Exposure to prenatal stressors and infant autonomic nervous system regulation of stress.

OBJECTIVES: The purpose of this study was to determine the relationship between fetal exposure to maternal prenatal stressors and infant parasympathetic (PNS) and sympathetic (SNS) nervous function at 3 timepoints across the first year of life. BACKGROUND: Autonomic nervous system impairments may mediate associations between gestational exposure to stressors and later infant health problems. Heart rate variability (HRV) provides a sensitive index of PNS and SNS function. However, no studies have assessed longitudinal associations between prenatal stressors and infant HRV measures of both PNS and SNS over the first year of life. METHODS: During the third trimester of pregnancy, 233 women completed measures of life stressors and depression. At 1, 6 and 12 months of age, a stressor protocol was administered while infant electrocardiographic (ECG) data were collected from a baseline through a post-stressor period. HRV measures of PNS and SNS activity (HF, LF, LF/HF ratio) were generated from ECG data. We used multilevel regression to examine the aims, adjusting for maternal depression and neonatal morbidity. RESULTS: There were no associations between prenatal stressors and any baseline or reactivity HRV metric over the infant's first year of life. However, exposure to more stressors was associated with lower post-stressor LF HRV at both 6 (ß = -.44, p = .001) and 12 (ß = -.37, p = .005) months of age. CONCLUSIONS: Findings suggest potential alterations in development of the vagally mediated baroreflex function as a result of exposure to prenatal stressors, with implications for the infants' ability to generate a resilient recovery in response to stressors.

Infant emotion regulation in the context of stress: Effects of heart rate variability and temperament.

Stressful events are inherently emotional. As a result, the ability to regulate emotions is critical in responding effectively to stressors. Differential abilities in the management of stress appear very early in life, compelling a need to better understand factors that may shape the capacity for emotion regulation (ER). Variations in both biologic and behavioural characteristics are thought to influence individual differences in ER development. We sought to determine the differential contributions of temperament and heart rate variability (HRV; an indicator of autonomic nervous system function) to infant resting state emotionality and emotional reactivity in response to a stressor at 6 months of age. Participants included 108 mother-infant dyads. Mothers completed a measure of infant temperament at 6 months postnatal. Mother and infant also participated in a standardized stressor (the Repeated Still Face Paradigm) at that time. Electrocardiographic data were acquired from the infant during a baseline resting state and throughout the stressor. Fast Fourier Transformation was used to analyse the high frequency (HF) domain of HRV, a measure of parasympathetic nervous system activity. Infant ER was measured via standardized coding of emotional distress behaviours from video-records at baseline and throughout the stressor. Severity of mothers' depressive symptoms was included as a covariate in analyses. Results of linear regression indicate that neither temperament nor HRV were associated significantly with an infant's emotional resting state, although a small effect size was found for the relationship between infant negative affectivity and greater emotional distress (ß = 0.23, p = 0.08) prior to the stressor. Higher HF-HRV (suggesting parasympathetic dominance) was related to greater emotional distress in response to the stressor (ß = 0.34, p = 0.009). This greater emotional reactivity may reflect a more robust capacity to mount an emotional response to the stressor when infants encounter it from a bedrock of parasympathetic activation. Findings may inform eventual markers for assessment of ER in infancy and areas for intervention to enhance infant management of emotions, especially during stressful events.

Associations of iron deficiency and depressive symptoms among young adult males and Females: NHANES 2017 to 2020.

Depression is one of the most prevalent mental health conditions throughout the lifespan. Notable differences in the prevalence of depression among females and males arise during adolescence and may peak during young adulthood. Since iron deficiency is a treatable condition that may contribute to depression, this topic among youth (18 to 25 years of age) needs to be further explored. Thus, our study examines the associations between three measures of iron (ferritin, serum iron, and transferrin saturation levels) with Patient Health Questionnaire-9 (PHQ-9) depressive symptoms and depression among young adult males and females using the National Health and Nutrition Examination Survey (NHANES) 2017-2020. Using multivariable Poisson and logistic regression models, adjusting for several demographic and clinical variables, we report 1) the prevalence of depression and 2) the associations between iron deficiency and depressive symptoms and depression among males and females. 917 participants were included in our study. More females (12.5 %) than males (6.8 %) had PHQ-9 depression. Males with ferritin (adjusted odds ratio [AOR] = 14.13, 95 % confidence interval [CI]: 1.51, 132.21), serum iron (AOR = 4.84, 95 % CI: 1.02, 22.92), and transferrin (AOR = 13.79, 95 % CI: 3.59, 53.06) deficiencies were at higher risk for depression, while females with ferritin deficiency (AOR = 0.34, 95 % CI: 0.11, 0.97) had a lower risk for depression. Our study highlights the need to focus on depression screening among young adults as well as risk factors for depression among this age group. Identifying risk factors and screening for iron deficiency, especially among females, should be considered as well.

The gut microbiota, HPA axis, and brain in adolescent-onset depression: Probiotics as a novel treatment.

Stress-associated disruptions in the development of frontolimbic regions may play a critical role in the emergence of adolescent-onset depression. These regions are particularly sensitive to Hypothalamic-Pituitary-Adrenal (HPA) axis signaling. The HPA axis is hyperactive in adolescent depression, and interventions that attenuate such hyperactivity hold promise as potential treatments. The Microbiome-Gut-Brain (MGB) axis is an important pathway through which stress dysregulates HPA-axis activity and thus exerts deleterious effects on the adolescent brain. Probiotic agents, which alter the gut microbiota composition by introducing bacterial strains with beneficial physiological effects, normalize aberrant HPA-axis activity and reduce depressive symptoms in both animal studies and adult clinical trials. While the potential utility of such agents in treating or preventing adolescent depression remains largely unexplored, recent data suggest the existence of an adolescent sensitive window during which probiotics may be especially efficacious in reducing depressive symptoms compared to effects observed in adult populations. In this review, we outline evidence that probiotic use may attenuate stress effects on frontolimbic development, providing a novel means of improving depressive symptoms among adolescent populations.

Osmotic Gradient Is a Factor That Influences the Gill Microbiota Communities in Oryzias melastigma.

The fish gill is the first tissue that is exposed to the external media and undergoes continuous osmotic challenges. Recently, our group published an article entitled "Integrated Omics Approaches Revealed the Osmotic Stress-Responsive Genes and Microbiota in Gill of Marine Medaka" in the journal mSystems (e0004722, 2022), and suggested the possible host-bacterium interaction in the fish gill during osmotic stress. The previous study was performed by the progressive fresh water transfer (i.e., seawater to fresh water transfer via 50% seawater (FW)). Our group hypothesized that osmotic gradient could be a factor that determines the microbiota communities in the gill. The current 16S rRNA metagenomic sequencing study found that the direct transfer (i.e., seawater to fresh water (FWd)) could result in different gill microbiota communities in the same fresh water endpoints. Pseduomonas was the dominant bacteria (more than 55%) in the FWd gill. The Kyoto Encyclopedia of Genes and Genomes and MetaCyc analysis further suggested that the FWd group had enhanced osmosensing pathways, such as the ATP-binding cassette transporters, taurine degradation, and energy-related tricarboxylic acid metabolism compared to the FW group.

Hypoxia-induced epigenetic transgenerational miRNAs dysregulation involved in reproductive impairment of ovary.

Hypoxia is a potent endocrine disruptor that is posing serious problems to the fish reproductive systems. Our previous studies reported that hypoxia could cause a transgenerational impairment of ovarian development and interfere hatching success in F2 offspring of marine medaka fish (Oryzias melastigma) through epigenetic regulation. As part of the epigenetic regulation, we investigated the involvement of microRNAs (miRNAs) in hypoxia-induced transgenerational reproductive impairments. In the present study, we used comparative small RNA sequencing to reveal that hypoxia caused miRNA dysregulation in ovaries of F0 hypoxia group and F2 transgenerational group. We found 4 common dysregulated miRNA in the F0 and F2 generations. Furthermore, integrated miRNA-mRNA analysis, followed by gene ontology enrichment analysis on the hypoxia-dysregulated miRNA-target genes further highlighted the importance of these dysregulated miRNAs in biological processes related to reproduction. More importantly, we identified 3 miRNA-mRNA pairs (novel miRNA-525-DIAPH2, novel miRNA-525-MYOCD, and novel miRNA-525-RAI14) that might play epigenetic roles in hypoxia-induced reproductive impairment. For the first time, our findings suggested the involvement of miRNA in hypoxia-induced reproductive impairments may be inherited via a transgenerational manner.

Integrated Omics Approaches Revealed the Osmotic Stress-Responsive Genes and Microbiota in Gill of Marine Medaka.

Aquatic fishes face osmotic stress continuously, and the gill is the first tissue that senses and responds to the external osmotic challenges. However, the understandings of how the gill microbiota could respond to osmotic stress and their potential host-bacterium relationships are limited. The objectives of the current study are to identify the hypotonic responsive genes in the gill cells and profile the gill microbiota communities after fresh water transfer experiment via transcriptome sequencing and 16S rRNA gene sequencing. Transcriptome sequencing identified 1,034 differentially expressed genes (DEGs), such as aquaporin and sodium potassium chloride cotransporter, after the fresh water transfer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis further highlighted the steroid biosynthesis and glycosaminoglycan biosynthesis pathways in the gill. Moreover, the 16S rRNA gene sequencing identified Vibrio as the dominant bacterium in the seawater, which changed to Pseudomonas and Cetobacterium after the fresh water transfer. The alpha diversity analysis suggested that the gill bacterial diversity was lower in the fresh water transferred group. The KEGG and MetaCyc analysis further predicted the alteration of the glycosaminoglycan and chitin metabolisms in the gill bacteria. Collectively, the common glycosaminoglycan and chitin pathways in both the gill cells and gill microbiota suggest the host-bacterium interaction in gill facilitates the fresh water acclimation. IMPORTANCE This is the first study using the transcriptome and 16S rRNA gene sequencing to report the hypotonic responsive genes in gill cells and the compositions of gill microbiota in marine medaka. The overlapped glycosaminoglycan- and chitin-related pathways suggest host-bacterium interaction in fish gill during osmotic stress.

Depression, Healthcare Utilization, Missed Work, and Health Behaviors Among US Young Workers: Data From the 2015 National Health Interview Survey.

OBJECTIVE: We examined the prevalence of depression and its impact on healthcare utilization, work absenteeism, and health behaviors among United States (US) young workers. METHODS: Data of 1053 young workers (ages 18 to 25) from the 2015 US National Health Interview Survey were analyzed to examine these associations. RESULTS: Seven percent of US young workers reported feeling often depressed (daily or weekly). Often depressed young workers had increased odds for healthcare provider visits, mental healthcare use, 1 to 2 emergency department visits, and 3 to 5 and more than or equal to 6 missed work days, smoking, and sleeping less than 7 hours. CONCLUSIONS: Our findings suggest that depressed young workers have increased needs for healthcare utilization and are at increased risk for missing work, smoking, and reduced sleep. Resources should be prioritized for depression screening and prevention programs at the workplace and healthcare settings.

Maternal depressive symptoms, poverty, and young motherhood increase the odds of early depressive and anxiety disorders for children born prematurely.

Children born preterm, compared to term, are at risk for behavioral problems. However, the prevalence and predictors of internalizing disorders among children born preterm are unclear. The purpose of this study was to identify the prevalence of depressive and anxiety disorders at 2 years of age among children born preterm and determine the extent to which poverty, maternal depressive symptoms, or young motherhood increase the likelihood of these disorders. Mothers and their infants (N = 105) were recruited from two neonatal intensive care units affiliated with a major U.S. university. A sociodemographic questionnaire, the Patient Health Questionnaire-9, and the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition scale scores from the Preschool Child Behavior Checklist were used to measure primary variables. We examined mothers' family satisfaction and quality of caregiving as well as children's degree of prematurity, morbidity, gender, cognitive functioning, and motor function as covariates. Fifteen percent of children met criteria for an anxiety disorder and another 15% for depression. Maternal depressive symptoms increased the odds of children developing both anxiety and depression, whereas young motherhood was associated with child anxiety and poverty with child depression. Results indicate the need for mental health assessment of children born preterm during their first 2 years of life and the importance of early therapeutic and tangible support to vulnerable mothers and children.

Los niños nacidos prematuramente, comparados con los no prematuros, están bajo riesgo de problemas de comportamiento. Sin embargo, la prevalencia y factores de predicción de la internalización de los trastornos entre niños nacidos prematuramente no están claras. El propósito de este estudio fue identificar la prevalencia de trastornos depresivos y de ansiedad a los 2 años de edad entre niños nacidos prematuramente y determinar hasta dónde la pobreza, los síntomas depresivos maternos o la maternidad joven aumentan la probabilidad de estos trastornos. A las madres y sus infantes (N = 105) se les reclutó de 2 unidades de cuidados intensivos neonatales afiliadas con una importante universidad de los Estados Unidos. Un cuestionario sociodemográfico, el PHQ-9 y los puntajes de la escala DSM-5 de la Lista de Verificación de la Conducta Prescolar del Niño se usaron para medir las variables primarias. Examinamos la satisfacción familiar y la calidad de la prestación del cuidado de las madres, así como el grado de prematuridad, la morbilidad, el género, el funcionamiento cognitivo, y la función motora de los niños como covariables. Quince por ciento de los niños cumplía los criterios para un trastorno de ansiedad y otro 15% para depresión. Los síntomas depresivos maternos aumentaron las posibilidades de que los niños desarrollaran tanto ansiedad como depresión, mientras que la maternidad joven se asoció con la ansiedad del niño y la pobreza con la depresión del niño. Los resultados indican la necesidad de evaluar la salud mental de niños nacidos prematuramente durante sus dos primeros años de vida y la importancia del temprano apoyo terapéutico y tangible a las madres y niños vulnerables.

Les enfants nés prématurés, comparés aux enfants né à terme, sont à risque de problèmes de comportement. Cependant, la prévalence et les prédicteurs de troubles d'intériorisation chez les enfants nés avant-terme ne sont pas claires. Le but de cette étude était d'identifier la prévalence des troubles dépressifs et des troubles d'anxiété à l'âge de 2 ans chez des enfants nés avant terme et de déterminer dans quelle mesure la pauvreté, les symptômes dépressifs maternels ou le statue de jeune mère augmente la probablbilité de ces troubles. Des mères et leurs nourrissons (N = 105) ont été recrutées dans deux services de réanimation néonatale dans une CHU américaine importante. Un questionnaie sociodémographique, le PHQ-9 et les scores de l'échelle DSM-5 de la Checklist de Comportement de l'Enfant d'Âge Préscolaire ont été utilisés pour mesurer les variables primaires. Nous avons examiné la satisfaction familiale des mères et la qualité du mode de soin ainsi que le degré de prématurité des enfants, leur morbidité, le genre, le fonctionnement cognitif et la fonction motrice comme covariants. Quinze pourcent des enfants ont rempli les critères pour un trouble de l'anxiété et un autre 15% pour la dépression. Les symptômes dépressifs maternels ont augmenté les chances que les enfants développent à la fois de l'anxiété et de la dépression, alors que le fait d'être une jeune mère était lié à l'anxiété de l'enfant et la pauvreté avec la dépression de l'enfant. Les résultats indiquent le besoin d'une évaluation de la santé mentale des enfants nés avant terme durant les deux premières années de leur vie et l'importance d'un soutien thérapeutique précoce et tangile pour les mères et les enfants vulnérables.

Gender differences in experience and reporting of acute symptoms among cleaning staff.

BACKGROUND: Cleaning tasks pose risks of hazardous chemical exposure and adverse health effects for cleaning workers. We examined gender differences among cleaning staff in the experience of chemical-related symptoms and in reporting to supervisors. METHODS: We analyzed cross-sectional reports from 171 university hospital or campus cleaning staff on chemical exposures to cleaning products, experience of acute symptoms, reporting of symptoms to supervisors, as well as demographic and psychosocial factors (risk perception, job demand/control, supervisor/co-worker support, and safety climate). Results were analized using multivariable logistic regression, adjusting for demographic, job, and psychosocial factors. Interactions of gender and psychosocial variables were also examined. RESULTS: Men and women reported different frequencies for exposure-related tasks. Acute symptoms of chemical exposure were more prevalent in women compared with men (46.0% vs. 25.4%; adjusted odds ratio [OR] = 2.63; 95% confidence interval [CI] 1.27-5.46). Women were more concerned about exposure to cleaning chemicals (p = 0.029) but reported symptoms to their supervisor less often than men (18.5% vs. 40.6%, adjusted OR = 0.28; 95% CI 0.09-0.93). More supervisor support was significantly associated with less frequent symptom experience among women (OR = 0.83; 95% CI 0.70-0.99). Asian workers and less educated workers were less likely than others to report symptoms to supervisors. Gender differences in symptom reporting to supervisors were not explained by psychosocial factors. CONCLUSIONS: Women may have increased susceptibility or perception of symptoms from cleaning compared to men, but this may be mitigated by supervisor support. Female Asian workers with lower education may perceive more significant barriers in reporting work-related symptoms to supervisors. Further research is needed to explore factors related to underreporting.

Sleep duration does not mediate the association between screen time and adolescent depression and anxiety: findings from the 2018 National Survey of Children's Health.

OBJECTIVE/BACKGROUND: Adolescence is a crucial time period in which individuals are at high risk for depression and anxiety. Associations between screen time and adolescent depression and anxiety have been inconclusive. We examined 1) the associations of screen time with adolescent depression and anxiety and 2) whether sleep duration mediates these relationships. METHODS: This study utilized data from the 2018 US. National Survey of Children's Health, a large cross-sectional population representative dataset with parent/caregiver responses. Multivariable logistic regression was used to estimate the associations between screen time and depression and anxiety in separate models. Path models were used to test the mediating role of sleep duration. Confounders, as sex, age, and sociodemographic variables were included in our adjusted models. RESULTS: Data of 10,907 adolescents aged 13 to 17 were included in this study. The average screen time was 3.76 h daily. Compared to no screen time, adolescents who used over 4 h of screen time per day had higher odds of depression (OR = 2.23, 95% CI:1.27-3.91) and anxiety (OR = 1.85, 95% CI: 1.26-2.72). Sleep duration did not mediate the associations between screen time and depression and anxiety. CONCLUSIONS: Further research is necessary to examine the associations of screen time content with depression and anxiety, as well as the effects of sleep quality in conjunction with sleep duration on the relationships of screen time and depression and anxiety.

Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy.

Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.

The use of glutathione to reduce oxidative stress status and its potential for modifying the extracellular matrix organization in cleft lip.

OBJECTIVE: Cleft lip (CL) is a common congenital anomaly that can be syndromic or non-syndromic. It can be triggered by the mutation of gene or environmental factors. The incidence of CL is about 1 out of 700 live births. Facial development is a complex process, and there is no existing therapy to prevent the disease development. One of the characteristics in this facial malformation is the increased presence of reactive oxygen species (ROS). In this study, we hypothesize that the antioxidant glutathione (GSH) could help to attenuate the oxidative stress in this disease. METHODS: Bioinformatics network pharmacology was applied to determine pharmacological targets and molecular mechanisms of GSH treatment for CL. Moreover, RNA-sequencing of the POLR1C knockdown osteoblast CL model was applied to validate the in silico data of using GSH in CL. RESULTS: Twenty-two core targets of GSH and CL were identified via various bioinformatics tools. The GO and KEGG analysis indicated that GSH could modulate two major families (matrix metalloproteinase and integrins), which are related to extracellular matrix modification and composition for facial development in CL. The findings from POLR1C knockdown model further supported the rescue response of GSH in CL. CONCLUSIONS: The study uncovered the possible pharmacological mechanism of GSH for treating CL. The data helps research group to focus on the specific pathways for understanding the biological action of GSH for treating the CL in the future.

Clinical Spectrum and Burden of Influenza-Associated Neurological Complications in Hospitalised Paediatric Patients.

BACKGROUND: Influenza is one of the most common causes of acute respiratory tract infections around the world. Influenza viruses can cause seasonal epidemics. There remains limited information on the impact of both seasonal influenza A and influenza B related hospitalisations from neurological complications in paediatric populations in Asia. OBJECTIVES: To examine both the clinical spectrum and healthcare burden of influenza-associated neurological complications (IANCs) within the paediatric population of Hong Kong. METHODS: We conducted a population-based retrospective study to identify all paediatric patients (<18 years) admitted to a public hospital in Hong Kong with a confirmed influenza A or B infection between 2014 and 2018 using the Clinical Data Analysis and Reporting System of the Hospital Authority. The clinical spectrum of the paediatric patients with IANCs was studied. The clinical burden of paediatric influenza patients with IANCs were compared to paediatric influenza patients without neurological complications. RESULTS: A total of 28,016 children admitted to the paediatric wards diagnosed to have influenza A or B infection were identified, accounting for 5.7% (28,016/489,955) of total paediatric admissions. 67.3% had influenza A and 32.7% had influenza B, and 8.9% had IANCs. The mean annual incidence of IANCs in children was 57 per 100,000 population. The spectrum of IANCs in our paediatric patients included febrile seizures (80.6%), myositis (11.4%), seizures with fever (5.4%), influenza-associated encephalitis/encephalopathy (IAE) (2.6%) and rarely Guillain-Barré syndrome (0.04%). Most paediatric patients with IANCs (85.5%) presented at a young age of <6 years. Paediatric patients with IANCs had significant longer hospital stays (p < 0.001), higher percentages of mechanical ventilation use (p < 0.05) and PICU admissions (p < 0.001), and higher mortality rates (p < 0.001) compared to those without neurological complications. Amongst those with IANCs, IAE was the sole cause of all seven reported mortalities. CONCLUSIONS: Seasonal influenza A & B is a common cause of hospitalisation for paediatric patients in Hong Kong. We found neurological complications from influenza A and B caused a significantly higher clinical burden compared to those without neurological complications. Children in younger age groups (<6 years old) are at highest risk and thus increasing vaccination coverage to this age group is recommended.

Characterization of stanniocalcin-1 expression in macrophage differentiation.

Human stanniocalcin-1 (STC1) is a paracrine factor associated with inflammation and carcinogenesis. The role of STC1 in the pro- and anti-inflammatory functions of differentiating macrophage, however, is not clear. In this study, our data showed that phorbol 12-myristate 13-acetate (PMA) treatment induced human leukemia monocytic cells (ThP-1) differentiation to M0 macrophages. The differentiation was accompanied by a significant increase in the mRNA expression levels of STC1, the pro-inflammatory cytokine TNFα, and anti-inflammatory markers, CD163 & CD206. An intermitted removal of PMA treatment reduced the mRNA levels of STC1 and TNFα but had no noticeable effects on the anti-inflammatory markers. The correlation in the expression of STC1 and pro-inflammatory markers in differentiating macrophages was investigated, using siRNASTC1-transfected PMA-induced cells. Consistently, the transcripts levels of TNFα and IL-6 were significantly reduced. Moreover, LPS/IFNγ-induced M1-polarization showed remarkably higher expression levels of STC1 than IL-4/IL-13-induced M2-macrophages and PMA-induced M0-macrophages. Transcriptomic analysis of siRNASTC1-transfected M1-polarized cells revealed an upregulation of TBC1 domain family member 3 (TBC1D3G). The gene regulates the payload of macrophage-released extracellular vesicles to mediate inflammation. The conditioned media from siRNASTC1-transfected M1-polarized cells were found to reduce Hep3B cell motility. The data suggest that the expression of STC1 were associated with macrophage differentiation, but preferentially to M1 polarization.

Effects of stanniocalcin-1 overexpressing hepatocellular carcinoma cells on macrophage migration.

Human stanniocalcin-1 (STC1) is a glycoprotein known to participate in inflammation and tumor progression. However, its role in cancer-macrophage interaction at the tumor environment is not known. In this study, the co-culture of the human metastatic hepatocellular carcinoma cell line (MHCC97L) stably transfected with a control vector (MHCC97L/P), or STC1-overexpressing vector (MHCC97L/S1) with human leukemia monocytic cell line (THP-1) was conducted. We reported that MHCC97L/S1 suppressed the migratory activity of THP-1. Real-time PCR analysis revealed the downregulation of the pro-migratory factors, monocyte-chemoattractant protein receptors, CCR2 and CCR4, and macrophage-migratory cytokine receptor, CSF-1R. Transcriptomic analysis of the THP-1 cells co-cultured with either MHCC97L/P or MHCC97L/S1, detected 1784 differentially expressed genes. The Ingenuity Canonical Pathway analysis predicted that RhoA signaling was associated with the inhibition of the cell migration. Western blot analysis revealed a significant reduction of Ser19-phosphorylation on MLC2, a Rho-A downstream target, in the THP-1 cells. Xenograft tumors derived from MHCC97/S1 in mice showed a remarkable decrease in infiltrating macrophages. Collectively, this is the first report to demonstrate the inhibitory effect of STC1-overexpressing cancer cells on macrophage migration/infiltration. Our data support further investigations on the relationship between tumor STC1 level and macrophage infiltration.

Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells.

In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.

Ectopic expression of recipient CD47 inhibits mouse macrophage-mediated immune rejection against human stem cell transplants.

Like conventional transplants, immunosuppression is required to facilitate survival and function of human embryonic stem cell (hESC) derivatives after implantation into xenogeneic recipients. We have previously reported that T cells alone are sufficient to reject allogeneic murine ESC derivatives; and strategies that inhibit T-cell activation, including coreceptor and costimulation blockade, prevent hESC derivatives from being rejected. This study aimed to investigate, in addition to T cells, whether macrophages contribute to transplant rejection of hESC xenografts with nonobese diabetic (NOD)/SCID mice that lack functional T and B cells but have macrophages. We show that acute rejection against hESC-derived endothelial cells (hESC-ECs) was mediated, to some degree, by infiltrating macrophages that phagocytosed them. Transgenic expression of murine CD47 on cell surface of hESC-ECs mitigates macrophage-mediated phagocytosis and improves their survival after transplantation. Our results highlight that innate immune cells, such as macrophages, can reject hESC derivatives, raising concern against the use of NOD/SCID as transplant recipients for testing in vivo function of hESC-derived tissues. Augmenting CD47 signaling promotes survival and function of hESC derivatives after xenogeneic transplantation.-Leung, C. S., Li, J., Xu, F., Wong, A. S. L., Lui, K. O. Ectopic expression of recipient CD47 inhibits mouse macrophage-mediated immune rejection against human stem cell transplants.

Association of Depressive Symptoms with Consumption of Analgesics among Adolescents.

PURPOSE: To investigate the prevalence of depressive symptoms, pain (headaches and stomachaches), and analgesic consumption in addition to the association between depressive symptoms and analgesic consumption among adolescents. DESIGN AND METHODS: This cross-sectional study was conducted in southern Sweden. The survey was distributed among students in grade 8 (aged 13-15 years, n = 878). RESULTS: The prevalence of depressive symptoms (Center for Epidemiological Studies Depression Scale ≥16) was 37% among girls and 13% among boys. The prevalence rate of analgesic consumption to ease headaches and/or stomachaches during the last several weeks was 57% among girls and 29% among boys. Depressive symptoms are significantly associated with analgesic consumption among adolescents even after controlling for pain. CONCLUSION: The knowledge that there is a higher use of analgesics in adolescents with depressive symptoms implies that healthcare professionals should focus on complex psychosocial problems, not only physiological pain, in adolescents. PRACTICE IMPLICATIONS: Over the counter analgesics are frequently used by adolescents. Head and stomachaches are common reasons for students to visit the school nurse and primary healthcare facility. School nurses and pediatric nurses have to be aware of the link between depressive symptoms and pain in addition to the higher use of analgesics in adolescents with depressive symptoms. It is important to reduce the cause of the pain in order to prevent depressive symptoms and also analgesic overuse.

Dietary Exposure to the Environmental Chemical, PFOS on the Diversity of Gut Microbiota, Associated With the Development of Metabolic Syndrome.

The gut microbiome is a dynamic ecosystem formed by thousands of diverse bacterial species. This bacterial diversity is acquired early in life and shaped over time by a combination of multiple factors, including dietary exposure to distinct nutrients and xenobiotics. Alterations of the gut microbiota composition and associated metabolic activities in the gut are linked to various immune and metabolic diseases. The microbiota could potentially interact with xenobiotics in the gut environment as a result of their board enzymatic capacities and thereby affect the bioavailability and toxicity of the xenobiotics in enterohepatic circulation. Consequently, microbiome-xenobiotic interactions might affect host health. Here, we aimed to investigate the effects of dietary perfluorooctane sulfonic acid (PFOS) exposure on gut microbiota in adult mice and examine the induced changes in animal metabolic functions. In mice exposed to dietary PFOS for 7 weeks, body PFOS and lipid contents were measured, and to elucidate the effects of PFOS exposure, the metabolic functions of the animals were assessed using oral glucose-tolerance test and intraperitoneal insulin-tolerance and pyruvate-tolerance tests; moreover, on Day 50, cecal bacterial DNA was isolated and subject to 16S rDNA sequencing. Our results demonstrated that PFOS exposure caused metabolic disturbances in the animals, particularly in lipid and glucose metabolism, but did not substantially affect the diversity of gut bacterial species. However, marked modulations were detected in the abundance of metabolism-associated bacteria belonging to the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Cyanobacteria, including, at different taxonomic levels, Turicibacteraceae, Turicibacterales, Turicibacter, Dehalobacteriaceae, Dehalobacterium, Allobaculum, Bacteroides acidifaciens, Alphaproteobacteria, and 4Cod-2/YS2. The results of PICRUSt analysis further indicated that PFOS exposure perturbed gut metabolism, inducing notable changes in the metabolism of amino acids (arginine, proline, lysine), methane, and a short-chain fatty acid (butanoate), all of which are metabolites widely recognized to be associated with inflammation and metabolic functions. Collectively, our study findings provide key information regarding the biological relevance of microbiome-xenobiotic interactions associated with the ecology of gut microbiota and animal energy metabolism.