Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation.

BACKGROUND: Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process. METHODS: Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α. RESULTS: The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth. CONCLUSION: These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.

Fungal Spore Richness and Abundance of Allergenic Taxa: Comparing a Portable Impactor and Passive Trap Indoors and Outdoors in an Urban Setting.

Fungal spores are common airborne allergens, and fungal richness has been implicated in allergic disease. Amplicon sequencing of environmental DNA from air samples is a promising method to estimate fungal spore richness with semi-quantification of hundreds of taxa and can be combined with quantitative PCR to derive abundance estimates. However, it remains unclear how the choice of air sampling method influences these estimates. This study compared active sampling with a portable impactor and passive sampling with a passive trap over different durations to estimate fungal spore richness and the abundance of allergenic taxa. Air sampling was conducted indoors and outdoors at 12 residences, including repeated measurements with a portable impactor and passive traps with 1-day and 7-day durations. ITS2 amplicon sequence data were transformed to spore equivalents estimated by quantitative PCR, repeated active samples were combined, and abundance-based rarefaction was performed to standardize sample coverage for estimation of genus-level richness and spore abundance. Rarefied fungal richness was similar between methods indoors but higher for passive traps with a 7-day duration outdoors. Rarefied abundance of allergenic genera was similar between methods but some genera had lower abundance for passive traps with a 1-day duration, which differed indoors and outdoors indicating stochasticity in the collection of spores on collocated samplers. This study found that similar estimates of fungal spore richness and abundance of allergenic taxa can be obtained using a portable impactor or a passive trap within one day and that increased passive sample duration provides limited additional information.

Investigating the effect of hypertension on vascular cognitive impairment by using the resting-state functional connectome.

Hypertension (HTN) affects over 1.2 billion individuals worldwide and is defined as systolic blood pressure (BP) ≥ 140 mmHg and diastolic BP ≥ 90 mmHg. Hypertension is also considered a high risk factor for cerebrovascular diseases, which may lead to vascular cognitive impairment (VCI). VCI is associated with executive dysfunction and is also a transitional stage between hypertension and vascular dementia. Hence, it is essential to establish a reliable approach to diagnosing the severity of VCI. In 28 HTN (51-83 yrs; 18 males, 10 females) and 28 healthy controls (HC) (51-75 yrs; 7 males, 21 females), we investigated which regions demonstrate alterations in the resting-state functional connectome due to vascular cognitive impairment in HTN by using the amplitude of the low-frequency fluctuations (ALFF), regional homogeneity (ReHo), graph theoretical analysis (GTA), and network-based statistic (NBS) methods. In the group comparison between ALFF/ReHo, HTN showed reduced spontaneous activity in the regions corresponding to vascular or metabolic dysfunction and enhanced brain activity, mainly in the primary somatosensory cortex and prefrontal areas. We also observed cognitive dysfunction in HTN, such as executive function, processing speed, and memory. Both the GTA and NBS analyses indicated that the HTN demonstrated complex local segregation, worse global integration, and weak functional connectivity. Our findings show that resting-state functional connectivity was altered, particularly in the frontal and parietal regions, by hypertensive individuals with potential vascular cognitive impairment.

More than a piece of cake: Noun classifier processing in primary progressive aphasia.

INTRODUCTION: Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. METHODS: We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. RESULTS: Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. DISCUSSION: This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. HIGHLIGHTS: Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Regulation of hepatitis B virus replication by autophagic membranes.

Autophagy (i.e. macroautophagy) plays a significant role in the replication of hepatitis B virus (HBV). In our recent study, we examined the underlying mechanism and discovered that autophagic membranes participated in different steps of the HBV life cycle. We found that phagophores are involved in the assembly of HBV nucleocapsids, autophagosomes participate in the trafficking of HBV nucleocapsids, amphisomes likely participate in the maturation and egress of mature HBV particles, and autolysosomes negatively regulate HBV replication. Our work provides important insights for understanding the relationship between autophagic membranes and HBV replication and raises the possibility of targeting the autophagic pathway for the development of novel drugs against HBV.

Autophagic membranes participate in hepatitis B virus nucleocapsid assembly, precore and core protein trafficking, and viral release.

Hepatitis B virus (HBV) DNA replication takes place inside the viral core particle and is dependent on autophagy. Here we show that HBV core particles are associated with autophagosomes and phagophores in cells that productively replicate HBV. These autophagic membrane-associated core particles contain almost entirely the hypophosphorylated core protein and are DNA replication competent. As the hyperphosphorylated core protein can be localized to phagophores and the dephosphorylation of the core protein is associated with the packaging of viral pregenomic RNA (pgRNA), these results are in support of the model that phagophores can serve as the sites for the packaging of pgRNA. In contrast, in cells that replicate HBV, the precore protein derivatives, which are related to the core protein, are associated with autophagosomes but not with phagophores via a pathway that is independent of its signal peptide. Interestingly, when the core protein is expressed by itself, it is associated with phagophores but not with autophagosomes. These observations indicate that autophagic membranes are differentially involved in the trafficking of precore and core proteins. HBV induces the fusion of autophagosomes and multivesicular bodies and the silencing of Rab11, a regulator of this fusion, is associated with the reduction of release of mature HBV particles. Our studies thus indicate that autophagic membranes participate in the assembly of HBV nucleocapsids, the trafficking of HBV precore and core proteins, and likely also the egress of HBV particles.

Assessment of brain connectome alterations in male chronic smokers using structural and generalized q-sampling MRI.

An association has been shown between chronic cigarette smoking and structural abnormalities in the brain areas related to several functions relevant to addictive behavior. However, few studies have focused on the structural alternations of chronic smoking by using magnetic resonance imaging (MRI). Also, it remains unclear how structural alternations are associated with tobacco-dependence severity and the positive/negative outcome expectances. The q-sampling imaging (GQI) is an advanced diffusion MRI technique that can reconstruct more precise and consistent images of complex oriented fibers than other methods. We aimed to use GQI to evaluate the impact of the neurological structure caused by chronic smoking. Sixty-seven chronic smokers and 43 nonsmokers underwent a MRI scan. The tobacco dependence severity and the positive/negative outcome expectancies were assessed via self-report. We used GQI with voxel-based statistical analysis (VBA) to evaluate structural brain and connectivity abnormalities. Graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also performed to identify the structural network differences among groups. Chronic smokers had smaller GM and WM volumes in the bilateral frontal lobe and bilateral frontal region. The GM/WM volumes correlated with dependence severity and outcome expectancies in the brain areas involving high-level functions. Chronic smokers had shape changes in the left hippocampal head and tail and the inferior brain stem. Poorer WM integrity in chronic smokers was found in the left middle frontal region, the right superior fronto-occipital fasciculus, the right temporal region, the left parahippocampus, the left anterior internal capsule, and the right inferior parietal region. WM integrity correlated with dependence severity and outcome expectancies in brain areas involving high-level functions. Chronic smokers had decreased local segregation and global integration among the brain regions and networks. Our results provide further evidence indicating that chronic smoking may be associated with brain structure and connectivity changes.

Pathogenicity and virulence of Hepatitis B virus.

Hepatitis B virus (HBV) is a hepatotropic virus and an important human pathogen. There are an estimated 296 million people in the world that are chronically infected by this virus, and many of them will develop severe liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). HBV is a small DNA virus that replicates via the reverse transcription pathway. In this review, we summarize the molecular pathways that govern the replication of HBV and its interactions with host cells. We also discuss viral and non-viral factors that are associated with HBV-induced carcinogenesis and pathogenesis, as well as the role of host immune responses in HBV persistence and liver pathogenesis.

Terpene Synthase-b and Terpene Synthase-e/f Genes Produce Monoterpenes for Phalaenopsis bellina Floral Scent.

Orchids are the most species-rich plants and highly interactive with pollinators via visual or olfactory cues. Biosynthesis and emission of volatile organic compounds (VOCs) to the atmosphere facilitate the olfactory cues and ensure successful pollination. Phalaenopsis bellina is a scented orchid with monoterpenes as major VOCs, comprising linalool, geraniol, and their derivatives. Comparative transcriptomics analysis identified four terpene synthase-b (TPS-b) genes and two TPS-e/f genes with differential gene expression between scented and scentless Phalaenopsis species. Here, we confirmed their differential expression between scented and scentless Phalaenopsis orchids and excluded one TPS-b candidate. We analyzed the temporal and spatial expression and functionally characterized these TPSs. Both TPS-b and TPS-e/f genes showed an increased expression on blooming day or 3 days post-anthesis (D + 3) before the optimal emission of floral scent on D + 5, with especially high expression of PbTPS5 and PbTPS10. The TPS-b genes are expressed exclusively in reproductive organs, whereas the TPS-e/f genes are expressed in both reproductive and vegetative organs. In planta functional characterization of both PbTPS5 and PbTPS10 in tobacco and scentless Phalaenopsis plants did not produce terpenoids. Further ectopic expression in scented Phalaenopsis cultivar P. I-Hsin Venus showed that linalool was the main product, with PbTPS10 displaying 3-fold higher activity than PbTPS5. On in vitro enzyme assay with purified recombinant TPS-b proteins ectopically expressed in Escherichia coli, geraniol was the product catalyzed by PbTPS5 and PbTPS9. PbTPS3 was a linalool/(ß)-cis-ocimene synthase and PbTPS4 a linalool synthase. In conclusion, both TPS-b and TPS-e/f enzymes orchestrated floral monoterpene biosynthesis in P. bellina.

Evolution of Terpene Synthases in Orchidaceae.

Terpenoids are the largest class of plant secondary metabolites and are one of the major emitted volatile compounds released to the atmosphere. They have functions of attracting pollinators or defense function, insecticidal properties, and are even used as pharmaceutical agents. Because of the importance of terpenoids, an increasing number of plants are required to investigate the function and evolution of terpene synthases (TPSs) that are the key enzymes in terpenoids biosynthesis. Orchidacea, containing more than 800 genera and 28,000 species, is one of the largest and most diverse families of flowering plants, and is widely distributed. Here, the diversification of the TPSs evolution in Orchidaceae is revealed. A characterization and phylogeny of TPSs from four different species with whole genome sequences is available. Phylogenetic analysis of orchid TPSs indicates these genes are divided into TPS-a, -b, -e/f, and g subfamilies, and their duplicated copies are increased in derived orchid species compared to that in the early divergence orchid, A. shenzhenica. The large increase of both TPS-a and TPS-b copies can probably be attributed to the pro-duction of different volatile compounds for attracting pollinators or generating chemical defenses in derived orchid lineages; while the duplications of TPS-g and TPS-e/f copies occurred in a species-dependent manner.

An Exploration of the Own-Age Effect on Facial Emotion Recognition in Normal Elderly People and Individuals with the Preclinical and Demented Alzheimer's Disease.

BACKGROUND: The issue of whether there exists an own-effect on facial recognition in the elderly remains equivocal. Moreover, currently the literature of this issue in pathological aging is little. OBJECTIVE: Our study was thus to explore the issue in both of healthy older people and patients with ADMethods:In study 1, 27 older and 31 younger healthy adults were recruited; in study 2, 27 healthy older adults and 80 patients (including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups) were recruited. Participants received the Taiwan Facial Emotion Recognition Task (FER Task), and a clinical neuropsychological assessment. RESULTS: No significant differences on the FER test were found among our groups, except for sadness recognition in which our MCI and AD patients' scores were remarkably lower than their healthy counterparts. The own-age effect was not significantly evident in healthy younger and older adults, except for recognizing neutral photos. Our patients with MCI and AD tended to have the effect, particularly for the sad recognition in which the effect was significantly evident in terms of error features (mislabeling it as anger in younger-face and neutral in older-face photos). CONCLUSION: Our results displayed no remarkable own-age effect on facial emotional recognition in the healthy elderly (including SCD). However, it did not appear the case for MCI and AD patients, especially their recognizing those sadness items, suggesting that an inclusion of the FER task particularly involving those items of low-intensity emotion in clinical neuropsychological assessment might be contributory to the early detection of AD-related pathological individuals.

Toll-Like Receptor 21 of Chicken and Duck Recognize a Broad Array of Immunostimulatory CpG-oligodeoxynucleotide Sequences.

CpG-oligodeoxynucleotides (CpG-ODNs) mimicking the function of microbial CpG-dideoxynucleotides containing DNA (CpG-DNA) are potent immune stimuli. The immunostimulatory activity and the species-specific activities of a CpG-ODN depend on its nucleotide sequence properties, including CpG-hexamer motif types, spacing between motifs, nucleotide sequence, and length. Toll-like receptor (TLR) 9 is the cellular receptor for CpG-ODNs in mammalian species, while TLR21 is the receptor in avian species. Mammalian cells lack TLR21, and avian cells lack TLR9; however, both TLRs are expressed in fish cells. While nucleotide sequence properties required for a CpG-ODN to strongly activate mammalian TLR9 and its species-specific activities to different mammalian TLR9s are better studied, CpG-ODN activation of TLR21 is not yet well investigated. Here we characterized chicken and duck TLR21s and investigated their activation by CpG-ODNs. Chicken and duck TLR21s contain 972 and 976 amino acid residues, respectively, and differ from TLR9s as they do not have an undefined region in their ectodomain. Cell-based TLR21 activation assays were established to investigate TLR21 activation by different CpG-ODNs. Unlike grouper TLR21, which was preferentially activated by CpG-ODN with a GTCGTT hexamer motif, chicken and duck TLR21s do not distinguish among different CpG-hexamer motifs. Additionally, these two poultry TLR21s were activated by CpG-ODNs with lengths ranging from 15 to 31 nucleotides and with different spacing between CpG-hexamer motifs. These suggested that compared to mammalian TLR9 and grouper TLR21, chicken and duck TLR21s have a broad CpG-ODN sequence recognition profile. Thus, they could also recognize a wide array of DNA-associated molecular patterns from microbes. Moreover, CpG-ODNs are being investigated as antimicrobial agents and as vaccine adjuvants for different species. This study revealed that there are more optimized CpG-ODNs that can be used in poultry farming as anti-infection agents compared to CpG-ODN choices available for other species.

Adjuvant Effect of Toll-Like Receptor 9 Activation on Cancer Immunotherapy Using Checkpoint Blockade.

Immunotherapy using checkpoint blockade has revolutionized cancer treatment, improving patient survival and quality of life. Nevertheless, the clinical outcomes of such immunotherapy are highly heterogeneous between patients. Depending on the cancer type, the patient response rates to this immunotherapy are limited to 20-30%. Based on the mechanism underlying the antitumor immune response, new therapeutic strategies have been designed with the aim of increasing the effectiveness and specificity of the antitumor immune response elicited by checkpoint blockade agents. The activation of toll-like receptor 9 (TLR9) by its synthetic agonists induces the antitumor response within the innate immunity arm, generating adjuvant effects and priming the adaptive immune response elicited by checkpoint blockade during the effector phase of tumor-cell killing. This review first describes the underlying mechanisms of action and current status of monotherapy using TLR9 agonists and immune checkpoint inhibitors for cancer immunotherapy. The rationale for combining these two agents is discussed, and evidence indicating the current status of such combination therapy as a novel cancer treatment strategy is presented.

Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer.

There is a positive feedback loop driving tumorigenesis and tumor growth through coordinated regulation of epigenetics, inflammation, and stemness. Nevertheless, the molecular mechanism linking these processes is not well understood. In this study, we analyzed the correlation of de-ubiquitinases (DUBs) expression with survival data from the OncoLnc database. Among the DUBs analyzed, ubiquitin specific protease 4 (USP4) had the lowest negative Cox coefficient. Low expression of USP4 was associated with poor survival among lung cancer patients and was inversely correlated with expression of stemness and inflammation markers. Expression of USP4 were reduced at more advanced stages of lung cancer. Mechanistically, expression of USP4 was downregulated in snail1-overexpressing and stemness-enriched lung cancer cells. Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation. Stable knockdown of USP4 in lung cancer cells enhanced inflammatory responses, stemness properties, chemotherapy resistance, and the expression of molecules allowing escape from immunosurveillance. Further, mice injected with USP4 knockdown lung cancer cells demonstrated enhanced tumorigenesis and tumor growth. These results reveal that the Snail1-mediated suppression of USP4 is a potential mechanism to orchestrate epigenetic regulation, inflammation and stemness for macrophage-promoted tumor progression.

Changes in the relationship between ambient fine particle concentrations and childhood lung function over 5 years.

BACKGROUND: Exposure to ambient fine particles, particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5), is a public health concern. Concentrations of ambient PM2.5 have changed temporally in the past 10 years after a series of action policies for improving air quality were implemented in Taiwan. In this study, temporal changes in the relationship between PM2.5 and lung function among children were investigated. METHODS: A nationwide respiratory health survey was conducted among Taiwanese elementary and middle school students in 2011 and again in 2016-2017. A questionnaire was administered to students, for whom forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured using spirometry. During the study period, monthly concentrations of ambient PM2.5 were obtained from the monitoring stations of the Environmental Protection Administration. Lung function measurements were compared with ambient PM2.5 exposure using mixed-effects models. RESULTS: In the 2011 survey (mean PM2.5: 40.6 µg/m3), exposure to PM2.5 in the preceding 1-2 months was associated with a 2.2% decrease (95% confidence interval [CI]: -4.1%, -0.3%) in FVC and a 2.3% decrease (95% CI: -4.0%, -0.5%) in FEV1. By contrast, a significant relationship between PM2.5 concentrations and lung function was not observed in the 2016-2017 survey (mean PM2.5: 30.0 µg/m3). CONCLUSIONS: As improvement in air quality over time, the negative relationship between PM2.5 and childhood lung function tend to be not significant.

RNA sequencing analysis of Cymbidium goeringii identifies floral scent biosynthesis related genes.

BACKGROUND: Cymbidium goeringii belongs to the Orchidaceae, which is one of the most abundant angiosperm families. Cymbidium goeringii consist with high economic value and characteristics include fragrance and multiple flower colors. Floral scent is one of the important strategies for ensuring fertilization. However, limited genetic data is available in this non-model plant, and little known about the molecular mechanism responsible for floral scent in this orchid. Transcriptome and expression profiling data are needed to identify genes and better understand the biological mechanisms of floral scents in this species. Present transcriptomic data provides basic information on the genes and enzymes related to and pathways involved in flower secondary metabolism in this plant. RESULTS: In this study, RNA sequencing analyses were performed to identify changes in gene expression and biological pathways related scent metabolism. Three cDNA libraries were obtained from three developmental floral stages: closed bud, half flowering stage and full flowering stage. Using Illumina technique 159,616,374 clean reads were obtained and were assembled into 85,868 final unigenes (average length 1194 nt), 33.85% of which were annotated in the NCBI non redundant protein database. Among this unigenes 36,082 were assigned to gene ontology and 23,164 were combined with COG groups. Total 33,417 unigenes were assigned in 127 pathways according to the Kyoto Encyclopedia of Genes and Genomes pathway database. According these transcriptomic data we identified number of candidates genes which differentially expressed in different developmental stages of flower related to fragrance biosynthesis. In q-RT-PCR most of the fragrance related genes highly expressed in half flowering stage. CONCLUSIONS: RNA-seq and DEG data provided comprehensive gene expression information at the transcriptional level that could be facilitate the molecular mechanisms of floral biosynthesis pathways in three developmental phase's flowers in Cymbidium goeringii, moreover providing useful information for further analysis on C. goeringii, and other plants of genus Cymbidium.

Prenatal perfluorooctanoic acid exposure is associated with early onset atopic dermatitis in 5-year-old children.

Atopic dermatitis (AD) is the most common childhood skin disease and the first step of atopic march. Perfluoroalkyl substance (PFAS) exposure is associated with atopic diseases, including AD. However, whether PFAS exposure is related to earlier AD onset remains unclear. We aimed to investigate the association between prenatal PFAS exposure and earlier onset of AD in children in a 5-year follow-up study. From 2001 to 2005, 1264 mother-infant pairs were recruited from eight Taiwanese maternity hospitals. PFAS levels were analyzed from cord blood. Information on children's health status, including AD occurrence, was obtained via phone interviews at multiple time points. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) concentrations were measured by ultra-high performance liquid chromatography/tandem mass spectrometry. Cox proportional hazards models assessed associations between prenatal PFAS exposure and early onset AD. Overall, 863 mother-infant pairs with complete measurements were recruited. The prevalence of physician-diagnosed AD before 5 years of age was 7.1%. PFOA and PFOS concentrations were grouped based on whether they were above the 75th percentile. PFOA exposure was positively associated with earlier onset of AD (Kaplan-Meier estimate, p = 0.014). In the Cox model, after adjusting for sex, family income, parental atopy, breast feeding, and maternal age at childbirth, significance was observed in children above the upper quartile (≥75th) of the PFOA group (hazard ratio: 1.89; 95% confidence interval, 1.10-3.16). Our findings suggested that children with higher prenatal PFOA exposure have a higher risk of earlier AD development. Minimizing early life PFAS exposure may help inhibit AD development.

The Effect of Ganoderma Microsporum immunomodulatory proteins on alleviating PM2.5-induced inflammatory responses in pregnant rats and fine particulate matter-induced neurological damage in the offsprings.

Fine particulate matter 2.5 (PM2.5) induces free radicals and oxidative stress in animals, leading to a range of illnesses. In this study, Ganoderma Microsporum immunomodulatory (GMI) proteins were administered to alleviate PM2.5-induced inflammatory responses in mother rats, and PM2.5-induced inflammatory responses and neurological damage in their offspring. The results suggested that GMI administration decreased the risk of neurological disorders in mother rats and their offspring by reducing the white blood cell count, lessening inflammatory responses and PM2.5-induced memory impairment, and preventing dendritic branches in the hippocampi from declining and microRNAs from PM2.5-induced modulation.

Perinatal polychlorinated biphenyls and polychlorinated dibenzofurans exposure are associated with DNA methylation changes lasting to early adulthood: Findings from Yucheng second generation.

Epigenome-wide DNA methylation has not been studied in men perinatally exposed to PCBs and dioxins. Therefore, we examined whether perinatal exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) induces sustained methylation changes lasting to early adulthood. We used the Illumina HumanMethylation450 BeadChip to assess DNA methylation in whole blood among Yucheng second generation (people perinatal exposed to high PCBs and PCDFs) compared with referents. Thirty male offspring from the Yucheng cohort were randomly selected and matched with 30 male offspring from the Yucheng' neighborhood referents with similar backgrounds. Methylation differences between the Yucheng second generation and non-exposed referents were identified using a P value < 1.06 × 10-7. Differential DNA methylation with epigenome-wide statistical significance was observed for 20 CpGs mapped to 11 genes, and 19 CpGs were correlated with gestational levels of PCBs or PCDF toxic equivalency (PCDF-TEQ) with the same direction of effect. Among the 11 genes, AHRR and CYP1A1 are involved in the aryl hydrocarbon receptor signaling pathway known to mediate dioxin toxicity. MYO1G, FRMD4A, ARL4C, OLFM1, and WWC3 were previously reported to be related to carcinogenesis. This is the first study examining genome-wide DNA methylation among people perinatally exposed to high concentrations of PCBs and PCDFs. We observed novel differential methylation of several genes, indicating that modifications of DNA methylation associated with perinatal PCB and PCDF exposure may persist in exposed offspring for more than 20 years. Furthermore, involvement of several carcinogesis-related genes suggested a potential in utero epigenetic mechanisms.

In Vitro and In Vivo Analysis of the Effects of 3,5-DMA and Its Metabolites in Neural Oxidative Stress and Neurodevelopmental Toxicity.

3,5-Dimethylaniline (3,5-DMA), a monocyclic aromatic amine, is widely present in a spectrum of sources including tobacco, dyes, combustion products, and suspended particulates. 3,5-DMA and its metabolites form superoxides, resulting in apoptosis or oncogenesis. Data of a direct effect of 3,5-DMA on the nervous system, especially the developing brain, are lacking. Therefore, we investigated the effects of 3,5-DMA and its metabolites on fetal neurite growth and brain development using in vitro cell cultures of primary cortical neurons to observe whether these compounds caused neuronal cytotoxicity and affected neurite structural development. With increasing concentrations of 3,5-DMA (10, 50, 100, 500, 1000 µM) and its major metabolite 5-dimethylaminophenol (3,5-DMAP) (10, 50, 100, 500, 1000 µM), reactive oxygen species (ROS), cytotoxicity, and DNA damage increased significantly in the cells and dendritic arborization decreased. The addition of 5 mM N-acetylcysteine, an ROS scavenger, reduced ROS in the cells and alleviated the neuronal damage. In vivo studies in Sprague Dawley pregnant rats suggested that exposure to 3,5-DMA (10, 30, 60, 100 mg/kg/day) subcutaneously from GD15 to GD17 led to fetal cerebral cortex thinning. BrdU labeling showed that 3,5-DMA reduced the number and generation of cortical cells. To detect the laminar position of newly generated neurons, cortex layer markers such as Satb2, Ctip2, and Tbr1 were used. 3,5-DMA perturbed the cortical layer distribution in developing fetal rats. In summary, this is the first study to provide evidence for 3,5-DMA and its metabolites causing anomalies of the fetal central nervous system development through ROS production.