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1.  Olfactory perception and behavioral effects of sex pheromone gland components in Helicoverpa armigera and Helicoverpa assulta 
Scientific Reports  2016;6:22998.
Two sympatric species Helicoverpa armigera and Helicoverpa assulta use (Z)-11-hexadecenal and (Z)-9-hexadecenal as sex pheromone components in reverse ratio. They also share several other pheromone gland components (PGCs). We present a comparative study on the olfactory coding mechanism and behavioral effects of these additional PGCs in pheromone communication of the two species using single sensillum recording, in situ hybridization, calcium imaging, and wind tunnel. We classify antennal sensilla types A, B and C into A, B1, B2, C1, C2 and C3 based on the response profiles, and identify the glomeruli responsible for antagonist detection in both species. The abundance of these sensilla types when compared with the number of OSNs expressing each of six pheromone receptors suggests that HarmOR13 and HassOR13 are expressed in OSNs housed within A type sensilla, HarmOR14b within B and C type sensilla, while HassOR6 and HassOR16 within some of C type sensilla. We find that for H. armigera, (Z)-11-hexadecenol and (Z)-11-hexadecenyl acetate act as behavioral antagonists. For H. assulta, instead, (Z)-11-hexadecenyl acetate acts as an agonist, while (Z)-9-hexadecenol, (Z)-11-hexadecenol and (Z)-9-hexadecenyl acetate are antagonists. The results provide an overall picture of intra- and interspecific olfactory and behavioral responses to all PGCs in two sister species.
PMCID: PMC4792173  PMID: 26975244
2.  Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells*  
Objective: To construct a recombinant adenovirus vector-carrying human growth and differentiation factor-5 (GDF-5) gene, investigate the biological effects of adenovirus-mediated GDF-5 (Ad-GDF-5) on extracellular matrix (ECM) expression in human degenerative disc nucleus pulposus (NP) cells, and explore a candidate gene therapy method for intervertebral disc degeneration (IDD). Methods: Human NP cells of a degenerative disc were isolated, cultured, and infected with Ad-GDF-5 using the AdEasy-1 adenovirus vector system. On Days 3, 7, 14, and 21, the contents of the sulfated glycosaminoglycan (sGAG), deoxyribonucleic acid (DNA) and hydroxyproline (Hyp), synthesis of proteoglycan and collagen II, gene expression of collagen II and aggrecan, and NP cell proliferation were assessed. Results: The adenovirus was an effective vehicle for gene delivery with prolonged expression of GDF-5. Biochemical analysis revealed increased sGAG and Hyp contents in human NP cells infected by Ad-GDF-5 whereas there was no conspicuous change in basal medium (BM) or Ad-green fluorescent protein (GFP) groups. Only cells in the Ad-GDF-5 group promoted the production of ECM, as demonstrated by the secretion of proteoglycan and up-regulation of collagen II and aggrecan at both protein and mRNA levels. The NP cell proliferation was significantly promoted. Conclusions: The data suggest that Ad-GDF-5 gene therapy is a potential treatment for IDD, which restores the functions of degenerative intervertebral disc through enhancing the ECM production of human NP cells.
PMCID: PMC4710838  PMID: 26739524
Intervertebral disc; Degeneration; Growth and differentiation factor-5 (GDF-5); Adenovirus; Gene therapy; Nucleus pulposus
3.  Identification and Expression Analysis of BURP Domain-Containing Genes in Medicago truncatula 
BURP domain-containing proteins belong to a newly identified protein class that is unique to plants and plays an important role in plant development and metabolism. Although systematic characterization of BURP domain-containing proteins have been carried out in many species, such as rice, poplar and maize, little is known about BURP domain-containing proteins in Medicago. In this study, multiple bioinformatics approaches were employed to identify all the members of BURP family genes in Medicago. A complete set of 39 BURP family genes were identified. These genes have diverse structures and were distributed on chromosome 1–8 except 7. According to phylogenetic analysis, these BURP family genes could be classified into eight classes. Motif and exon-intron organization, stress-related cis-elements in promoter regions and microarray analysis of MtBURPs were also performed. Furthermore, transcript level analysis of MtBURP genes in response to drought stress revealed that all of the 39 BURP genes were regulated by drought stress. The results of this study reveal a comprehensive overview of the Medicago BURP gene family and provide the first step toward the selection of MtBURP genes for cloning and functional analysis of the BURP gene family in Medicago truncatula.
PMCID: PMC4829796  PMID: 27148311
abiotic stress; bioinformatics; BURP genes; Medicago truncatula
4.  Roles of palmitoylation and the KIKK membrane-targeting motif in leukemogenesis by oncogenic KRAS4A 
We have previously shown that palmitoylation is essential for NRAS leukemogenesis, suggesting that targeting RAS palmitoylation may be an effective therapy for NRAS-related cancers. For KRAS-driven cancer, although much research has been focused on the KRAS4B splice variant, which does not undergo palmitoylation, KRAS4A has recently been shown to play an essential role in the development of carcinogen-induced lung cancer in mice and to be widely expressed in human cancers. However, the role of palmitoylation in KRAS4A tumorigenesis is not clear.
The expression of KRAS4A in KRAS-mutated leukemia cell lines and acute myeloid leukemia (AML) cells were checked using western blotting and reverse transcriptions-quantitative polymerase chain reaction (RT-qPCR) analysis, respectively. The leukemogenic potentials of oncogenic KRAS4A and its palmitoylation-defective mutants were examined by a mouse bone marrow transduction and transplantation model and the in vitro transformation assays. The activation of the RAS downstream signaling pathways and the membrane localizations of the KRAS4A and its mutants were analyzed via western blot analysis and confocal microscopy, respectively.
We show here that KRAS4A is expressed in human leukemia cell lines and in AML cells harboring KRAS mutations and that mutation at the palmitoylation site of oncogenic KRAS4A significantly abrogates its leukemogenic potential. However, unlike NRAS, palmitoylation-defective KRAS4A still induces leukemia in mice, albeit with a much longer latency. Using NRAS/KRAS4A chimeric constructs, we found that the KIKK motif of KRAS4A contributes to the transforming activity of KRAS4A. Mutations at both palmitoylation site and the KIKK motif abolish the ability of oncogenic KRAS4A to induce leukemia in mice.
Our studies suggest that therapies targeting RAS palmitoylation may also be effective in treating KRAS4A associated malignancies and that interfering the KIKK membrane-targeting motif would enhance the therapeutic effectiveness.
PMCID: PMC4696201  PMID: 26715448
RAS; Leukemogenesis; Drug target; Plasma membrane translocation; Signal transduction
5.  Repair of articular cartilage defects in rabbits through tissue-engineered cartilage constructed with chitosan hydrogel and chondrocytes*  
Objective: In our previous work, we prepared a type of chitosan hydrogel with excellent biocompatibility. In this study, tissue-engineered cartilage constructed with this chitosan hydrogel and costal chondrocytes was used to repair the articular cartilage defects. Methods: Chitosan hydrogels were prepared with a crosslinker formed by combining 1,6-diisocyanatohexane and polyethylene glycol. Chitosan hydrogel scaffold was seeded with rabbit chondrocytes that had been cultured for one week in vitro to form the preliminary tissue-engineered cartilage. This preliminary tissue-engineered cartilage was then transplanted into the defective rabbit articular cartilage. There were three treatment groups: the experimental group received preliminary tissue-engineered cartilage; the blank group received pure chitosan hydrogels; and, the control group had received no implantation. The knee joints were harvested at predetermined time. The repaired cartilage was analyzed through gross morphology, histologically and immunohistochemically. The repairs were scored according to the international cartilage repair society (ICRS) standard. Results: The gross morphology results suggested that the defects were repaired completely in the experimental group after twelve weeks. The regenerated tissue connected closely with subchondral bone and the boundary with normal tissue was fuzzy. The cartilage lacuna in the regenerated tissue was similar to normal cartilage lacuna. The results of ICRS gross and histological grading showed that there were significant differences among the three groups (P<0.05). Conclusions: Chondrocytes implanted in the scaffold can adhere, proliferate, and secrete extracellular matrix. The novel tissue-engineered cartilage constructed in our research can completely repair the structure of damaged articular cartilage.
PMCID: PMC4642872  PMID: 26537209
Articular cartilage; Chitosan hydrogel; Repair; Tissue engineering
6.  CCAAT/enhancer-binding protein α is required for hepatic outgrowth via the p53 pathway in zebrafish 
Scientific Reports  2015;5:15838.
CCAAT/enhancer-binding protein α (C/ebpα) is a transcription factor that plays important roles in the regulation of hepatogenesis, adipogenesis and hematopoiesis. Disruption of the C/EBPα gene in mice leads to disturbed liver architecture and neonatal death due to hypoglycemia. However, the precise stages of liver development affected by C/ebpα loss are poorly studied. Using the zebrafish embryo as a model organism, we show that inactivation of the cebpa gene by TALENs results in a small liver phenotype. Further studies reveal that C/ebpα is distinctively required for hepatic outgrowth but not for hepatoblast specification. Lack of C/ebpα leads to enhanced hepatic cell proliferation and subsequent increased cell apoptosis. Additional loss of p53 can largely rescue the hepatic defect in cebpa mutants, suggesting that C/ebpα plays a role in liver growth regulation via the p53 pathway. Thus, our findings for the first time demonstrate a stage-specific role for C/ebpα during liver organogenesis.
PMCID: PMC4649991  PMID: 26511037
7.  PTEN Interacts with Histone H1 and Controls Chromatin Condensation 
Cell reports  2014;8(6):2003-2014.
Chromatin organization and dynamics are integral to global gene transcription. Histone modification influences chromatin status and gene expression. PTEN plays multiple roles in tumor suppression, development and metabolism. Here we report on the interplay of PTEN, histone H1 and chromatin. We show that loss of PTEN leads to dissociation of histone H1 from chromatin and decondensation of chromatin. PTEN deletion also results in elevation of histone H4 acetylation at lysine 16, an epigenetic marker for chromatin activation. We found that PTEN and histone H1 physically interact through their C-terminal domains. Disruption of the PTEN C-terminus promotes the chromatin association of MOF acetyltransferase and induces H4K16 acetylation. Hyperacetylation of H4K16 impairs the association of PTEN with histone H1, which constitutes regulatory feedback that may deteriorate chromatin stability. Our results demonstrate that PTEN controls chromatin condensation, thus influencing gene expression. We propose that PTEN regulates global gene transcription profiling through histones and chromatin remodeling.
PMCID: PMC4201947  PMID: 25199838
8.  Genome-wide Association Study Identifies Peanut Allergy-Specific Loci and Evidence of Epigenetic Mediation in U.S. Children 
Nature communications  2015;6:6304.
Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.
PMCID: PMC4340086  PMID: 25710614
9.  Shifts in Abundance and Diversity of Soil Ammonia-Oxidizing Bacteria and Archaea Associated with Land Restoration in a Semi-Arid Ecosystem 
PLoS ONE  2015;10(7):e0132879.
The Grain to Green Project (GGP) is an unprecedented land restoration action in China. The project converted large areas (ca 10 million ha) of steep-sloped/degraded farmland and barren land into forest and grassland resulting in ecological benefits such as a reduction in severe soil erosion. It may also affect soil microorganisms involved in ammonia oxidization, which is a key step in the global nitrogen cycle. The methods for restoration that are typically adopted in semi-arid regions include abandoning farmland and growing drought tolerant grass (Lolium perenne L.) or shrubs (Caragana korshinskii Kom.). In the present study, the effects of these methods on the abundance and diversity of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) were evaluated via quantitative real-time PCR, terminal restriction fragment length polymorphism and clone library analysis of amoA genes. Comparisons were made between soil samples from three restored lands and the adjacent farmland in Inner Mongolia. Both the abundance and community composition of AOB were significantly different between the restored lands and the adjacent control. Significantly lower nitrification activity was observed for the restored land. Clone library analysis revealed that all AOB amoA gene sequences were affiliated with Nitrosospira. Abundance of the populations that were associated with Nitrosospira sp. Nv6 which had possibly adapted to high concentrations of inorganic nitrogen, decreased on the restored land. Only a slight difference in the AOB communities was observed between the restored land with and without the shrub (Caragana korshinskii Kom.). A minor effect of land restoration on AOA was observed. In summary, land restoration negatively affected the abundance of AOB and soil nitrification activities, suggesting the potential role of GGP in the leaching of nitrates, and in the emission of N2O in related terrestrial ecosystems.
PMCID: PMC4501784  PMID: 26172994
10.  The Lipoxygenase Gene Family in Poplar: Identification, Classification, and Expression in Response to MeJA Treatment 
PLoS ONE  2015;10(4):e0125526.
Lipoxygenases (LOXs) are important dioxygenases in cellular organisms. LOXs contribute to plant developmental processes and environmental responses. However, a systematic and comprehensive analysis has not been focused on the LOX gene family in poplar. Therefore, in the present study, we performed a comprehensive analysis of the LOX gene family in poplar.
Using bioinformatics methods, we identified a total of 20 LOX genes. These LOX genes were clustered into two subfamilies. The gene structure and motif composition of each subfamily were relatively conserved. These genes are distributed unevenly across nine chromosomes. The PtLOX gene family appears to have expanded due to high tandem and low segmental duplication events. Microarray analysis showed that a number of PtLOX genes have different expression pattern across disparate tissues and under various stress treatments. Quantitative real-time PCR (qRT-PCR) analysis was further performed to confirm the responses to MeJA treatment of the 20 poplar LOX genes. The results show that the PtLOX genes are regulated by MeJA (Methyl jasmonate) treatment.
This study provides a systematic analysis of LOX genes in poplar. The gene family analysis reported here will be useful for conducting future functional genomics studies to uncover the roles of LOX genes in poplar growth and development.
PMCID: PMC4415952  PMID: 25928711
11.  Comparison of two different laparotomy methods for modeling rabbit VX2 hepatocarcinoma 
AIM: To compare two different laparotomy methods for modeling rabbit VX2 hepatocarcinoma.
METHODS: Thirty New Zealand rabbits were randomly divided into two groups: A and B. Group A was assigned a traditional laparotomy method (embedding tumor fragments directly into the liver with tweezers). Group B was subjected to an improved laparotomy method (injection of tumor fragments into the liver through a 15 G syringe needle). The operation time, incision length, incision infection rate, and mortality rate were compared between the two groups after laparotomy. Magnetic resonance imaging (MRI) was performed to evaluate tumor formation rates and the characteristics of the tumors 2 wk after laparotomy.
RESULTS: The mean operation times for the two groups (Group A vs Group B) were 23.2 ± 3.4 min vs 17.5 ± 2.9 min (P < 0.05); the incision length was 3.3 ± 0.5 cm vs 2.4 ± 0.6 cm (P < 0.05); and the mortality rate after 2 wk was 26.7% vs 0% (P < 0.05); all of these outcomes were significantly different between the two groups. The incision infection rates in the two groups were 6.7% vs 0% (P > 0.05), which were not significantly different. MRI performed after 2 weeks showed that the tumor formation rates in the two groups were 90.9% vs 93.3% (P > 0.05). These rates were not significantly different between the two groups. The celiac implantation rate and abdominal wall metastasis rate in the two groups were 36.4% vs 13.3% (P < 0.05) and 27.2% vs 6.7% (P < 0.05), respectively, which were significantly different between the two groups.
CONCLUSION: The tumor formation rates were not significantly different between the two methods for modeling rabbit VX2 hepatocarcinoma. However, the improved method is recommended because it has certain advantages.
PMCID: PMC4408459  PMID: 25945000
Rabbit VX2 hepatocarcinoma; Laparotomy; Modeling; Magnetic resonance imaging
12.  Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation 
Nucleic Acids Research  2015;43(10):5081-5098.
Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1α/2α methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis.
PMCID: PMC4446437  PMID: 25897119
13.  Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide 
EBioMedicine  2015;2(6):563-571.
Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL.
We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2.
More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179–20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089–14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS.
In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.
•The EMG mutations were associated with poor prognosis in APL.•Sanz risk system was useful to predict the CR and OS upon ATRA/ATO treatment.
PMCID: PMC4535155  PMID: 26285909
Acute promyelocytic leukemia; Epigenetic; Prognosis; Mutation
14.  Preterm Birth and Random Plasma Insulin Levels at Birth and in Early Childhood 
JAMA  2014;311(6):587-596.
Although previous reports have linked preterm birth with insulin resistance in children and adults, it is not known whether altered insulin homeostasis is detectable at birth and tracks from birth onwards.
To investigate whether preterm birth is associated with elevated plasma insulin levels at birth and whether this association persists into early childhood.
Design, Setting, and Participation
A prospective birth cohort of 1358 children recruited at birth from 1998 to 2010 and followed prospectively from 2005 to 2012 at the Boston Medical Center, Boston, MA.
Main Outcome Measures
Random plasma insulin levels were measured at two time points: at birth (cord blood) and in early childhood (venous blood) (median age (25th–75th percentile): 1.4 (0.8–3.3) years) among four gestational age groups: term (≥37 weeks), and further grouped into full term (≥39 weeks) and early term (37–38 weeks); preterm (<37 weeks), and further grouped into late preterm (34–36 weeks) and early preterm (<34 weeks).
The geometric mean (95% confidence interval(CI)) of insulin levels for full term, early term, late preterm and early preterm births was 9.2(8.4–10.0), 10.3(9.3–11.5), 13.2(11.8–14.8) and 18.9(16.6–21.4) µU/ml, respectively at birth, and 11.2(10.3–12.0), 12.4(11.3–13.6), 13.3(11.9–14.8) and 14.6(12.6–16.9) µU/ml, respectively in early childhood. At birth, insulin levels were 1.13(95% CI: 0.97–1.28), 1.45(95%CI: 1.25–1.65) and 2.05(95%CI: 1.69–2.42) folds higher for early term, late preterm and early preterm, respectively, than those born full term. In early childhood, plasma random insulin levels in those born early term, late preterm and early preterm were 1.12(95%CI: 0.99–1.25), 1.19(95%CI: 1.02–1.35), and 1.31(95%CI: 1.10–1.52) folds higher, respectively, than those born full term. The association was attenuated after adjustment for postnatal weight gain and was not significant after adjustment for insulin levels at birth. Children ranked in the top insulin tertile at birth were more likely to remain in the top tertile in early childhood relative to children ranked in the lowest tertile (41.2% vs. 28.6%).
Conclusion and Relevance
There was an inverse association between gestational age and elevated plasma insulin levels at birth and in early childhood. The implications for future development of insulin resistance and type 2 diabetes warrant further investigation.
PMCID: PMC4392841  PMID: 24519298
15.  Temporal and spatial temperature distributions on glabrous skin irradiated by a 1940 nm continuous-wave laser stimulator 
Biomedical Optics Express  2015;6(4):1451-1463.
For predicting pain stimulation effects and avoiding damage in 1940nm laser evoked potentials (LEPs) experiments, a 2-layer finite element model (FEM-2) was constructed. A series of experiments were conducted on ex-vivo pig skin pieces to verify temperature distribution predicted by this model. Various laser powers and beam radii were employed. Experimental data of time-dependent temperature responses in different sub-skin depths and space-dependent surface temperature was recorded by thermocouple instrument. By comparing with the experimental data and model results, FEM-2 model was proved to predict temperature distributions accurately. A logarithmic relationship between laser power density and temperature increment was revealed by the results. It is concluded that power density is an effective parameter to estimate pain and damage effect. The obtained results also indicated that the proposed FEM-2 model can be extended to predict pain and damage thresholds of human skin samples and thus contribute to LEPs study.
PMCID: PMC4399682  PMID: 25909027
(140.0140) Lasers and laser optics; (140.3330) Laser damage; (140.6810) Thermal effects; (140.3580) Lasers, solid-state; (170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues
16.  Sumoylation of CCAAT/enhancer-binding protein α is implicated in hematopoietic stem/progenitor cell development through regulating runx1 in zebrafish 
Scientific Reports  2015;5:9011.
The small ubiquitin-related modifier (SUMO) participates in various cellular processes, including maintenance of genome integrity, nuclear transport, transcription and signal transduction. However, the biological function of sumoylation in hematopoiesis has not been fully explored. We show here that definitive hematopoietic stem/progenitor cells (HSPCs) are depleted in SUMO-deficient zebrafish embryos. Impairment of sumoylation attenuates HSPC generation and proliferation. The hyposumoylation triggered HSPC defects are CCAAT/enhancer-binding protein α (C/ebpα) dependent. Critically, a SUMO-C/ebpα fusion rescues the defective hematopoiesis in SUMO-deficient embryos, at least in part through restored runx1 expression. While C/ebpα-dependent transcription is involved in myeloid differentiation, our studies here reveal that C/ebpα sumoylation is essential for HSPC development during definitive hematopoiesis.
PMCID: PMC4355724  PMID: 25757417
17.  Early Life Origins of Metabolic Syndrome: The Role of Environmental Toxicants 
Metabolic syndrome (MetS) affects more than 47 million people in the U.S. Even more alarming, MetS, once regarded as an “adult problem”, has become increasingly common in children. To date, most related research and intervention efforts have occurred in the adult medicine arena, with limited understanding of the root causes and lengthy latency of MetS. This review highlights new science on the early life origins of MetS, with a particular focus on exposure to two groups of environmental toxicants: endocrine disrupting chemicals (EDCs) and metals during the prenatal and early postnatal periods, and their specific effects and important differences in the development of MetS. It also summarizes available data on epigenetic effects, including the role of EDCs in the androgen/estrogen pathways. Emerging evidence supports the link between exposures to environmental toxicants during early life and the development of MetS later in life. Additional research is needed to address important research gaps in this area, including prospective birth cohort studies to delineate temporal and dose-response relationships, important differences in the effects of various environmental toxicants and their joint effects on MetS, as well as epigenetic mechanisms underlying the effects of specific toxicants such as EDCs and metals.
PMCID: PMC4037145  PMID: 24883264
diabetes; environmental toxicants; metabolic syndrome; obesity; prenatal exposure
18.  DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish 
DNA methyltransferase 1 (Dnmt1) regulates expression of many critical genes through maintaining parental DNA methylation patterns on daughter DNA strands during mitosis. It is essential for embryonic development and diverse biological processes, including maintenance of hematopoietic stem and progenitor cells (HSPCs). However, the precise molecular mechanism of how Dnmt1 is involved in HSPC maintenance remains unexplored.
An N-ethyl-N-nitrosourea (ENU)-based genetic screening was performed to identify putative mutants with defects in definitive HSPCs during hematopoiesis in zebrafish. The expression of hematopoietic markers was analyzed via whole mount in situ hybridization assay (WISH). Positional cloning approach was carried out to identify the gene responsible for the defective definitive hematopoiesis in the mutants. Analyses of the mechanism were conducted by morpholino-mediated gene knockdown, mRNA injection rescue assays, anti-phosphorylated histone H3 (pH3) immunostaining and TUNEL assay, quantitative real-time PCR, and bisulfite sequencing analysis.
A heritable mutant line with impaired HSPCs of definitive hematopoiesis was identified. Positional cloning demonstrated that a stop codon mutation was introduced in dnmt1 which resulted in a predicted truncated Dnmt1 lacking the DNA methylation catalytic domain. Molecular analysis revealed that expression of CCAAT/enhancer-binding protein alpha (C/ebpa) was upregulated, which correlated with hypomethylation of CpG islands in the regulation regions of cebpa gene in Dnmt1 deficient HSPCs. Overexpression of a transcriptional repressive SUMO-C/ebpa fusion protein could rescue hematological defects in the dnmt1 mutants. Finally, dnmt1 and cebpa double null embryos exhibited no obvious abnormal hematopoiesis indicated that the HSPC defects triggered by dnmt1 mutation were C/ebpa dependent.
Dnmt1 is required for HSPC maintenance via cebpa regulation during definitive hematopoiesis in zebrafish.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0115-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4372312  PMID: 25886310
Dnmt1; C/ebpa; HSPCs; Zebrafish
19.  Placental transfer and concentrations of cadmium, mercury, lead, and selenium in mothers, newborns, and young children 
There is an emerging hypothesis that exposure to cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in utero and early childhood could have long-term health consequences. However, there are sparse data on early life exposures to these elements in US populations, particularly in urban minority samples. This study measured levels of Cd, Hg, Pb, and Se in 50 paired maternal, umbilical cord, and postnatal blood samples from the Boston Birth Cohort (BBC). Maternal exposure to Cd, Hg, Pb, and Se was 100% detectable in red blood cells (RBCs), and there was a high degree of maternal–fetal transfer of Hg, Pb, and Se. In particular, we found that Hg levels in cord RBCs were 1.5 times higher than those found in the mothers. This study also investigated changes in concentrations of Cd, Hg, Pb, and Se during the first few years of life. We found decreased levels of Hg and Se but elevated Pb levels in early childhood. Finally, this study investigated the association between metal burden and preterm birth and low birthweight. We found significantly higher levels of Hg in maternal and cord plasma and RBCs in preterm or low birthweight births, compared with term or normal birthweight births. In conclusion, this study showed that maternal exposure to these elements was widespread in the BBC, and maternal–fetal transfer was a major source of early life exposure to Hg, Pb, and Se. Our results also suggest that RBCs are better than plasma at reflecting the trans-placental transfer of Hg, Pb, and Se from the mother to the fetus. Our study findings remain to be confirmed in larger studies, and the implications for early screening and interventions of preconception and pregnant mothers and newborns warrant further investigation.
PMCID: PMC4329243  PMID: 24756102
cadmium (Cd); mercury (Hg); lead (Pb) and selenium (Se); maternal–fetal transfer; early life exposure
20.  Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit 
The present study aimed at establishing feasibility of delivering short interfering RNA (siRNA) to target the coagulation cascade in rat and rabbit, two commonly used species for studying thrombosis and hemostasis. siRNAs that produced over 90% mRNA knockdown of rat plasma prekallikrein and rabbit Factor X (FX) were identified from in vitro screens. An ionizable amino lipid based lipid nanoparticle (LNP) formulation for siRNA in vivo delivery was characterized as tolerable and exerting no appreciable effect on coagulability at day 7 postdosing in both species. Both prekallikrein siRNA-LNP and FX siRNA-LNP resulted in dose-dependent and selective knockdown of target gene mRNA in the liver with maximum reduction of over 90% on day 7 following a single dose of siRNA-LNP. Knockdown of plasma prekallikrein was associated with modest clot weight reduction in the rat arteriovenous shunt thrombosis model and no increase in the cuticle bleeding time. Knockdown of FX in the rabbit was accompanied with prolongation in ex vivo clotting times. Results fit the expectations with both targets and demonstrate for the first time, the feasibility of targeting coagulation factors in rat, and, more broadly, targeting a gene of interest in rabbit, via systemic delivery of ionizable LNP formulated siRNA.
PMCID: PMC4345307  PMID: 25625614
coagulation; Factor X; lipid nanoparticle; plasma kallikrein; siRNA
21.  Specific olfactory neurons and glomeruli are associated to differences in behavioral responses to pheromone components between two Helicoverpa species 
Sex pheromone communication of moths helps to understand the mechanisms underlying reproductive isolation and speciation. Helicoverpa armigera and Helicoverpa assulta use (Z)-11-hexadecenal (Z11-16:Ald) and (Z)-9-hexadecenal (Z9-16:Ald) as pheromone components in reversed ratios, 97:3 and 5:95, respectively. H. armigera also produces trace amount of (Z)-9-tetradecenal (Z9-14:Ald) in the sex pheromone gland, but H. assulta does not. Wind tunnel studies revealed that the addition of small amounts (0.3%) of Z9-14:Ald to the main pheromone blend of H. armigera increased the males' attraction, but at higher doses (1%, 10%) the same compound acted as an inhibitor. In H. assulta, Z9-14:Ald reduced male attraction when presented as 1% to the pheromone blend, but was ineffective at lower concentrations (0.3%). Three types (A–C) of sensilla trichodea in antennae were identified by single sensillum recording, responding to Z11-16:Ald, Z9-14:Ald, and both Z9-16:Ald and Z9-14:Ald, respectively. Calcium imaging in the antennal lobes (ALs) revealed that the input information of the three chemicals was transmitted to three units of the macroglomerular complex (MGC) in ALs in both species: a large glomerulus for the major pheromone components, a small one for the minor pheromone components, and a third one for the behavioral antagonists. The type A and C neurons tuned to Z11-16:Ald and Z9-16:Ald had a reversed target in the MGC between the two species. In H. armigera, low doses (1, 10 μg) of Z9-14:Ald dominantly activated the glomerulus which processes the minor pheromone component, while a higher dose (100 μg) also evoked an equal activity in the antagonistic glomerulus. In H. assulta, instead, Z9-14:Ald always strongly activated the antagonistic glomerulus. These results suggest that Z9-14:Ald plays different roles in the sexual communication of two Helicoverpa species through activation of functionally different olfactory pathways.
PMCID: PMC4523827  PMID: 26300751
behavior; sex pheromone; olfactory sensory neurons; calcium imaging; antennal lobe
22.  Distribution and Determinants of Plasma Homocysteine Levels in Rural Chinese Twins across the Lifespan 
Nutrients  2014;6(12):5900-5914.
Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome.
PMCID: PMC4277006  PMID: 25529062
homocysteine; Chinese twins; heritability; gender difference; smoking
23.  The IQD Gene Family in Soybean: Structure, Phylogeny, Evolution and Expression 
PLoS ONE  2014;9(10):e110896.
Members of the plant-specific IQ67-domain (IQD) protein family are involved in plant development and the basal defense response. Although systematic characterization of this family has been carried out in Arabidopsis, tomato (Solanum lycopersicum), Brachypodium distachyon and rice (Oryza sativa), systematic analysis and expression profiling of this gene family in soybean (Glycine max) have not previously been reported. In this study, we identified and structurally characterized IQD genes in the soybean genome. A complete set of 67 soybean IQD genes (GmIQD1–67) was identified using Blast search tools, and the genes were clustered into four subfamilies (IQD I–IV) based on phylogeny. These soybean IQD genes are distributed unevenly across all 20 chromosomes, with 30 segmental duplication events, suggesting that segmental duplication has played a major role in the expansion of the soybean IQD gene family. Analysis of the Ka/Ks ratios showed that the duplicated genes of the GmIQD family primarily underwent purifying selection. Microsynteny was detected in most pairs: genes in clade 1–3 might be present in genome regions that were inverted, expanded or contracted after the divergence; most gene pairs in clade 4 showed high conservation with little rearrangement among these gene-residing regions. Of the soybean IQD genes examined, six were most highly expressed in young leaves, six in flowers, one in roots and two in nodules. Our qRT-PCR analysis of 24 soybean IQD III genes confirmed that these genes are regulated by MeJA stress. Our findings present a comprehensive overview of the soybean IQD gene family and provide insights into the evolution of this family. In addition, this work lays a solid foundation for further experiments aimed at determining the biological functions of soybean IQD genes in growth and development.
PMCID: PMC4208818  PMID: 25343341
24.  Inhibitory Effect of Hydroxysafflor Yellow A on Mouse Skin Photoaging Induced by Ultraviolet Irradiation 
Rejuvenation Research  2013;16(5):404-413.
Chronic exposure to ultraviolet (UV) irradiation is believed to be the major cause of skin damage that results in premature aging of the skin, so called photoaging, characterized by increases in skin thickness, formation of wrinkles, and loss of skin elasticity. UV induces damage to skin mainly by oxidative stress and collagen degradation. In this study, we examined the photo-protective effect of hydroxysafflor yellow A (HSYA), a major active chemical component isolated from Carthamus tinctorius L., by topical application on the skin of mice. Exposure of the dorsal depilated skin of mice to UV radiation four times a week for 10 weeks induced epidermal hyperplasia, elastin accumulation, collagen degradation, etc. HSYA at the doses of 50, 100, and 200 μg/mouse was topically applied immediately following each UV exposure. The effects of HSYA were evaluated by a series of tests, including macroscopic and histopathological evaluation of skin, pinch test, and redox homeostasis of skin homogenates. Results showed that the UV-induced skin damage was significantly improved after HSYA treatment, especially at doses of 100 and 200 μg/mouse. This protective effect is possibly related to the anti-oxidative property of HSYA and mediated by promoting endogenous collagen synthesis. This is the first study providing preclinical evidence for the protective effect of HSYA against photoaging.
PMCID: PMC3804320  PMID: 23822553
25.  EAF2 Suppresses Hypoxia-Induced Factor 1α Transcriptional Activity by Disrupting Its Interaction with Coactivator CBP/p300 
Molecular and Cellular Biology  2014;34(6):1085-1099.
Previous studies revealed that the potential tumor suppressor EAF2 binds to and stabilizes pVHL, suggesting that EAF2 may function by disturbing the hypoxia signaling pathway. However, the extent to which EAF2 affects hypoxia and the mechanisms underlying this activity remain largely unknown. In this study, we found that EAF2 is a hypoxia response gene harboring the hypoxia response element (HRE) in its promoter. By taking advantage of the pVHL-null cell lines RCC4 and 786-O, we demonstrated that hypoxia-induced factor 1α (HIF-1α), but not HIF-2α, induced EAF2 under hypoxia. Subsequent experiments showed that EAF2 bound to and suppressed HIF-1α but not HIF-2α transactivity. In addition, we observed that EAF2 inhibition of HIF-1α activity resulted from the disruption of p300 recruitment and that this occurred independently of FIH-1 (factor inhibiting HIF-1) and Sirt1. Furthermore, we found that EAF2 protected cells against hypoxia-induced cell death and inhibited cellular uptake of glucose under hypoxic conditions, suggesting that EAF2 indeed may act by modulating the hypoxia-signaling pathway. Our findings not only uncover a unique feedback regulation loop between EAF2 and HIF-1α but also provide a novel insight into the mechanism of EAF2 tumor suppression.
PMCID: PMC3958035  PMID: 24421387

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