining early access to the resources at the eventual destination. For situations where early access to resources would provide an advantage, specific sets of locomotor traits might be found among individuals that are earlier migrators. We tested for associations between migration timing and traits related to escape responses, climbing, and morphology in the amphidromous Hawaiian stream goby, 'o'opu nōpili (Sicyopterus stimpsoni). In this species, juvenile fish migrate in pulses over several days immediately following flash floods. We collected daily measurements of escape responses and waterfall climbing from juvenile fish arriving at streams from the ocean. We found that escape performance showed mainly stochastic variation across migrating individuals tested on successive days. In contrast, some metrics of climbing performance decrease over successive pulses during a migration event. We also found more variation in body shape among fish from early pulses during migration events compared to later in pulses. These results could have implications for guiding conservation efforts, identifying critical time windows for protection as periods with the greatest likelihood of successful migrants.

Change in cognitive performance during seven-year follow-up in midlife is associated with sex, age, and education – The Cardiovascular Risk in Young Finns Study

ObjectiveSex, age, and education are associated with the level of cognitive performance. We investigated whether these factors modulate the change in cognitive performance in midlife by leveraging the longitudinal data from the Cardiovascular Risk in Young Finns Study (YFS).MethodsParticipants of the YFS cohort performed a computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB) in 2011 and 2018 (n = 1671, age 41–56 years in 2018). Overall cognitive performance and domains representing learning and memory, working memory, reaction time, and information processing were extracted by common principal component analysis from the longitudinal cognitive data. Linear models adjusted for baseline cognitive performance were used to study the association of sex, age, and education with changes in overall cognitive performance and in the cognitive domains.ResultsCognitive performance decreased in all domains (overall cognition -0.56 SD, p < 0.001; working memory -0.81 SD, p < 0.001; learning and memory -0.70 SD, p < 0.001; reaction time -0.06 SD, p = 0.019; information processing -0.03 SD, p = 0.016). The decrease in working memory and information processing was greater in females compared to males. Cognitive performance decreased more in older participants in all domains. Education alleviated the decrease in cognitive performance in all domains except reaction time. The beneficial effect of education was greater for males.ConclusionsThis study describes the natural course of aging-related changes in cognitive performance in midlife, the critical time window for early prevention of clinical cognitive decline. These findings provide a reference for studies focusing on determinants of pathological cognitive decline deviating from normal changes in cognitive performance.

Recently Identified Mesoproterozoic Strata in South‐Central Idaho Document Late‐Stage Rifting of the Nuna Supercontinent in Western Laurentia

AbstractSedimentary basins are valuable archives of tectonic processes involved in continental rifting. The northern Rocky Mountains preserve the Belt Supergroup, one of the most complete records of Mesoproterozoic strata on Earth; however, debate remains about its tectonic origin. We investigated a recently identified package of Mesoproterozoic strata at Leaton Gulch near Challis, Idaho, using a combination of traditional and newer sedimentological tools. Results suggest that the Leaton Gulch stratigraphic section was deposited in a fluvial setting ca. 1,380–1,317 Ma, spanning the poorly documented interval between late Belt Supergroup deposition at ∼1,370 Ma and recently characterized Deer Trail Group strata that are less than 1,300 Ma. Detrital zircon age distributions from Leaton Gulch demonstrate a similar provenance signature to Missoula Group rocks of the upper Belt Supergroup; however, Leaton Gulch strata are up to ∼70 Ma younger than most prior age constraints on Belt Supergroup rocks. Regional metabentonites (interpreted as metamorphosed reworked tuffs) found within Leaton Gulch and Missoula Group strata show dominantly radiogenic εHf(t), with a range of −8 to +15, interpreted as a mix of primary mantle and remelted metasedimentary sources. Zircon trace element data of the metabentonite from Leaton Gulch suggest a 1,450–1,300 Ma geochemically consistent and moderate–high silica melt source. Collectively, the strata of Leaton Gulch record basin sedimentation during a critical window of Mesoproterozoic time. We speculate that sedimentation during late‐stage Belt Supergroup deposition thickened and stepped westward, abandoning the main Belt basin, culminating with breakup of the Nuna Supercontinent.

Narrative review of occupational exposures and noncommunicable diseases.

Within the scope of the Exposome Project for Health and Occupational Research on applying the exposome concept to working life health, we aimed to provide a broad overview of the status of knowledge on occupational exposures and associated health effects across multiple noncommunicable diseases (NCDs) to help inform research priorities. We conducted a narrative review of occupational risk factors that can be considered to have "consistent evidence for an association," or where there is "limited/inadequate evidence for an association" for 6 NCD groups: nonmalignant respiratory diseases; neurodegenerative diseases; cardiovascular/metabolic diseases; mental disorders; musculoskeletal diseases; and cancer. The assessment was done in expert sessions, primarily based on systematic reviews, supplemented with narrative reviews, reports, and original studies. Subsequently, knowledge gaps were identified, e.g. based on missing information on exposure-response relationships, gender differences, critical time-windows, interactions, and inadequate study quality. We identified over 200 occupational exposures with consistent or limited/inadequate evidence for associations with one or more of 60+ NCDs. Various exposures were identified as possible risk factors for multiple outcomes. Examples are diesel engine exhaust and cadmium, with consistent evidence for lung cancer, but limited/inadequate evidence for other cancer sites, respiratory, neurodegenerative, and cardiovascular diseases. Other examples are physically heavy work, shift work, and decision latitude/job control. For associations with limited/inadequate evidence, new studies are needed to confirm the association. For risk factors with consistent evidence, improvements in study design, exposure assessment, and case definition could lead to a better understanding of the association and help inform health-based threshold levels. By providing an overview of knowledge gaps in the associations between occupational exposures and their health effects, our narrative review will help setting priorities in occupational health research. Future epidemiological studies should prioritize to include large sample sizes, assess exposures prior to disease onset, and quantify exposures. Potential sources of biases and confounding need to be identified and accounted for in both original studies and systematic reviews.

Mu-opioid receptor activation in the habenula modulates synaptic transmission and depression-like behaviors

Opioid system dysregulation in response to stress is known to lead to psychiatric disorders including major depression. Among three different types of opioid receptors, the mu-type receptors (mORs) are highly expressed in the habenula complex, however, the action of mORs in this area and its interaction with stress exposure is largely unknown. Therefore, we investigated the roles of mORs in the habenula using male rats of an acute learned helplessness (aLH) model. First, we found that mOR activation decreased both excitatory and inhibitory synaptic transmission onto the lateral habenula (LHb). Intriguingly, this mOR-induced synaptic depression was reduced in an animal model of depression compared to that of controls. In naïve animals, we found an unexpected interaction between mORs and the endocannabinoid (eCB) signaling occurring in the LHb, which mediates presynaptic alteration occurring with mOR activation. However, we did not observe presynaptic alteration by mOR activation after stress exposure. Moreover, selective mOR activation in the habenula before, but not after, stress exposure effectively reduced helpless behaviors compared to aLH animals. Our observations are consistent with clinical reports suggesting the involvement of mOR signaling in depression, and additionally reveal a critical time window of mOR action in the habenula for ameliorating helplessness symptoms.