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1.  Perioperative dynamics and significance of amino acid profiles in patients with cancer 
Background
Metabolome analysis including amino acid profile is under investigation as an approach in cancer screening. The present study aims to analyze plasma free amino acid (PFAA) profiles in cancer patients and investigate their potential as biomarkers of malignancy.
Methods
Plasma samples from 56 gastric cancer patients, 28 breast cancer patients, 33 thyroid cancer patients, and 137 age-matched healthy controls were collected in the study. PFAA levels were measured and their perioperative alterations were analyzed. Biological effects of ten cancer-related amino acids were further validated in gastric and breast cancer cells.
Results
We found that PFAA profiles of cancer patients differed significantly from those of healthy controls. Decreased concentrations of PFAAs were associated with lymph node metastases in gastric cancer. Levels of PFAAs such as aspartate and alanine increased after tumor resection. PFAA levels correlated with clinical tumor markers in gastric cancer patients and pathological immunohistochemistry markers in breast cancer patients. Specifically, alanine, arginine, aspartate and cysteine had proliferative effects on breast cancer cells. Proliferation of gastric cancer cells was promoted by cysteine, but inhibited by alanine and glutamic acid. Furthermore, alanine treatment decreased total and stable fraction of gastric cancer cells, and alanine and glutamic acid induced apoptosis of gastric cancer cells.
Conclusions
PFAA patterns in cancer patients are altered perioperatively. Tumor-related amino acids identified by dynamic study of PFAA patterns may have the potential to be developed as novel biomarkers for diagnosis and prognosis of cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0408-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0408-1
PMCID: PMC4332895  PMID: 25622826
Amino acid profile; Plasma; Metabolism; Cancer; Perioperation
2.  Integrated metagenomics and network analysis of soil microbial community of the forest timberline 
Scientific Reports  2015;5:7994.
The forest timberline responds quickly and markedly to climate changes, rendering it a ready indicator. Climate warming has caused an upshift of the timberline worldwide. However, the impact on belowground ecosystem and biogeochemical cycles remain elusive. To understand soil microbial ecology of the timberline, we analyzed microbial communities via 16s rRNA Illumina sequencing, a microarray-based tool named GeoChip 4.0 and a random matrix theory-based association network approach. We selected 24 sampling sites at two vegetation belts forming the timberline of Shennongjia Mountain in Hubei Province of China, a region with extraordinarily rich biodiversity. We found that temperature, among all of measured environmental parameters, showed the most significant and extensive linkages with microbial biomass, microbial diversity and composition at both taxonomic and functional gene levels, and microbial association network. Therefore, temperature was the best predictor for microbial community variations in the timberline. Furthermore, abundances of nitrogen cycle and phosphorus cycle genes were concomitant with NH4+-N, NO3−-N and total phosphorus, offering tangible clues to the underlying mechanisms of soil biogeochemical cycles. As the first glimpse at both taxonomic and functional compositions of soil microbial community of the timberline, our findings have major implications for predicting consequences of future timberline upshift.
doi:10.1038/srep07994
PMCID: PMC4303876  PMID: 25613225
3.  Association between Chloroplast and Mitochondrial DNA sequences in Chinese Prunus genotypes (Prunus persica, Prunus domestica, and Prunus avium) 
BMC Plant Biology  2015;15:4.
Background
The nuclear DNA is conventionally used to assess the diversity and relatedness among different species, but variations at the DNA genome level has also been used to study the relationship among different organisms. In most species, mitochondrial and chloroplast genomes are inherited maternally; therefore it is anticipated that organelle DNA remains completely associated. Many research studies were conducted simultaneously on organelle genome. The objectives of this study was to analyze the genetic relationship between chloroplast and mitochondrial DNA in three Chinese Prunus genotypes viz., Prunus persica, Prunus domestica, and Prunus avium.
Results
We investigated the genetic diversity of Prunus genotypes using simple sequence repeat (SSR) markers relevant to the chloroplast and mitochondria. Most of the genotypes were genetically similar as revealed by phylogenetic analysis. The Y2 Wu Xing (Cherry) and L2 Hong Xin Li (Plum) genotypes have a high similarity index (0.89), followed by Zi Ye Li (0.85), whereas; L1 Tai Yang Li (plum) has the lowest genetic similarity (0.35). In case of cpSSR, Hong Tao (Peach) and L1 Tai Yang Li (Plum) genotypes demonstrated similarity index of 0.85 and Huang Tao has the lowest similarity index of 0.50. The mtSSR nucleotide sequence analysis revealed that each genotype has similar amplicon length (509 bp) except M5Y1 i.e., 505 bp with CCB256 primer; while in case of NAD6 primer, all genotypes showed different sizes. The MEHO (Peach), MEY1 (Cherry), MEL2 (Plum) and MEL1 (Plum) have 586 bps; while MEY2 (Cherry), MEZI (Plum) and MEHU (Peach) have 585, 584 and 566 bp, respectively. The CCB256 primer showed highly conserved sequences and minute single polymorphic nucleotides with no deletion or mutation. The cpSSR (ARCP511) microsatellites showed the harmonious amplicon length. The CZI (Plum), CHO (Peach) and CL1 (Plum) showed 182 bp; whileCHU (Peach), CY2 (Cherry), CL2 (Plum) and CY1 (Cherry) showed 181 bp amplicon lengths.
Conclusions
These results demonstrated high conservation in chloroplast and mitochondrial genome among Prunus species during the evolutionary process. These findings are valuable to study the organelle DNA diversity in different species and genotypes of Prunus to provide in depth insight in to the mitochondrial and chloroplast genomes.
doi:10.1186/s12870-014-0402-4
PMCID: PMC4310034  PMID: 25592231
Organelle DNA sequences; Prunus; SSR markers; Genetic diversity; Prunus persica; Prunus domestica; Prunus avium
4.  Comparison of Temporal Transcriptomic Profiles from Immature Lungs of Two Rat Strains Reveals a Viral Response Signature Associated with Chronic Lung Dysfunction 
PLoS ONE  2014;9(12):e112997.
Early life respiratory viral infections and atopic characteristics are significant risk factors for the development of childhood asthma. It is hypothesized that repeated respiratory viral infections might induce structural remodeling by interfering with the normal process of lung maturation; however, the specific molecular processes that underlie these pathological changes are not understood. To investigate the molecular basis for these changes, we used an established Sendai virus infection model in weanling rats to compare the post-infection transcriptomes of an atopic asthma susceptible strain, Brown Norway, and a non-atopic asthma resistant strain, Fischer 344. Specific to this weanling infection model and not described in adult infection models, Sendai virus in the susceptible, but not the resistant strain, results in morphological abnormalities in distal airways that persist into adulthood. Gene expression data from infected and control lungs across five time points indicated that specific features of the immune response following viral infection were heightened and prolonged in lungs from Brown Norway rats compared with Fischer 344 rats. These features included an increase in macrophage cell number and related gene expression, which then transitioned to an increase in mast cell number and related gene expression. In contrast, infected Fischer F344 lungs exhibited more efficient restoration of the airway epithelial morphology, with transient appearance of basal cell pods near distal airways. Together, these findings indicate that the pronounced macrophage and mast cell responses and abnormal re-epithelialization precede the structural defects that developed and persisted in Brown Norway, but not Fischer 344 lungs.
doi:10.1371/journal.pone.0112997
PMCID: PMC4249857  PMID: 25437859
5.  Viral Bronchiolitis in Young Rats Causes Small Airway Lesions that Correlate with Reduced Lung Function 
Viral illness with wheezing during infancy is associated with the inception of childhood asthma. Small airway dysfunction is a component of childhood asthma, but little is known about how viral illness at an early age may affect the structure and function of small airways. We used a well-characterized rat model of postbronchiolitis chronic airway dysfunction to address how postinfectious small airway lesions affect airway physiological function and if the structure/function correlates persist into maturity. Brown Norway rats were sham- or virus inoculated at 3 to 4 weeks of age and allowed to recover from the acute illness. At 3 to 14 months of age, physiology (respiratory system resistance, Newtonian resistance, tissue damping, and static lung volumes) was assessed in anesthetized, intubated rats. Serial lung sections revealed lesions in the terminal bronchioles that reduced luminal area and interrupted further branching, affecting 26% (range, 13–39%) of the small airways at 3 months of age and 22% (range, 6–40%) at 12 to 14 months of age. At 3 months of age (n = 29 virus; n = 7 sham), small airway lesions correlated with tissue damping (rs = 0.69) but not with Newtonian resistance (rs = 0.23), and Newtonian resistance was not elevated compared with control rats, indicating that distal airways were primarily responsible for the airflow obstruction. Older rats (n = 7 virus; n = 6 sham) had persistent small airway dysfunction and significantly increased Newtonian resistance in the postbronchiolitis group. We conclude that viral airway injury at an early age may induce small airway lesions that are associated quantitatively with small airway physiological dysfunction early on and that these defects persist into maturity.
doi:10.1165/rcmb.2013-0096OC
PMCID: PMC3931103  PMID: 23763491
asthma; lung growth and development; airway injury and repair
6.  Esophageal Adenocarcinoma and Its Rare Association with Barrett’s Esophagus in Henan, China 
PLoS ONE  2014;9(10):e110348.
Incidence of esophageal adenocarcinoma (EAC) has increased sharply in Western Europe and United States over the past three decades. Nearly all cases of EAC in the west are thought to be associated with Barrett’s esophagus (BE) at the time of diagnosis. Regions in the Henan province of China have one of world’s highest incidences of esophageal cancer, yet recent temporal trends in the relative rates of EAC with respect to esophageal squamous-cell carcinoma (ESCC), as well as its association with Barrett’s esophagus (BE), have not been reported. In this report, we present large-scale longitudinal clinical and histological data on 5401 esophageal cancers (EC) patients diagnosed during the recent 10-year period (2002–2011) at Henan Cancer Hospital, China. All 217 esophageal adenocarcinoma (EAC) patients from these 5401 EC patients were examined to better understand the relationship between Barrett’s esophagus (BE) and EAC. We found that EAC was relatively rare and accounted for approximately 5% of all esophageal cancers each year during 2002–2011. There is no evidence of significant temporal trends in the rate of EAC relative to ESCC. Only 10 out of 217 (4.6%) EAC cases were detected to have any evidence of Barrett’s esophagus. This result raises the possibility of a different etiological basis for EAC in China motivating more detailed epidemiological, clinical and molecular characterization of EAC in China in order to better understand the neoplastic development of EAC.
doi:10.1371/journal.pone.0110348
PMCID: PMC4198241  PMID: 25333822
7.  Ultrasensitive UPLC-MS-MS Method for the Quantitation of Etheno-DNA Adducts in Human Urine 
Etheno-DNA adducts are generated from the metabolism of exogenous carcinogens and endogenous lipid peroxidation. We and others have previously reported that 1,N6-ethenodeoxyadenosine (εdA) and 3,N4-ethenodeoxycytidine (εdC) are present in human urine and can be utilized as biomarkers of oxidative stress. In this study, we report a new ultrasensitive UPLC-ESI-MS/MS method for the analysis of εdA and εdC in human urine, capable of detecting 0.5 fmol εdA and 0.3 fmol εdC in 1.0 mL of human urine, respectively. For validation of the method, 20 human urine samples were analyzed, and the results revealed that the mean levels of εdA and εdC (SD) fmol/µmol creatinine are 5.82 ± 2.11 (range 3.0–9.5) for εdA and 791.4 ± 328.8 (range 116.7–1264.9) for εdC in occupational benzene-exposed workers and 2.10 ± 1.32 (range 0.6–4.7) for εdA and 161.8 ± 200.9 (range 1.8–557.5) for εdC in non-benzene-exposed workers, respectively. The ultrasensitive detection method is thus suitable for applications in human biomonitoring and molecular epidemiology studies.
doi:10.3390/ijerph111010902
PMCID: PMC4211013  PMID: 25337939
UPLC-MS/MS; 1,N6-ethenodeoxyadenosine; 3,N4-ethenodeoxycytidine; lipid peroxidation; human biomonitoring
8.  Myelin Basic Protein Induces Neuron-Specific Toxicity by Directly Damaging the Neuronal Plasma Membrane 
PLoS ONE  2014;9(9):e108646.
The central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was blocked by acidic lipids and competed by other basic proteins. Further studies revealed that MBP induced damage to neuronal membrane integrity and function by depolarizing the resting membrane potential, increasing the permeability to cations and other molecules, and decreasing the membrane fluidity. At last, artificial liposome vesicle assay showed that MBP directly disturbed acidic lipid bilayer and resulted in increased membrane permeability. These results revealed that MBP induces neurotoxicity through its direct interaction with acidic components on the extracellular surface of neuronal membrane, which may suggest a possible contribution of MBP to the pathogenesis in the CNS disorders with myelin damage.
doi:10.1371/journal.pone.0108646
PMCID: PMC4177931  PMID: 25255088
9.  New Chinese record of the genus Spinonychiurus (Collembola, Onychiuridae), with the description of a new species 
ZooKeys  2014;19-26.
A new collembolan species is described, Spinonychiurus sinensis sp. n., which has seven chaetae in the distal row of the tibiotarsi. It is placed in the genus Spinonychiurus due to two important characters: the two subsegments on Abd. III sternum and the absence of d0 on the head. This is the first report of the genus Spinonychiurus in China. The diagnosis of Spinonychiurus is broadened and the key to the world species is provided.
doi:10.3897/zookeys.439.7789
PMCID: PMC4196254  PMID: 25317055
Taxonomy; Thalassaphorurini; tibiotarsi; key
10.  Effects of Increased Iodine Intake on Thyroid Disorders 
Endocrinology and Metabolism  2014;29(3):240-247.
Iodine is a micronutrient essential for the production of thyroid hormones. Iodine deficiency is the most common cause of preventable mental impairment worldwide. Universal salt iodization (USI) has been introduced in many countries as a cost-effective and sustainable way to eliminate iodine deficiency disorders for more than 25 years. Currently, the relationship between USI and iodine excess has attracted more attention. Iodine excess can lead to hypothyroidism and autoimmune thyroiditis, especially for susceptible populations with recurring thyroid disease, the elderly, fetuses, and neonates. Nationwide USI was introduced in China in 1996. This review focused on the effects of iodine excess worldwide and particularly in China.
doi:10.3803/EnM.2014.29.3.240
PMCID: PMC4192807  PMID: 25309781
Iodine excess; Universal salt iodization; Thyroid diseases
11.  Assessment of left ventricular twist mechanics by speckle tracking echocardiography reveals association between LV twist and myocardial fibrosis in patients with hypertrophic cardiomyopathy 
We aimed to investigate whether left ventricular (LV) twist analysis can detect the extent of myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). This prospective case–control study recruited 81 consecutive patients with HCM examined between January 2012 and April 2013. Data of 76 patients were analyzed after excluding 5 patients whose echocardiographic images were of poor quality. Healthy volunteers (n = 46) served as controls. Both groups underwent comprehensive echocardiographic examination (i.e., Bas-Rotation, AP-Rotation, LVEF, LADs, IVST, LAVi, E/Em, LVMI, advanced LV-twist analysis by speckle tracking echocardiography) and magnetic resonance imaging. Between-group differences were analyzed by independent t test; logistic regression analysis was performed to identify effect factors. No significant differences were found between baseline characteristics of HCM and control groups (all p > 0.05). HCM patients had significantly higher Bas-Rotation, AP-Rotation, LV Twist, LVEF, LADs, IVST, LAVi, E/Em and LVMI than controls (all p < 0.0001) and significantly lower LVDd and E/A (both p < 0.001). Bas-Rotation, AP-Rotation, LV-Twist, LADs, IVST, LAVi, E/Em and LVMI were significantly higher in HCM patients with fibrosis than in those without fibrosis (p < 0.001), but no significant differences in other echocardiographic parameters were found between those with and without fibrosis. Age, Bas-Rotation, AP-Rotation, LV twist, LADs, IVST, LAVi, E/A, E/Em, and LVMI were significant effect factors for fibrosis. AUROC analysis showed that LV twist had high discriminatory power to detect extent of myocardial fibrosis (AUC 0.996, 95 % CI 0.989–1.004, p < 0.001). Left ventricular twist mechanics are associated with the extent of myocardial fibrosis. LV-twist assessment by STE may be clinically useful.
Electronic supplementary material
The online version of this article (doi:10.1007/s10554-014-0509-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10554-014-0509-6
PMCID: PMC4232740  PMID: 25106760
Hypertrophic cardiomyopathy; Cardiac magnetic resonance; Speckle tracking echocardiography; Myocardial fibrosis
12.  A Heavy Metal-Associated Protein (AcHMA1) from the Halophyte, Atriplex canescens (Pursh) Nutt., Confers Tolerance to Iron and Other Abiotic Stresses When Expressed in Saccharomyces cerevisiae 
Many heavy metals are essential for metabolic processes, but are toxic at elevated levels. Metal tolerance proteins provide resistance to this toxicity. In this study, we identified and characterized a heavy metal-associated protein, AcHMA1, from the halophyte, Atriplex canescens. Sequence analysis has revealed that AcHMA1 contains two heavy metal binding domains. Treatments with metals (Fe, Cu, Ni, Cd or Pb), PEG6000 and NaHCO3 highly induced AcHMA1 expression in A. canescens, whereas NaCl and low temperature decreased its expression. The role of AcHMA1 in metal stress tolerance was examined using a yeast expression system. Expression of the AcHMA1 gene significantly increased the ability of yeast cells to adapt to and recover from exposure to excess iron. AcHMA1 expression also provided salt, alkaline, osmotic and oxidant stress tolerance in yeast cells. Finally, subcellular localization of an AcHMA1/GFP fusion protein expressed in tobacco cells showed that AcHMA1 was localized in the plasma membrane. Thus, our results suggest that AcHMA1 encodes a membrane-localized metal tolerance protein that mediates the detoxification of iron in eukaryotes. Furthermore, AcHMA1 also participates in the response to abiotic stress.
doi:10.3390/ijms150814891
PMCID: PMC4159888  PMID: 25153638
HMA (heavy metal-associated) domain; Atriplex canescens; Fe tolerance; abiotic stress; yeast expression
13.  Compare mDCs and pDCs between two distinct patients groups in acute HIV-1 infection 
The role of DCs in primary HIV-1 infection remains uncertain. In this study, we enrolled two different groups of subjects with acute HIV-1 infection. One group progressed to CD4 counts below 200 cells/μl within 2 years of HIV-1 infection (CD4 Low Group), while the other group maintained CD4 counts above 500 cells/μl (CD4 High Group). We did not find statistical difference in the pDC number between the two groups during acute HIV-1 infection. However, the mDC number was significantly lower in the CD4 Low Group than in the CD4 High Group.
doi:10.1186/1742-6405-11-22
PMCID: PMC4124773  PMID: 25104967
Acute HIV-1 infection; DCs; Rapid disease progression
15.  Onychiurid species from Wanda Mountains in China, with descriptions of two new species (Collembola, Onychiuridae) 
ZooKeys  2014;99-111.
A checklist of onychiurid species from the Wanda Mountains in China is presented. Eighteen species belonging to twelve genera have been found, including two new species. Bionychiurus qinglongensis sp. n. can be easily distinguished from other known species of the genus by the absence of pseudocelli on Th. I tergum and fewer number of vesicles in postantennal organ. Onychiurus heilongjiangensis sp. n. is diagnosed by pseudocellar formulae as 32/133/33352 dorsally and 3/011/31120 ventrally, parapseudocellar formula as 0/000/111001+1m, ratio of anal spine/unguis as 0.6, unguiculus without inner basal lamella, and male ventral organ absent.
doi:10.3897/zookeys.425.7724
PMCID: PMC4137309  PMID: 25147452
Taxonomy; new species; Bionychiurus qinglongensis sp. n.; Onychiurus heilongjiangensis sp. n.
16.  Sperm, but Not Oocyte, DNA Methylome Is Inherited by Zebrafish Early Embryos 
Cell  2013;153(4):773-784.
SUMMARY
5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes, including zebrafish gametes and early embryos. The oocyte methylome is significantly hypomethylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division and is progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo’s methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos.
doi:10.1016/j.cell.2013.04.041
PMCID: PMC4081501  PMID: 23663777
17.  P300 Aberration in First-Episode Schizophrenia Patients: A Meta-Analysis 
PLoS ONE  2014;9(6):e97794.
Background
Decreased P300 amplitude is one of the most consistent findings in patients with schizophrenia. However, whether prolonged P300 latency occurs in patients with schizophrenia, especially first-episode schizophrenia (FES) patients, remains controversial.
Methods
A meta-analyses of P300 aberration in FES patients and healthy control(HC) group was conducted. The meta-regression analysis was performed using a random effects model. The pooled standardized effect size (PSES) was calculated as the division of the difference between the means of the two groups by the common standard deviation.
Results
A total of 569 FES patients and 747 HCs were included in this meta- analysis. P300 amplitude was significantly reduced (PSES = −0.83, 95% CI: −1.02–0.65, P = 0.00001) and P300 latency was delayed significantly in FES patients (PSES = −0.48, 95% CI: 0.14–0.81, P = 0.005). The meta-regression analysis showed that task difficulty was a source of heterogeneity.
Conclusions
The meta-analysis confirms that disrupted information processing is found in FES patients, which is manifested by smaller P300 amplitude and delayed P300 latency.
doi:10.1371/journal.pone.0097794
PMCID: PMC4059623  PMID: 24933577
18.  Transcriptome Analysis of Shade-Induced Inhibition on Leaf Size in Relay Intercropped Soybean 
PLoS ONE  2014;9(6):e98465.
Multi-species intercropping is a sustainable agricultural practice worldwide used to utilize resources more efficiently. In intercropping systems, short crops often grow under vegetative shade of tall crops. Soybean, one important legume, is often planted in intercropping. However, little is known about the mechanisms of shade inhibition effect on leaf size in soybean leaves at the transcriptome level. We analyzed the transcriptome of shaded soybean leaves via RNA-Seq technology. We found that transcription 1085 genes in mature leaves and 1847 genes in young leaves were significantly affected by shade. Gene ontology analyses showed that expression of genes enriched in polysaccharide metabolism was down-regulated, but genes enriched in auxin stimulus were up-regulated in mature leaves; and genes enriched in cell cycling, DNA-replication were down-regulated in young leaves. These results suggest that the inhibition of higher auxin content and shortage of sugar supply on cell division and cell expansion contribute to smaller and thinner leaf morphology, which highlights potential research targets such as auxin and sugar regulation on leaves for crop adaptation to shade in intercropping.
doi:10.1371/journal.pone.0098465
PMCID: PMC4041726  PMID: 24886785
19.  Beta-catenin (CTNNB1) induces Bmp expression in urogenital sinus epithelium and participates in prostatic bud initiation and patterning 
Developmental biology  2013;376(2):125-135.
Fetal prostate development is initiated by androgens and patterned by androgen dependent and independent signals. How these signals integrate to control epithelial cell differentiation and prostatic bud patterning is not fully understood. To test the role of beta-catenin (Ctnnb1) in this process, we used a genetic approach to conditionally delete or stabilize Ctnnb1 in urogenital sinus (UGS) epithelium from which the prostate derives. Two opposing mechanisms of action were revealed. By deleting Ctnnb1, we found it is required for separation of UGS from cloaca, emergence or maintenance of differentiated UGS basal epithelium and formation of prostatic buds. By genetically inducing a patchy subset of UGS epithelial cells to express excess CTNNB1, we found its excess abundance increases Bmp expression and leads to a global impairment of prostatic bud formation. Addition of NOGGIN partially restores prostatic budding in UGS explants with excess Ctnnb1. These results indicate a requirement for Ctnnb1 in UGS basal epithelial cell differentiation, prostatic bud initiation and bud spacing and suggest some of these actions are mediated in part through activation of BMP signaling.
doi:10.1016/j.ydbio.2013.01.034
PMCID: PMC3602957  PMID: 23396188
prostate; Bmp; Ctnnb1; urothelium; urogenital sinus; cloaca; rectourethral fistula; basal epithelium; noggin; androgen; lower urogenital tract
20.  Ulinastatin Exerts Synergistic Effects with Taxotere and Inhibits Invasion and Metastasis of Breast Cancer by Blocking Angiogenesis and the Epithelial–Mesenchymal Transition 
Abstract
Urinary trypsin inhibitor (UTI) ulinastatin as a broad-spectrum protease inhibitor has been widely used to treat acute pancreatitis and shock and to improve the surgical outcome in the clinic. In the present study, we investigated the potential antihuman breast cancer effects of UTI and its combination with taxotere (TXT). Human primary breast cancer cells and breast cancer cell line MDA-MB-231 cells were treated with UTI with or without TXT, and invasion and metastasis ability of these cells were evaluated, respectively, by a transwell assay. Reverse transcription–polymerase chain reaction was used to detect fibroblast growth factor, vascular endothelial growth factor c, epidermal growth factor, epidermal growth factor receptor, transforming growth factor-β1, and protein kinase B/AKT. We also investigated the in vivo role of UTI by using a xenograft mouse model, and immunohistochemical assay was employed to show the expression of factors involved in either angiogenesis or the epithelial–mesenchymal transition (EMT). Our results showed that UTI inhibited invasion and metastasis in both primary and MDA-MB-231 cells both in vivo and in vitro. Especially, UTI presented the significant combined effects with TXT on these cells in terms of angiogenesis blocking and EMT inhibition. These results suggest that UTI and its combination with TXT present therapeutic potential against breast cancer and deserve further preclinical and clinical studies.
doi:10.1089/cbr.2011.1122
PMCID: PMC3615695  PMID: 23477357
angiogenesis; breast cancer; epithelial–mesenchymal transition; invasion; metastasis; taxotere; ulinastatin
21.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
22.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
23.  Mortality and Treatment Outcomes of China's National Pediatric Antiretroviral Therapy Program 
Human immunodeficiency virus–positive children enrolled in China's national pediatric antiretroviral therapy program experience a mortality rate of 2.3 per 100 child-years, survival rate of 94%, and improved treatment outcomes including elevated CD4 percentage, hemoglobin, and weight-for-age and height-for-age z scores after 3 years of follow-up.
Background. The aim of this study was to describe 3-year mortality rates, associated risk factors, and long-term clinical outcomes of children enrolled in China's national free pediatric antiretroviral therapy (ART) program.
Methods. Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children ≤15 years old who initiated ART prior to December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4+ T-cell percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were created using generalized estimating equation models.
Results. Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75–2.78). The strongest factor associated with mortality was baseline WAZ score <−2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5–33.2), followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1–5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2–3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time.
Conclusions. Our finding that 94% of children engaged in this program are still alive and of improved health after 3 years of treatment demonstrates that China's national pediatric ART program is effective. This program needs to be expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized.
doi:10.1093/cid/cis941
PMCID: PMC3657487  PMID: 23175558
HIV; mortality; pediatric; antiretroviral therapy; China
24.  Grapevine microRNAs responsive to exogenous gibberellin 
BMC Genomics  2014;15:111.
Background
MicroRNAs (miRNAs), involving in various biological and metabolic processes, have been discovered and analyzed in quite a number of plants species, such as Arabidopsis, rice and other plants. However, there have been few reports about grapevine miRNAs in response to gibberelline (GA3).
Results
Solexa technology was used to sequence small RNA libraries constructed from grapevine berries treated with GA3 and the control. A total of 122 known and 90 novel grapevine miRNAs (Vvi-miRNAs) were identified. Totally, 137 ones were found to be clearly responsive to GA3, among which 58 were down-regulated, 51 were up-regulated, 21 could only be detected in the control, and seven were only detected in the treatment. Subsequently, we found that 28 of them were differentially regulated by GA3, with 12 conserved and 16 novel Vvi-miRNAs, based on the analysis of qRT-PCR essays. There existed some consistency in expression levels of GA3-responsive Vvi-miRNAs between high throughput sequencing and qRT-PCR essays. In addition, 117 target genes for 29 novel miRNAs were predicted.
Conclusions
Deep sequencing of short RNAs from grapevine berries treated with GA3 and the control identified 137 GA3-responsive miRNAs, among which 28 exhibited different expression profiles of response to GA3 in the diverse developmental stages of grapevine berries. These identified Vvi-miRNAs might be involved in the grapevine berry development and response to environmental stresses.
doi:10.1186/1471-2164-15-111
PMCID: PMC3937062  PMID: 24507455
Grapevine; Berry; microRNAs; Exogenous gibberellin; High throughput sequencing
25.  Roundabout receptors are critical for foregut separation from the body wall 
Developmental cell  2013;24(1):52-63.
Summary
In mammals, precise placement of organs is essential for survival. We show here that inactivation of Roundabout (Robo) receptors 1 and 2 in mice leads to mispositioning of the stomach in the thoracic instead of the abdominal cavity, which likely contributes to poor lung inflation and lethality at birth, reminiscent of congenital diaphragmatic hernia (CDH) cases in human. Unexpectedly in Robo mutant mice, preceding organ misplacement and diaphragm malformation, the primary defect is a delayed separation of foregut from the dorsal body wall. Foregut separation is a rarely considered morphogenetic event and our data indicate that it occurs via repulsion of Robo-expressing foregut cells away from the Slit ligand source. In human, genomic lesion containing Robo genes has been documented in CDH. Our findings suggest that separation of the foregut from the body wall is genetically controlled, and defects in this event may contribute to CDH.
doi:10.1016/j.devcel.2012.11.018
PMCID: PMC3551250  PMID: 23328398

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