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1.  Mechanisms of PDGF siRNA-mediated inhibition of bone cancer pain in the spinal cord 
Scientific Reports  2016;6:27512.
Patients with tumors that metastasize to bone frequently suffer from debilitating pain, and effective therapies for treating bone cancer are lacking. This study employed a novel strategy in which herpes simplex virus (HSV) carrying a small interfering RNA (siRNA) targeting platelet-derived growth factor (PDGF) was used to alleviate bone cancer pain. HSV carrying PDGF siRNA was established and intrathecally injected into the cavum subarachnoidale of animals suffering from bone cancer pain and animals in the negative group. Sensory function was assessed by measuring thermal and mechanical hyperalgesia. The mechanism by which PDGF regulates pain was also investigated by comparing the differential expression of pPDGFRα/β and phosphorylated ERK and AKT. Thermal and mechanical hyperalgesia developed in the rats with bone cancer pain, and these effects were accompanied by bone destruction in the tibia. Intrathecal injection of PDGF siRNA and morphine reversed thermal and mechanical hyperalgesia in rats with bone cancer pain. In addition, we observed attenuated astrocyte hypertrophy, down-regulated pPDGFRα/β levels, reduced levels of the neurochemical SP, a reduction in CGRP fibers and changes in pERK/ERK and pAKT/AKT ratios. These results demonstrate that PDGF siRNA can effectively treat pain induced by bone cancer by blocking the AKT-ERK signaling pathway.
PMCID: PMC4901320  PMID: 27282805
2.  Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis 
Scientific Reports  2016;6:24226.
Disseminated superficial porokeratosis (DSP) is a rare keratinization disorder of the epidermis. It is characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. We investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, we sequencing identified a nonsense variation c.412C > T (p.Arg138*) in the phosphomevalonate kinase gene (PMVK), which encodes a cytoplasmic enzyme catalyzing the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway. By co-segregation and haplotype analyses as well as exclusion testing of 500 normal control subjects, we demonstrated that this genetic variant was involved in the development of DSP in both families. We obtained further evidence from studies using HaCaT cells as models that this variant disturbed subcellular localization, expression and solubility of PMVK. We also observed apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues, with incomplete differentiation of keratinocytes. Our findings suggest that PMVK is a potential novel gene involved in the pathogenesis of DSP and PMVK deficiency or abnormal keratinocyte apoptosis could lead to porokeratosis.
PMCID: PMC4823745  PMID: 27052676
3.  Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis 
Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1β-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.
PMCID: PMC4002219  PMID: 23085948
IL-1β; mesenchymal stem cells; ulcerative colitis
4.  RelB/NF-κB links cell cycle transition and apoptosis to endometrioid adenocarcinoma tumorigenesis 
Cell Death & Disease  2016;7(10):e2402-.
Dysfunction of nuclear factor-κB (NF-κB) signaling has been causally associated with numerous human malignancies. Although the NF-κB family of genes has been implicated in endometrial carcinogenesis, information regarding the involvement of central regulators of NF-κB signaling in human endometrial cancer (EC) is limited. Here, we investigated the specific roles of canonical and noncanonical NF-κB signaling in endometrial tumorigenesis. We found that NF-κB RelB protein, but not RelA, displayed high expression in EC samples and cell lines, with predominant elevation in endometrioid adenocarcinoma (EEC). Moreover, tumor cell-intrinsic RelB was responsible for the abundant levels of c-Myc, cyclin D1, Bcl-2 and Bcl-xL, which are key regulators of cell cycle transition, apoptosis and proliferation in EEC. In contrast, p27 expression was enhanced by RelB depletion. Thus, increased RelB in human EC is associated with enhanced EEC cell growth, leading to endometrial cell tumorigenicity. Our results reveal that regulatory RelB in noncanonical NF-κB signaling may serve as a therapeutic target to block EC initiation.
PMCID: PMC5133976  PMID: 27711077
5.  Whole exome sequencing identifies a novel NRL mutation in a Chinese family with autosomal dominant retinitis pigmentosa 
Molecular Vision  2016;22:234-242.
To investigate the genetic basis and its relationship to the clinical manifestations in a four generation Chinese family with autosomal dominant retinitis pigmentosa.
Ophthalmologic examinations including fundus photography, fundus autofluorescence imaging, fundus fluorescein angiography, optical coherence tomography, and a best-corrected visual acuity test were performed to define the clinical features of the patients. We extracted the genomic DNA from peripheral blood samples. The proband’s genomic DNA was submitted to the whole exome sequencing.
Whole exome sequencing and the subsequent data analysis detected six candidate mutations in the proband of this pedigree. The novel c.146 C>T mutation in NRL was found to be the only mutation that co-segregated with the disease in this pedigree. This mutation resulted in a substitution of proline by a leucine at position 49 of NRL protein (p.P49L). Most importantly, the proline residue at position 49 of NRL is highly conserved from zebrafish to humans. The c.146 C>T mutation was not observed in 200 control individuals. What’s more, we performed the luciferase activity assay to prove that this mutation we detected alters the NRL protein function.
The c.146 C>T mutation in NRL gene causes autosomal dominant retinitis pigmentosa for this family. Our finding not only expands the mutation spectrum of NRL, but also demonstrates that whole-exome sequencing is a powerful strategy to detect causative genes and mutations in RP patients. This technique may provide a precise diagnosis for rare heterogeneous monogenic disorders such as RP.
PMCID: PMC4812529  PMID: 27081294
6.  Evaluation of several adjuvants in avian influenza vaccine to chickens and ducks 
Virology Journal  2011;8:321.
The effects of three different adjuvants, mineral oil, Montanide™ ISA 70M VG, and Montanide™ ISA 206 VG, were evaluated on reverse genetics H5N3 avian influenza virus cell cultured vaccine. The immune results of SPF chickens after challenging with highly pathogenic avian influenza (HPAI) virus demonstrated that mineral oil adjuvant group and 70M adjuvant group provided 100% protection efficiency, but 206 adjuvant group provided only 40%. Statistical analysis indicated that the protection effects of mineral oil adjuvant group and the 70M adjuvant showed no significant difference to each other, but with significant difference to 206 adjuvant group. All three groups could induce high titres of antibody after immunizing SPF ducks, but there was no significant difference among them. The immunization effect of 70M adjuvant group on SPF chickens were the best and showed significant difference compared with optimized 70Mi Montanide™ eight series adjuvants groups. These results suggest that 70M adjuvant could be a novel adjuvant for preparing avian influenza vaccine.
PMCID: PMC3141683  PMID: 21703008
7.  Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human 
Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.
PMCID: PMC5159431  PMID: 28018224
deoxypodophyllotoxin; physiologically based pharmacokinetic model; interspecies allometric scaling; unbound tissue-to-plasma concentration ratio; unbound fraction in plasma
8.  MicroRNA-127 targeting of mitoNEET inhibits neurite outgrowth, induces cell apoptosis and contributes to physiological dysfunction after spinal cord transection 
Scientific Reports  2016;6:35205.
Neuroregeneration and apoptosis are two important pathophysiologic changes after spinal cord injury (SCI), but their underlying mechanisms remain unclear. MicroRNAs (miRNAs) play a crucial role in the regulation of neuroregeneration and neuronal apoptosis, research areas that have been greatly expanded in recent years. Here, using miRNA arrays to profile miRNA transcriptomes, we demonstrated that miR-127-3p was significantly down-regulated after spinal cord transection (SCT). Then, bioinformatics analyses and experimental detection showed that miR-127-3p exhibited specific effects on the regulation of neurite outgrowth and the induction of neuronal apoptosis by regulating the expression of the mitochondrial membrane protein mitoNEET. Moreover, knockdown of MitoNEET leaded to neuronal loss and apoptosis in primary cultured spinal neurons. This study therefore revealed that miR-127-3p, which targets mitoNEET, plays a vital role in regulating neurite outgrowth and neuronal apoptosis after SCT. Thus, modificatioin of the mitoNEET expression, such as mitoNEET activition may provide a new strategy for the treatment of SCI in preclinical trials.
PMCID: PMC5066253  PMID: 27748416
9.  Functional Characterization of New Polyketide Synthase Genes Involved in Ochratoxin A Biosynthesis in Aspergillus Ochraceus fc-1 
Toxins  2015;7(8):2723-2738.
Ochratoxin A (OTA), a potentially carcinogenic mycotoxin which contaminates grains, is produced by several Aspergillus species. A comparative sequence analysis of the OTA-producing Aspergillus ochraceus fc-1 strain and other Aspergillus species was performed. Two new OTA-related polyketide synthase (PKS) (AoOTApks) genes were identified. The predicted amino acid sequence of AoOTApks-1 displayed high similarity to previously identified PKSs from OTA-producing A. carbonarius ITEM 5010 (67%; [PI] No. 173482) and A. niger CBS 513.88 (62%; XP_001397313). However, the predicted amino acid sequence of AoOTApks-2 displayed lower homology with A. niger CBS 513.88 (38%) and A. carbonarius ITEM 5010 (28%). A phylogenetic analysis of the β-ketosynthase and acyl-transferase domains of the AoOTApks proteins indicated that they shared a common origin with other OTA-producing species, such as A. carbonarius, A. niger, and A. westerdijkiae. A real-time reverse-transcription PCR analysis showed that the expression of AoOTApks-1 and -2 was positively correlated with the OTA concentration. The pks gene deleted mutants ∆AoOTApks-1 and ∆AoOTApks-2 produced nil and lesser OTA than the wild-type strain, respectively. Our study suggests that AoOTApks-1 could be involved in OTA biosynthesis, while AoOTApks-2 might be indirectly involved in OTA production.
PMCID: PMC4549720  PMID: 26213966
ochratoxin A; polyketide synthase; homologous recombination; biosynthetic pathway
10.  Infliximab Preferentially Induces Clinical Remission and Mucosal Healing in Short Course Crohn's Disease with Luminal Lesions through Balancing Abnormal Immune Response in Gut Mucosa 
Mediators of Inflammation  2015;2015:793764.
This study was undertaken to evaluate the efficacy of infliximab (IFX) in treatment of Crohn's disease (CD) patients. 106 CD patients were undergoing treatment with IFX from five hospitals in Shanghai, China. Clinical remission to IFX induction therapy was defined as Crohn's disease activity index (CDAI) < 150. Clinical response was assessed by a decrease in CDAI ≥ 70, and the failure as a CDAI was not significantly changed or increased. Ten weeks after therapy, 61 (57.5%) patients achieved clinical remission, 17 (16.0%) had clinical response, and the remaining 28 (26.4%) were failed. In remission group, significant changes were observed in CDAI, the Simple Endoscopic Score for Crohn's Disease (SES-CD), and serum indexes. Patients with short disease duration (22.2 ± 23.2 months) and luminal lesions showed better effects compared to those with long disease duration (71.0 ± 58.2 months) or stricturing and penetrating lesions. IFX markedly downregulated Th1/Th17-mediated immune response but promoted IL-25 production in intestinal mucosa from remission group. No serious adverse events occurred to terminate treatment. Taken together, our studies demonstrated that IFX is efficacious and safe in inducing clinical remission, promoting mucosal healing, and downregulating Th1/Th17-mediated immune response in short course CD patients with luminal lesions.
PMCID: PMC4383520  PMID: 25873771
11.  Genomic and transcriptomic analysis of NDM-1 Klebsiella pneumoniae in spaceflight reveal mechanisms underlying environmental adaptability 
Scientific Reports  2014;4:6216.
The emergence and rapid spread of New Delhi Metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae strains has caused a great concern worldwide. To better understand the mechanisms underlying environmental adaptation of those highly drug-resistant K. pneumoniae strains, we took advantage of the China's Shenzhou 10 spacecraft mission to conduct comparative genomic and transcriptomic analysis of a NDM-1 K. pneumoniae strain (ATCC BAA-2146) being cultivated under different conditions. The samples were recovered from semisolid medium placed on the ground (D strain), in simulated space condition (M strain), or in Shenzhou 10 spacecraft (T strain) for analysis. Our data revealed multiple variations underlying pathogen adaptation into different environments in terms of changes in morphology, H2O2 tolerance and biofilm formation ability, genomic stability and regulation of metabolic pathways. Additionally, we found a few non-coding RNAs to be differentially regulated. The results are helpful for better understanding the adaptive mechanisms of drug-resistant bacterial pathogens.
PMCID: PMC4147364  PMID: 25163721
12.  Characterization of human αβTCR repertoire and discovery of D-D fusion in TCRβ chains 
Protein & Cell  2014;5(8):603-615.
The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ~2% of the productive human TCRβ CDR3 sequences.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0060-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4130922  PMID: 24866699
TCR repertoire; next-generation sequencing; V/J usage; V-J pairing; CDR3; D-D fusion
13.  Characterization of human αβTCR repertoire and discovery of D-D fusion in TCRβ chains 
Protein & Cell  2014;5(8):603-615.
The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ~2% of the productive human TCRβ CDR3 sequences.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0060-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4130922  PMID: 24866699
TCR repertoire; next-generation sequencing; V/J usage; V-J pairing; CDR3; D-D fusion
14.  Analysis of Pvama1 genes from China-Myanmar border reveals little regional genetic differentiation of Plasmodium vivax populations 
Parasites & Vectors  2016;9:614.
With the premise of diminishing parasite genetic diversity following the reduction of malaria incidence, the analysis of polymorphic antigenic markers may provide important information about the impact of malaria control on local parasite populations. Here we evaluated the genetic diversity of Plasmodium vivax apical membrane antigen 1 (Pvama1) gene in a parasite population from the China-Myanmar border and compared it with global P. vivax populations.
We performed evolutionary analysis to examine the genetic diversity, natural selection, and population differentiation of 73 Pvama1 sequences acquired from the China-Myanmar border as well as 615 publically available Pvama1 sequences from seven global P. vivax populations.
A total of 308 Pvama1 haplotypes were identified among the global P. vivax isolates. The overall nucleotide diversity of Pvama1 gene among the 73 China-Myanmar border parasite isolates was 0.008 with 41 haplotypes being identified (Hd = 0.958). Domain I (DI) harbored the majority (26/33) of the polymorphic sites. The McDonald Kreitman test showed a significant positive selection across the ectodomain and the DI of Pvama1. The fixation index (F ST) estimation between the China-Myanmar border, Thailand (0.01) and Myanmar (0.10) showed only slight geographical genetic differentiation. Notably, the Sal-I haplotype was not detected in any of the analyzed global isolates, whereas the Belem strain was restricted to the Thai population. The detected mutations are mapped outside the overlapped region of the predicted B-cell epitopes and intrinsically unstructured/disordered regions.
This study revealed high levels of genetic diversity of Pvama1 in the P. vivax parasite population from the China-Myanmar border with DI displaying stronger diversifying selection than other domains. There were low levels of population subdivision among parasite populations from the Greater Mekong Subregion.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1899-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5129220  PMID: 27899135
Plasmodium vivax; Pvama1; Genetic diversity; China-Myanmar border; Malaria
15.  Dissemination and Mechanism for the MCR-1 Colistin Resistance 
PLoS Pathogens  2016;12(11):e1005957.
Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens. Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-borne mobile colistin resistance gene (mcr-1). However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood. Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr-1 gene. Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance. The soluble form of the membrane protein MCR-1 was successfully prepared and verified. Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA) potentially implies parallel evolutionary paths for the two genes. In conclusion, our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.
Author Summary
Colistin is an ultimate line of refuge against fatal infections by multidrug-resistant Gram-negative pathogens. The plasmid-mediated transfer of the mobile colistin resistance gene (mcr-1) represents a novel mechanism for antibacterial drug resistance, and also poses new threats to public health. However, the mechanistic aspects of the MCR-1 colistin resistance are not fully understood. Here we report comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota. Genetic studies determined that both the transmembrane region and a substrate-binding motif are essential for its function. Phylogenetic analyses revealed that MCR-1 is highly homologous to the PEA lipid A transferase in Paenibacillus, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA potentially implies parallel evolutionary paths for the two genes. Our results reveal mechanistic insights into the MCR-1-mediated colistin resistance.
PMCID: PMC5125707  PMID: 27893854
16.  Genetic diversity of the Plasmodium falciparum apical membrane antigen I gene in parasite population from the China-Myanmar border area 
To investigate the genetic diversity of the Plasmodium falciparum apical membrane antigen 1 (PfAMA1) gene in Southeast Asia, we determined PfAMA1 sequences from 135 field isolates collected from the China-Myanmar border area and compared them with 956 publically available PfAMA1 sequences from seven global P. falciparum populations. This analysis revealed high genetic diversity of PfAMA1 in global P. falciparum populations with a total of 229 haplotypes identified. The genetic diversity of PfAMA1 gene from the China-Myanmar border is not evenly distributed in the different domains of this gene. Sequence diversity in PfAMA1 from the China-Myanmar border is lower than that observed in Thai, African and Oceanian populations, but higher than that in the South American population. This appeared to correlate well with the levels of endemicity of different malaria-endemic regions, where hyperendemic regions favor genetic cross of the parasite isolates and generation of higher genetic diversity. Neutrality tests show significant departure from neutrality in the entire ectodomain and Domain I of PfAMA1 in the China-Myanmar border parasite population. We found evidence supporting a substantial continent-wise genetic structure among P. falciparum populations, with the highest genetic differentiation detected between the China-Myanmar border and the South American populations. Whereas no alleles were unique to a specific region, there were considerable geographical differences in major alleles and their frequencies, highlighting further necessity to include more PfAMA1 alleles in vaccine designs.
PMCID: PMC5069070  PMID: 26825252
Plasmodium falciparum; PfAMA1; genetic diversity; China-Myanmar border; malaria
17.  Identifying molecular signatures of hypoxia adaptation from sex chromosomes: A case for Tibetan Mastiff based on analyses of X chromosome 
Scientific Reports  2016;6:35004.
Genome-wide studies on high-altitude adaptation have received increased attention as a classical case of organismal evolution under extreme environment. However, the current genetic understanding of high-altitude adaptation emanated mainly from autosomal analyses. Only a few earlier genomic studies paid attention to the allosome. In this study, we performed an intensive scan of the X chromosome of public genomic data generated from Tibetan Mastiff (TM) and five other dog populations for indications of high-altitude adaptation. We identified five genes showing signatures of selection on the X chromosome. Notable among these genes was angiomotin (AMOT), which is related to the process of angiogenesis. We sampled additional 11 dog populations (175 individuals in total) at continuous altitudes in China from 300 to 4,000 meters to validate and test the association between the haplotype frequency of AMOT gene and altitude adaptation. The results suggest that AMOT gene may be a notable candidate gene for the adaptation of TM to high-altitude hypoxic conditions. Our study shows that X chromosome deserves consideration in future studies of adaptive evolution.
PMCID: PMC5054530  PMID: 27713520
18.  Mechanical assembly of complex, 3D mesostructures from releasable multilayers of advanced materials 
Science Advances  2016;2(9):e1601014.
Buckling-driven assembly of 3D mesostructures from releasable multilayers offers versatile design options for unique applications.
Capabilities for assembly of three-dimensional (3D) micro/nanostructures in advanced materials have important implications across a broad range of application areas, reaching nearly every class of microsystem technology. Approaches that rely on the controlled, compressive buckling of 2D precursors are promising because of their demonstrated compatibility with the most sophisticated planar technologies, where materials include inorganic semiconductors, polymers, metals, and various heterogeneous combinations, spanning length scales from submicrometer to centimeter dimensions. We introduce a set of fabrication techniques and design concepts that bypass certain constraints set by the underlying physics and geometrical properties of the assembly processes associated with the original versions of these methods. In particular, the use of releasable, multilayer 2D precursors provides access to complex 3D topologies, including dense architectures with nested layouts, controlled points of entanglement, and other previously unobtainable layouts. Furthermore, the simultaneous, coordinated assembly of additional structures can enhance the structural stability and drive the motion of extended features in these systems. The resulting 3D mesostructures, demonstrated in a diverse set of more than 40 different examples with feature sizes from micrometers to centimeters, offer unique possibilities in device design. A 3D spiral inductor for near-field communication represents an example where these ideas enable enhanced quality (Q) factors and broader working angles compared to those of conventional 2D counterparts.
PMCID: PMC5035128  PMID: 27679820
3D Assembly; multilayer; buckling; microfabrication; near field communication
19.  Transcriptome Analysis Reveals that Vitamin A Metabolism in the Liver Affects Feed Efficiency in Pigs 
G3: Genes|Genomes|Genetics  2016;6(11):3615-3624.
Feed efficiency (FE) is essential for pig production. In this study, 300 significantly differentially expressed (DE) transcripts, including 232 annotated genes, 28 cis-natural antisense transcripts (cis-NATs), and 40 long noncoding RNAs (lncRNAs), were identified between the liver of Yorkshire pigs with extremely high and low FE. Among these transcripts, 25 DE lncRNAs were significantly correlated with 125 DE annotated genes at a transcriptional level. These DE genes were enriched primarily in vitamin A (VA), fatty acid, and steroid hormone metabolism. VA metabolism is regulated by energy status, and active derivatives of VA metabolism can regulate fatty acid and steroid hormones metabolism. The key genes of VA metabolism (CYP1A1, ALDH1A2, and RDH16), fatty acid biosynthesis (FASN, SCD, CYP2J2, and ANKRD23), and steroid hormone metabolism (CYP1A1, HSD17B2, and UGT2B4) were significantly upregulated in the liver of high-FE pigs. Previous study with the same samples indicated that the mitochondrial function and energy expenditure were reduced in the muscle tissue of high-FE pigs. In conclusion, VA metabolism in liver tissues plays important roles in the regulation of FE in pigs by affecting energy metabolism, which may mediate fatty acid biosynthesis and steroid hormone metabolism. Furthermore, our results identified novel transcripts, such as cis-NATs and lncRNAs, which are also involved in the regulation of FE in pigs.
PMCID: PMC5100860  PMID: 27633790
Feed efficiency; liver; vitamin A metabolism; pig
20.  Protein and gene expression characteristics of heterogeneous nuclear ribonucleoprotein H1 in esophageal squamous cell carcinoma 
World Journal of Gastroenterology  2016;22(32):7322-7331.
To investigate the expression characteristics of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) mRNA and protein in cell lines and tissues of esophageal squamous cell carcinoma (ESCC).
Western blotting was used to assess the expression of HNRNPH1 protein in seven ESCC cell lines and 30 paired fresh tissue specimens. The subcellular localization of HNRNPH1 was determined by immunofluorescence in ESCC cells. The RNA sequencing data from 87 patients with ESCC were obtained from the cancer genome atlas (TCGA), and the expression and clinical characteristics analysis of different transcript variants of HNRNPH1 were evaluated in this dataset. In addition, immunohistochemistry was carried out to detect the expression of HNRNPH1 protein in 125 patients.
The expression of HNRNPH1 protein varied across different ESCC cell lines. It was exclusively restricted to the nucleus of the ESCC cells. There are two transcript variants of the HNRNPH1 gene. Variant 1 was constitutively expressed, and its expression did not change during tumorigenesis. In contrast, levels of variant 2 were low in non-tumorous tissues and were dramatically increased in ESCC (P = 0.0026). The high levels of variant 2 were associated with poorer differentiated tumors (P = 0.0287). Furthermore, in paired fresh tissue specimens, HNRNPH1 protein was overexpressed in 73.3% (22/30) of neoplastic tissues. HNRNPH1 was significantly upregulated in ESCC, with strong staining in 43.2% (54/125) of tumor tissues and 22.4% (28/125) of matched non-cancerous tissues (P = 0.0005). Positive HNRNPH1 expression was significantly associated with poor tumor differentiation degree (P = 0.0337).
The different alternative transcript variants of HNRNPH1 exhibited different expression changes during tumorigenesis. Its mRNA and protein were overexpressed in ESCC and associated with poorer differentiation of tumor cells. These findings highlight the potential of HNRNPH1 in the therapy and diagnosis of ESCC.
PMCID: PMC4997634  PMID: 27621578
Heterogeneous nuclear ribonucleoprotein H1; Esophageal squamous cell carcinoma; Alternative transcript variants; Biomarker
21.  Degradation of trichloroethene by siderite-catalyzed hydrogen peroxide and persulfate: Investigation of reaction mechanisms and degradation products 
A binary catalytic system, siderite-catalyzed hydrogen peroxide (H2O2) coupled with persulfate (S2O82−), was investigated for the remediation of trichloroethene (TCE) contamination. Batch experiments were conducted to investigate reaction mechanisms, oxidant decomposition rates, and degradation products. By using high performance liquid chromatography (HPLC) coupled with electron paramagnetic resonance (EPR), we identified four radicals (hydroxyl (HO·), sulfate (SO4−·), hydroperoxyl (HO2·), and superoxide (O2−·)) in the siderite-catalyzed H2O2-S2O82− system. In the absence of S2O82− (i.e., siderite-catalyzed H2O2), a majority of H2O2 was decomposed in the first hour of the experiment, resulting in the waste of HO·. The addition of S2O82− moderated the H2O2 decomposition rate, producing a more sustainable release of hydroxyl radicals that improved the treatment efficiency. Furthermore, the heat released by H2O2 decomposition accelerated the activation of S2O82−, and the resultant SO4−· was the primary oxidative agent during the first two hours of the reaction. Dichloroacetic acid was firstly detected by ion chromatography (IC). The results of this study indicate a new insight to the reaction mechanism for the catalytic binary H2O2-S2O82− oxidant system, and the delineation of radicals and the discovery of the chlorinated byproduct provide useful information for efficient treatment of chlorinated-solvent contamination in groundwater.
PMCID: PMC4520253  PMID: 26236152
Advanced oxidation; Chlorinated solvent; Radical identification; Byproduct
22.  Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate 
Ingenol mebutate possesses significant cytotoxicity and is clinically used to treat actinic keratosis. However, ingenol mebutate undergoes acyl migration which affects its bioactivity. Compound 3-O-angeloyl-20-O-acetyl ingenol (AAI, also known as 20-O-acetyl-ingenol-3-angelate or PEP008) is a synthetic derivative of ingenol mebutate. In this work, we report the AAI synthesis details and demonstrate AAI has higher cytotoxicity than ingenol mebutate in a chronic myeloid leukemia K562 cell line. Our data indicate that the increased activity of AAI originates from the improved intracellular stability of AAI rather than the increased binding affinity between AAI and the target protein protein kinase Cδ (PKCδ). AAI inhibits cell proliferation, induces G2/M phase arrest, disrupts the mitochondrial membrane potential, and stimulates apoptosis, as well as necrosis in K562 cells. Similar to ingenol mebutate, AAI activates PKCδ and extracellular signal regulated kinase (ERK), and inactivates protein kinase B (AKT). Furthermore, AAI also inhibits JAK/STAT3 pathway. Altogether, our studies show that ingenol derivative AAI is cytotoxic to K562 cells and modulates PKCδ/ERK, JAK/STAT3, and AKT signaling pathways. Our work suggests that AAI may be a new candidate of chemotherapeutic agent.
PMCID: PMC5000744  PMID: 27548156
3-O-angeloyl-20-O-acetyl ingenol; PEP008; 20-O-acetyl-ingenol-3-angelate; ingenol mebutat; apoptosis; chronic myeloid leukemia
23.  Cross-Species Antiviral Activity of Goose Interferons against Duck Plague Virus Is Related to Its Positive Self-Feedback Regulation and Subsequent Interferon Stimulated Genes Induction 
Viruses  2016;8(7):195.
Interferons are a group of antiviral cytokines acting as the first line of defense in the antiviral immunity. Here, we describe the antiviral activity of goose type I interferon (IFNα) and type II interferon (IFNγ) against duck plague virus (DPV). Recombinant goose IFNα and IFNγ proteins of approximately 20 kDa and 18 kDa, respectively, were expressed. Following DPV-enhanced green fluorescent protein (EGFP) infection of duck embryo fibroblast cells (DEFs) with IFNα and IFNγ pre-treatment, the number of viral gene copies decreased more than 100-fold, with viral titers dropping approximately 100-fold. Compared to the control, DPV-EGFP cell positivity was decreased by goose IFNα and IFNγ at 36 hpi (3.89%; 0.79%) and 48 hpi (17.05%; 5.58%). In accordance with interferon-stimulated genes being the “workhorse” of IFN activity, the expression of duck myxovirus resistance (Mx) and oligoadenylate synthetases-like (OASL) was significantly upregulated (p < 0.001) by IFN treatment for 24 h. Interestingly, duck cells and goose cells showed a similar trend of increased ISG expression after goose IFNα and IFNγ pretreatment. Another interesting observation is that the positive feedback regulation of type I IFN and type II IFN by goose IFNα and IFNγ was confirmed in waterfowl for the first time. These results suggest that the antiviral activities of goose IFNα and IFNγ can likely be attributed to the potency with which downstream genes are induced by interferon. These findings will contribute to our understanding of the functional significance of the interferon antiviral system in aquatic birds and to the development of interferon-based prophylactic and therapeutic approaches against viral disease.
PMCID: PMC4974530  PMID: 27438848
goose interferon; duck plague virus; feedback regulation; antiviral activity; interferon stimulated gene
24.  Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension 
JCI insight  2016;1(8):e86987.
Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2–derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.
PMCID: PMC4918638  PMID: 27347562
25.  Endoscopic agger nasi type Draf IIb treatment for frontal sinus lesions 
Treatment of frontal sinus using surgery is complicated owing to the complex anatomical structure of the sinus region. The aim of the present study was to investigate the efficacy and safety of Draf IIb endoscopic frontal sinus surgery treatment for frontal sinus lesions using the agger nasi approach on 19 patients (28 left or and right nasal cavities). A 10–12 mm excision of the upper frontal maxilla was performed for endoscopic resection between the middle turbinate and lateral nasal wall. No serious complications in frontal sinus surgery treatment for the removal of the frontal sinus were observed. Patients were followed up after surgery for 6–36 months. Chronic sinusitis and nasal polyps were identified in 10 cases (19 left or and right nasal cavities; disease control, 15 left or and right nasal cavities; and disease partial control, 4 left or and right nasal cavities). Frontal sinus inverted papilloma was observed in 9 cases (9 left or and right nasal cavities). Frontal sinus inverted papilloma were successfully treated in 8 cases, and 1 case of recurrence was observed. In conclusion, the nasal endoscopic Draf IIb agger nasi approach is a minimally invasive treatment for frontal sinus lesions. This surgical procedure is safe and less complicated and may be applied in the clinic.
PMCID: PMC4998003  PMID: 27588056
agger nasi; Draf IIb; frontal sinus

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