The persistence of Mycobacterium leprae (M. leprae) infection is largely dependent on the types of host immune responses being induced. Macrophage, a crucial modulator of innate and adaptive immune responses, could be directly infected by M. leprae. We therefore postulated that M. leprae-infected macrophages might have altered immune functions.

In this study, in order to find novel biologically active pyrazole oxime compounds, a series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety were synthesized. Preliminary bioassays indicated that most title compounds were found to display good to excellent acaricidal activity against Tetranychus cinnabarinus at a concentration of 200 μg/mL, and some designed compounds still showed excellent acaricidal activity against Tetranychus cinnabarinus at the concentration of 10 μg/mL, especially since the inhibition rates of compounds 8e, 8f, 8l, 8m, 8n, 8p, and 8q were all 100.00%. Interestingly, some target compounds exhibited moderate to good insecticidal activities against Plutella xylostella and Aphis craccivora at a concentration of 200 μg/mL; furthermore, compounds 8e and 8l possessed outstanding insecticidal activities against Plutella xylostella under the concentration of 50 μg/mL.

The consequences of ubiquitous exposure to environmental chemicals remain poorly defined. Non-targeted metabolomic profiling is an emerging method to identify biomarkers of the physiological response to such exposures. We investigated the effect of three commonly used ingredients in personal care products, diethyl phthalate (DEP), methylparaben (MPB) and triclosan (TCS), on the blood metabolome of female Sprague-Dawley rats. Animals were treated with low levels of these chemicals comparable to human exposures during prepubertal and pubertal windows as well as chronically from birth to adulthood. Non-targeted metabolomic profiling revealed that most of the variation in the metabolites was associated with developmental stage. The low-dose exposure to DEP, MPB and TCS had a relatively small, but detectable impact on the metabolome. Multiple metabolites that were affected by chemical exposure belonged to the same biochemical pathways including phenol sulfonation and metabolism of pyruvate, lyso-plasmalogens, unsaturated fatty acids and serotonin. Changes in phenol sulfonation and pyruvate metabolism were most pronounced in rats exposed to DEP during the prepubertal period. Our metabolomics analysis demonstrates that human level exposure to personal care product ingredients has detectable effects on the rat metabolome. We highlight specific pathways such as sulfonation that warrant further study.

Recent interest in reference-free deconvolution of DNA methylation data has led to several supervised methods, but these methods do not easily permit the interpretation of underlying cell types.

The zoonotic agent Toxoplasma gondii is distributed world-wide, and can infect a broad range of hosts including humans. Microneme protein 16 of T. gondii (TgMIC16) is responsible for binding to aldolase, and is associated with rhomboid cleavage and presence of trafficking signals during invasion. However, little is known of the TgMIC16 sequence diversity among T. gondii isolates from different hosts and geographical locations.

The aim of the study is to determine whether low doses of "endocrine disrupting chemicals" (EDCs) affect the development and proliferative activity of the mammary glands (MGs). Adult parous/nulliparous female Sprague-Dawley (SD) rats were treated from post-natal day (PND) 1 until PND 180 with diethylphthalate (DEP), methylparaben (MPB), triclosan (TCS) and a mixture at doses comparable to human exposure. The doses (mg/kg b.w./day) were: DEP=0.173; MPB=0.105; TCS=0.05. EDC treatment resulted in mortality rates >20% in pups as early as lactation day 7. Significant morphological/histological changes were observed at the end of lactation in the MGs of EDC-treated dams. The total transcriptome profile as well as lactation-related genes in MGs also corroborate the morphological findings as more profound gene expression changes are present only at the weaning period. The study highlights the heightened sensitivity of the MGs during critical windows of exposure, particularly pregnancy and lactation, with an impact on pups' survival.

T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of one kind of principal phase I drug-metabolizing enzymes (cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.

Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection.

The GATA-binding protein 4 gene (GATA4) encodes a zinc-finger transcription factor that plays a key role in embryogenesis and cardiac development. Variants in the GATA4 gene have been implicated in several congenital heart diseases (CHD), such as the tetralogy of Fallot (ToF), atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and dilated cardiomyopathy (DCM). We studied a four-generation Chinese ASD family and identified a novel GATA4 mutation (c.A899C, p.K300T) in all surviving affected members and two carriers with incomplete penetrance. Bioinformatics programs (PolyPhen-2, SIFT, and MutationTaster) predicted the mutation to be deleterious. The lysine at the mutation position was highly conserved from Drosophila to humans and was recognized as a methylation location in the GATA4 protein. The involvement of the lysine methylation in cardiogenesis by attenuating the transcriptional activity of GATA4 in mice has been previously examined. Our study broadens the mutation spectrum of the GATA4 gene and reveals for the first time a mutation at the methylation position of GATA4 associated with ASD.

Calcium-dependent protein kinases (CDPKs) are found in plants and some Apicomplexan parasites but not in animals or fungi. CDPKs have been shown to play important roles in various calcium-signaling pathways such as host cell invasion, egress and protein secretion in Toxoplasma gondii. The objectives of the present study were to examine the T. gondii CDPK genes expression patterns during different development stages and stress responses.

Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.

Cardiac fibrosis is the most important mechanism contributing to cardiac remodeling after myocardial infarction (MI). VPO1 is a heme enzyme that uses hydrogen peroxide (H2O2) to produce hypochlorous acid (HOCl). Our previous study has demonstrated that VPO1 regulates myocardial ischemic reperfusion and renal fibrosis. We investigated the role of VPO1 in cardiac fibrosis after MI. The results showed that VPO1 expression was robustly upregulated in the failing human heart with ischemic cardiomyopathy and in a murine model of MI accompanied by severe cardiac fibrosis. Most importantly, knockdown of VPO1 by tail vein injection of VPO1 siRNA significantly reduced cardiac fibrosis and improved cardiac function and survival rate. In VPO1 knockdown mouse model and cardiac fibroblasts cultured with TGF-β1, VPO1 contributes to cardiac fibroblasts differentiation, migration, collagen I synthesis and proliferation. Mechanistically, the fibrotic effects following MI of VPO1 manifested partially through HOCl formation to activate Smad2/3 and ERK1/2. Thus, we conclude that VPO1 is a crucial regulator of cardiac fibrosis after MI by mediating HOCl/Smad2/3 and ERK1/2 signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.

BackgroundDepression and/or anxiety during pregnancy have been associated with impaired fetal growth and neurodevelopment. Because placental imprinted genes play a central role in fetal development and respond to environmental stressors, we hypothesized that imprinted gene expression would be affected by prenatal depression and anxiety.MethodsPlacental gene expression was compared between mothers with prenatal depression and/or anxiety/obsessive compulsive disorder/panic and control mothers without psychiatric history (n=458) in the Rhode Island Child Health Study.ResultsTwenty-nine genes were identified as being significantly differentially expressed between placentae from infants of mothers with both depression and anxiety (n=54), with depression (n=89), or who took perinatal psychiatric medications (n=29) and control mother/infant pairs, with most genes having decreased expression in the stressed group. Among placentae from infants of mothers with depression, we found no differences in expression by medication use, indicating that our results are related to the stressor rather than the treatments. We did not find any relationship between the stress-associated gene expression and neonatal neurodevelopment, as measured using the Neonatal Intensive Care Unit Network Neurobehavioral Scale.ConclusionsThis variation in expression may be part of an adaptive mechanism by which the placenta buffers the infant from the effects of maternal stress.

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

BACKGROUND The present study aimed to evaluate whether the fat mass and obesity-associated (FTO) gene polymorphisms are associated with risk of intervertebral disc degeneration (IDD) in a largest Chinese Han population. MATERIAL AND METHODS There were 502 IDD patients and 497 healthy controls enrolled in this study. Nineteen single nucleotide polymorphisms (SNPs) in the FTO gene were tested using the Sequenom MassARRAY platform. The Hardy-Weinberg equilibrium test, followed by allelic, genotypic, haplotypic association, and SNP interaction analyses were used for SNP evaluation. The Genotype-Tissue Expression (GTEx) database was used to evaluate expression quantitative trait loci (eQTL) value of polymorphism. Spearman rank correlation and logistic regression analyses were used for assessing the internal relation between genotypic changes and the risk of IDD. RESULTS Seventeen SNPs survived the Hardy-Weinberg equilibrium test. Allelic analysis showed that allele T of SNP rs1121980 was a risk allele. Haplotypic and SNP interaction analyses suggested that 2 haplotypes and 5 SNP combinations were associated with the predisposition of IDD respectively. GTEx database revealed that the SNP rs1121980 might interfere with the expression of the FTO gene in the muscle-skeletal system. Through clinical statistics analysis, the different genotypes of rs1121980 can present different disease severity of IDD. CONCLUSIONS Our study suggests that rs1121980 can become a biomarker for the screening and prognosis of IDD. The 2 haplotype blocks and 5 SNP-SNP combinations that we discovered might be indicative of the onset of IDD. Therefore, our study might serve as evidence for future IDD molecular diagnosis.

To evaluate the overall diagnostic value related to magnetic resonance imaging (MRI) in patients with early osteonecrosis of the femoral head.

Gastric cancer is one of the most common and lethal malignant cancers worldwide, and numerous epidemiological studies have demonstrated that Helicobacter pylori (H. pylori) infection plays a key role in the development of gastric carcinomas. Our previous studies showed that aquaporin 3 (AQP3) is overexpressed in gastric carcinoma and promotes the migration and proliferation of human gastric carcinoma cells, suggesting that AQP3 may be a potentially important determinant of gastric carcinoma. However, the role of AQP3 in H. pylori carcinogenesis is unknown.

Intracranial aneurysm (IA) is one of the most lethal forms of cerebrovascular diseases characterized by endothelial dysfunction, vascular smooth muscle cell phenotypic modulation, inflammation and consequently loss of vessel cells and extracellular matrix degradation. Besides environmental factors, genetics seem to be a very important factor in the genesis of this disease. Previous mRNA expression studies revealed a large number of differentially expressed genes between IA and control tissue. However, microRNAs (miRNA), small non-coding RNAs which are post-transcriptional regulators of gene expression, have been barely studied. Studying miRNAs could provide a hypothetical mechanism underlying rupture of IA.

Toxoplasma gondii can infect almost all warm-blood animals including human beings. The plant-like calcium-dependent protein kinases (CDPKs) harbored by T. gondii are involved in gliding motility, cell invasion, egress and some other developmental processes, and so have been implicated as important virulence factors.

Neocortical development involves ordered specification of forebrain cortical progenitors to various neuronal subtypes, ultimately forming the layered cortical structure. Modeling of this process using human pluripotent stem cells (hPSCs) would enable mechanistic studies of human neocortical development, while providing new avenues for exploration of developmental neocortical abnormalities. Here, we show that preserving hPSCs aggregates - allowing embryoid body formation - while adding basic fibroblast growth factor (bFGF) during neuroepithelial development generates neural rosettes showing dorsal forebrain identity, including Mash1(+) dorsal telencephalic GABAergic progenitors. Structures that mirrored the organization of the cerebral cortex formed after rosettes were seeded and cultured for 3 weeks in the presence of FGF18, BDNF and NT3. Neurons migrated along radial glia scaffolding, with deep-layer CTIP2(+) cortical neurons appearing after 1 week and upper-layer SATB2(+) cortical neurons forming during the second and third weeks. At the end of differentiation, these structures contained both glutamatergic and GABAergic neurons, with glutamatergic neurons being most abundant. Thus, this differentiation protocol generated an hPSC-based model that exhibits temporal patterning and a neuronal subtype ratio similar to that of the developing human neocortex. This model was used to examine the effects of cocaine during neocorticogenesis. Cocaine caused premature neuronal differentiation and enhanced neurogenesis of various cortical neuronal subtypes. These cocaine-induced changes were inhibited by the cytochrome P450 inhibitor cimetidine. This in vitro model enables mechanistic studies of neocorticogenesis, and can be used to examine the mechanisms through which cocaine alters the development of the human neocortex.