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author:("Liu, jinfeng")
1.  Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors 
Although the shortcomings of small molecular antitumor drugs were efficiently improved by being entrapped into nanosized vehicles, premature drug release and insufficient tumor targeting demand innovative approaches that boost the stability and tumor responsiveness of drug-loaded nanocarriers. Here, we show the use of the core cross-linking method to generate a micelle with enhanced drug encapsulation ability and sensitivity of drug release in tumor. This kind of micelle could increase curcumin (Cur) delivery to HeLa cells in vitro and improve tumor accumulation in vivo. We designed and synthesized the core cross-linked micelle (CCM) with polyethylene glycol and folic acid-polyethylene glycol as the hydrophilic units, pyridyldisulfide as the cross-linkable and hydrophobic unit, and disulfide bond as the cross-linker. CCM showed spherical shape with a diameter of 91.2 nm by the characterization of dynamic light scattering and transmission electron microscope. Attributed to the core cross-linking, drug-loaded CCM displayed higher Nile Red or Cur-encapsulated stability and better sensitivity to glutathione than noncross-linked micelle (NCM). Cellular uptake and in vitro antitumor studies proved the enhanced endocytosis and better cytotoxicity of CCM-Cur against HeLa cells, which had a high level of glutathione. Meanwhile, the folate receptor-mediated drug delivery (FA-CCM-Cur) further enhanced the endocytosis and cytotoxicity. Ex vivo imaging studies showed that CCM-Cur and FA-CCM-Cur possessed higher tumor accumulation until 24 hours after injection. Concretely, FA-CCM-Cur exhibited the highest tumor accumulation with 1.7-fold of noncross-linked micelle Cur and 2.8-fold of free Cur. By combining cross-linking of the core with active tumor targeting of FA, we demonstrated a new and effective way to design nanocarriers for enhanced drug encapsulation, smart tumor responsiveness, and elevated tumor accumulation.
doi:10.2147/IJN.S101649
PMCID: PMC4807950  PMID: 27051287
core cross-linking; folic acid targeting; self-assembling; curcumin; drug delivery; micelles
2.  Environmental temperature differentially modulates C. elegans longevity through a thermosensitive TRP channel 
Cell reports  2015;11(9):1414-1424.
Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan while higher temperatures shorten it. Though this “temperature law” is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans. We found that while exposure to low temperatures at the adult stage prolongs lifespan, low temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan, but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover unexpected complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life.
doi:10.1016/j.celrep.2015.04.066
PMCID: PMC4758836  PMID: 26027928
3.  Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer 
Scientific Reports  2016;6:21225.
Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.
doi:10.1038/srep21225
PMCID: PMC4753416  PMID: 26876480
4.  Transcriptome Characterization of Gnetum parvifolium Reveals Candidate Genes Involved in Important Secondary Metabolic Pathways of Flavonoids and Stilbenoids 
Gnetum is a small, unique group of Gnetophyta with a controversial phylogenetic position. Gnetum parvifolium is an important Chinese traditional medicinal plant, which is rich in bioactive compounds such as flavonoids and stilbenoids. These compounds provide significant medicinal effects, mostly as antioxidant, anticancer, and antibacterial agents. However, the mechanisms involved in the biosynthesis and regulation of these compounds in G. parvifolium are still unknown. In this study, we found that flavonoids and stilbene compounds accumulated at different levels in various tissues of G. parvifolium. We further obtained and analyzed massive sequence information from pooled samples of G. parvifolium by transcriptome sequencing, which generated 94,816 unigenes with an average length of 724 bp. Functional annotation of all these unigenes revealed that many of them were associated with several important secondary metabolism pathways including flavonoids and stilbenoids. In particular, several candidate unigenes (PAL-, C4H-, 4CL-, and STS-like genes) involved in stilbenoids biosynthesis were highly expressed in leaves and mature fruits. Furthermore, high temperature and UV-C strongly induced the expression of these genes and enhanced stilbene production (i.e., resveratrol and piceatannol) in leaves of young seedlings. Our present transcriptomic and biochemical data on secondary metabolites in G. parvifolium should encourage further investigation on evolution, ecology, functional genomics, and breeding of this plant with strong pharmaceutical potential.
doi:10.3389/fpls.2016.00174
PMCID: PMC4778121  PMID: 26973657
Gnetophyta; Gnetum; evolution; natural bioactive compounds; gene expression
5.  Population Variation Reveals Independent Selection toward Small Body Size in Chinese Debao Pony 
Genome Biology and Evolution  2015;8(1):42-50.
Body size, one of the most important quantitative traits under evolutionary scrutiny, varies considerably among species and among populations within species. Revealing the genetic basis underlying this variation is very important, particularly in humans where there is a close relationship with diseases and in domestic animals as the selective patterns are associated with improvements in production traits. The Debao pony is a horse breed with small body size that is unique to China; however, it is unknown whether the size-related candidate genes identified in Western breeds also account for the small body size of the Debao pony. Here, we compared individual horses from the Debao population with other two Chinese horse populations using single nucleotide polymorphisms (SNPs) identified with the Equine SNP 65 Bead Chip. The previously reported size-related candidate gene HMGA2 showed a significant signature for selection, consistent with its role observed in human populations. More interestingly, we found a candidate gene TBX3, which had not been observed in previous studies on horse body size that displayed the highest differentiation and most significant association, and thus likely is the dominating factor for the small stature of the Debao pony. Further comparison between the Debao pony and other breeds of horses from around the world demonstrated that TBX3 was selected independently in the Debao pony, suggesting that there were multiple origins of small stature in the horse.
doi:10.1093/gbe/evv245
PMCID: PMC4758242  PMID: 26637467
selective signature; di; XP-EHH; genetic differentiation; association; TBX3
6.  Metabotropic GABA signalling modulates longevity in C. elegans 
Nature Communications  2015;6:8828.
The nervous system plays an important but poorly understood role in modulating longevity. GABA, a prominent inhibitory neurotransmitter, is best known to regulate nervous system function and behaviour in diverse organisms. Whether GABA signalling affects aging, however, has not been explored. Here we examined mutants lacking each of the major neurotransmitters in C. elegans, and find that deficiency in GABA signalling extends lifespan. This pro-longevity effect is mediated by the metabotropic GABAB receptor GBB-1, but not ionotropic GABAA receptors. GBB-1 regulates lifespan through G protein-PLCβ signalling, which transmits longevity signals to the transcription factor DAF-16/FOXO, a key regulator of lifespan. Mammalian GABAB receptors can functionally substitute for GBB-1 in lifespan control in C. elegans. Our results uncover a new role of GABA signalling in lifespan regulation in C. elegans, raising the possibility that a similar process may occur in other organisms.
The C. elegans nervous system influences organismal lifespan but mechanistic details are poorly understood. Here, Chun et al. show that the neurotransmitter GABA regulates worm lifespan by acting on GABAB receptors in motor neurons, which activate the transcription factor DAF-16 in the intestine.
doi:10.1038/ncomms9828
PMCID: PMC4667614  PMID: 26537867
7.  An unconditioned stimulus retrieval-extinction procedure to prevent the return of fear memory 
Biological psychiatry  2014;76(11):895-901.
Background
Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. In the present study, we introduced a technique to target all diverse cues associated with an aversive event that causes fear.
Methods
In the human experiments, the subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In the animal experiments, rats underwent contextual fear conditioning under a similar protocol as the used in the human experiments. We also explored the molecular alterations after US reactivation in rats.
Results
We found that presentation of a lower-intensity US following extinction disrupted the associations between the different CSs and reactivated US in both humans and rats. This disruptive effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of AMPA glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats.
Conclusions
These findings demonstrate that a modified US retrieval-extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.
doi:10.1016/j.biopsych.2014.03.027
PMCID: PMC4480632  PMID: 24813334
fear memory; unconditioned stimulus; retrieval; extinction; reconsolidation; hippocampus
8.  Evaluation of the effects of different treatments for the elbow joint using joint proprioception and surface electromyography 
Journal of Physical Therapy Science  2015;27(12):3907-3909.
[Purpose] The purpose of this study was to examine the immediate effects of strength training and neuromuscular joint facilitation (NJF) distal resistance training on muscle strength and proprioception. [Subjects] The subjects were 15 young healthy people (29.3±4.1 y, 166.8±7.1 cm, 62.4 ± 11.6 ky). [Methods] Two isometric contraction techniques were applied on the elbow joint: elbow joint flexion muscle strength training (MST) and the elbow joint flexion pattern of NJF. Muscle strength (measured by surface electromyography [sEMG]) and joint position errors of the left upper limb were measured before and after one intervention session of MST and NJF. [Results] The decrease in error in elbow flexion angle repetition represented the improvement resulting from NJF. sEMG of the biceps brachii showed significant increases in the maximum discharge and average discharge after the intervention. [Conclusion] This result suggests that elbow joint proprioception and muscle strength can be improved by NJF together with proximal resistance training.
doi:10.1589/jpts.27.3907
PMCID: PMC4713817  PMID: 26834378
Neuromuscular joint facilitation; Joint position error; Elbow joint proprioception
9.  A Practical Surgical Technique to Expose the Mental Nerve in Narrowing Genioplasty 
Summary:
In this article, the authors present a practical surgical technique using the anatomical character of the inferior alveolar nerve to fully expose the mental nerve (MN) in narrowing genioplasty. During the procedure, a rectangular mandibular outer cortex adjacent to the mental foramen is removed before the osteotomy. The objective is to avoid the injury of the MN from the reciprocating saw or bur and offer abundant space for the surgical operation. The technique has a minimal learning curve and will be useful to plastic surgeons to minimize unintentional cutting or pulling injury to the MN in narrowing genioplasty.
doi:10.1097/GOX.0000000000000536
PMCID: PMC4727706  PMID: 26893979
10.  Genome-wide association study in Chinese Holstein cows reveal two candidate genes for somatic cell score as an indicator for mastitis susceptibility 
BMC Genetics  2015;16:111.
Backgrounds
Bovine mastitis is a typical inflammatory disease causing seriously economic loss. Genome-wide association study (GWAS) can be a powerful method to promote marker assistant selection of this kind of complex disease. The present study aimed to analyze and identify single nucleotide polymorphisms (SNPs) and candidate genes that associated with mastitis susceptibility traits in Chinese Holstein.
Results
Forty eight SNPs were identified significantly associated with mastitis resistance traits in Chinese Holstein cows, which are mainly located on the BTA 14. A total of 41 significant SNPs were linked to 31 annotated bovine genes. Gene Ontology and pathway enrichment revealed 5 genes involved in 32 pathways, in which, TRAPPC9 and ARHGAP39 genes participate cell differentiation and developmental pathway together. The six common genome-wide significant SNPs are found located within TRAPPC9 and flanking ARHGAP39 genes.
Conclusions
Our data identified the six SNPs significantly associated with SCS EBVs, which suggest that their linked two genes (TRAPPC9 and ARHGAP39) are novel candidate genes of mastitis susceptibility in Holsteins.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0263-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-015-0263-3
PMCID: PMC4570044  PMID: 26370837
Genome-wide association study; EBVs of somatic cell scores; Chinese Holstein cows; Mixed model based single locus regression analysis; Mastitis susceptibility
11.  Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction 
Myocardial infarction (MI) is a major cause of death and disability worldwide. In the last decade, mesenchymal stem cells (MSCs) based cell therapy has emerged as a promising therapeutic strategy. Although great advance have been made using MSCs to treat MI, the low viability of transplanted MSCs severely limits the efficiency of MSCs therapy. Here, we show evidence that ex vivo pre-treatment with melatonin, an endogenous hormone with newly found anti-oxidative activity, could improve survival and function of adipose tissue derived MSCs (ADSCs) in vitro as well as in vivo. ADSCs with 5 μM melatonin pre-treatment for 24 hrs showed increased expression of the antioxidant enzyme catalase and Cu/Zn superoxide dismutase (SOD-1), as well as pro-angiogenic and mitogenic factors like insulin-like growth factor 1, basic fibroblast growth factor, hepatocyte growth factor (HGF), epidermal growth factor. Furthermore, melatonin pre-treatment protected MSCs from reactive oxygen species (ROS) induced apoptosis both directly by promoting anti-apoptosis kinases like p-Akt as well as blocking caspase cascade, and indirectly by restoring the ROS impaired cell adhesion. Using a rat model of MI, we found that melatonin pre-treatment enhanced the viability of engrafted ADSCs, and promoted their therapeutic potency. Hopefully, our results may shed light on the design of more effective therapeutic strategies treating MI by MSCs in clinic.
doi:10.1111/jcmm.12610
PMCID: PMC4568927  PMID: 26081690
adipose tissue derived MSCs; melatonin; myocardial infarction; reactive oxygen species; rat model; apoptosis; viability; therapeutic strategy
12.  Lattice Strain Mapping of Platinum Nanoparticles on Carbon and SnO2 Supports 
Scientific Reports  2015;5:13126.
It is extremely important to understand the properties of supported metal nanoparticles at the atomic scale. In particular, visualizing the interaction between nanoparticle and support, as well as the strain distribution within the particle is highly desirable. Lattice strain can affect catalytic activity, and therefore strain engineering via e.g. synthesis of core-shell nanoparticles or compositional segregation has been intensively studied. However, substrate-induced lattice strain has yet to be visualized directly. In this study, platinum nanoparticles decorated on graphitized carbon or tin oxide supports are investigated using spherical aberration-corrected scanning transmission electron microscopy (Cs-corrected STEM) coupled with geometric phase analysis (GPA). Local changes in lattice parameter are observed within the Pt nanoparticles and the strain distribution is mapped. This reveals that Pt nanoparticles on SnO2 are more highly strained than on carbon, especially in the region of atomic steps in the SnO2 lattice. These substrate-induced strain effects are also reproduced in density functional theory simulations, and related to catalytic oxygen reduction reaction activity. This study suggests that tailoring the catalytic activity of electrocatalyst nanoparticles via the strong metal-support interaction (SMSI) is possible. This technique also provides an experimental platform for improving our understanding of nanoparticles at the atomic scale.
doi:10.1038/srep13126
PMCID: PMC4539540  PMID: 26283473
13.  Investigation of a Measles Outbreak in China to Identify Gaps in Vaccination Coverage, Routes of Transmission, and Interventions 
PLoS ONE  2015;10(7):e0133983.
Background
A measles outbreak occurred in a western county of China in 2013, the year after China’s historic nadir of measles. We conducted a field investigation to identify gaps in measles vaccination coverage and immunization program weaknesses, and to provide recommendations for measles outbreak response and immunization program improvement.
Methods
We analyzed surveillance data from 2008 to 2013 to describe the measles epidemiology of the county. Measles-containing vaccine coverage was estimated using two methods: previously-reported administrative coverage and an estimation of coverage by clinic-kept vaccination records (n = 542). We conducted a rapid field coverage assessment in a migrant population village to evaluate coverage after emergency vaccination. We conducted a review of hospital records of measles cases to address the role hospital transmission played during the early stage of this outbreak.
Results
There were 153 cases in the outbreak, primarily among children too young to vaccinate, unvaccinated children less than 3 years old, and adults. Measles-containing vaccine coverage by the field assessment showed that 20% of children aged 8–17 months had zero doses, and 9% of ≥2 years old children had fewer than two doses. The vaccination statuses of all adult cases were either zero doses or unknown. At least 61% of cases had been hospitalized. The proportion of cases who had been hospital-exposed 7 to 21 days prior to rash onset decreased from 52% to 22% after hospitals strengthen their isolation measures.
Conclusions
This outbreak was a result of measles vaccination coverage gaps among young children and adults, and insufficient hospital isolation of cases. The lower coverage seen in the field estimation compared with reported coverage showed that reported coverage could have been overestimated. Hospitals were sites of transmission in the early stage of the outbreak. A strict hospital isolation policy could decrease spread of measles. Emergency vaccination was associated with stopping measles transmission in low coverage areas.
doi:10.1371/journal.pone.0133983
PMCID: PMC4514761  PMID: 26208216
14.  Unraveling a molecular determinant for clathrin-independent internalization of the M2 muscarinic acetylcholine receptor 
Scientific Reports  2015;5:11408.
Endocytosis and postendocytic sorting of G-protein-coupled receptors (GPCRs) is important for the regulation of both their cell surface density and signaling profile. Unlike the mechanisms of clathrin-dependent endocytosis (CDE), the mechanisms underlying the control of GPCR signaling by clathrin-independent endocytosis (CIE) remain largely unknown. Among the muscarinic acetylcholine receptors (mAChRs), the M4 mAChR undergoes CDE and recycling, whereas the M2 mAChR is internalized through CIE and targeted to lysosomes. Here we investigated the endocytosis and postendocytic trafficking of M2 mAChR based on a comparative analysis of the third cytoplasmic domain in M2 and M4 mAChRs. For the first time, we identified that the sequence 374KKKPPPS380 servers as a sorting signal for the clathrin-independent internalization of M2 mAChR. Switching 374KKKPPPS380 to the i3 loop of the M4 mAChR shifted the receptor into lysosomes through the CIE pathway; and therefore away from CDE and recycling. We also found another previously unidentified sequence that guides CDE of the M2 mAChR, 361VARKIVKMTKQPA373, which is normally masked in the presence of the downstream sequence 374KKKPPPS380. Taken together, our data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent.
doi:10.1038/srep11408
PMCID: PMC4476042  PMID: 26094760
15.  GABAB receptor upregulates fragile X mental retardation protein expression in neurons 
Scientific Reports  2015;5:10468.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome (FXS), which leads to intellectual disability and social impairment. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the mammalian central nervous system, and its metabotropic GABAB receptor has been implicated in various mental disorders. The GABAB receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, but the signaling events linking the GABAB receptor and FMRP are unknown. In this study, we found that GABAB receptor activation upregulated cAMP response element binding protein-dependent Fmrp expression in cultured mouse cerebellar granule neurons via two distinct mechanisms: the transactivation of insulin-like growth factor-1 receptor and activation of protein kinase C. In addition, a positive allosteric modulator of the GABAB receptor, CGP7930, stimulated Fmrp expression in neurons. These results suggest a role for GABAB receptor in Fmrp regulation and a potential interest of GABAB receptor signaling in FXS improvement.
doi:10.1038/srep10468
PMCID: PMC4447080  PMID: 26020477
16.  RNAi interrogation of dietary modulation of development, metabolism, behavior, and aging in C. elegans 
Cell reports  2015;11(7):1123-1133.
Diet affects nearly every aspect of animal life, such as development, metabolism, behavior and aging, both directly by supplying nutrients and indirectly through gut microbiota. C. elegans feeds on bacteria, and like other animals, different bacterial diets induce distinct dietary responses in the worm. However, the lack of certain critical tools hampers the use of worms as a model for dietary signaling. Here, we genetically-engineered the bacterial strain OP50, the standard laboratory diet for C. elegans, making it compatible for dsRNA production and delivery. Using this RNAi-compatible OP50 strain and the other bacterial strain HT115, we feed worms different diets while delivering RNAi to interrogate the genetic basis underlying diet-dependent differential modulation of development, metabolism, behavior, and aging. We show by RNAi that neuroendocrine and mTOR pathways are involved in mediating differential dietary responses. This genetic tool greatly facilitates the use of C. elegans as a model for dietary signaling.
doi:10.1016/j.celrep.2015.04.024
PMCID: PMC4439342  PMID: 25959815
17.  Pretreatment of Adipose Derived Stem Cells with Curcumin Facilitates Myocardial Recovery via Antiapoptosis and Angiogenesis 
Stem Cells International  2015;2015:638153.
The poor survival rate of transplanted stem cells in ischemic myocardium has limited their therapeutic efficacy. Curcumin has potent antioxidant property. This study investigates whether prior curcumin treatment protects stem cells from oxidative stress injury and improves myocardial recovery following cells transplantation. Autologous Sprague-Dawley rat adipose derived mesenchymal stem cells (ADSCs) were pretreated with or without curcumin. The hydrogen peroxide/serum deprivation (H2O2/SD) medium was used to mimic the ischemic condition in vitro. Cytoprotective effects of curcumin on ADSCs were evaluated. Curcumin pretreatment significantly increased cell viability and VEGF secretion, and decreased cell injury and apoptosis via regulation of PTEN/Akt/p53 and HO-1 signal proteins expression. The therapeutic potential of ADSCs implantation was investigated in myocardial ischemia-reperfusion injury (IRI) model. Transplantation of curcumin pretreated ADSCs not only resulted in better heart function, higher cells retention, and smaller infarct size, but also decreased myocardial apoptosis, promoted neovascularization, and increased VEGF level in ischemic myocardium. Together, priming of ADSCs with curcumin improved tolerance to oxidative stress injury and resulted in enhancement of their therapeutic potential of ADSCs for myocardial repair. Curcumin pretreatment is a promising adjuvant strategy for stem cells transplantation in myocardial restoration.
doi:10.1155/2015/638153
PMCID: PMC4436501  PMID: 26074974
18.  Transcriptome Analysis and Gene Expression Profiling of Abortive and Developing Ovules during Fruit Development in Hazelnut 
PLoS ONE  2015;10(4):e0122072.
Background
A high ratio of blank fruit in hazelnut (Corylus heterophylla Fisch) is a very common phenomenon that causes serious yield losses in northeast China. The development of blank fruit in the Corylus genus is known to be associated with embryo abortion. However, little is known about the molecular mechanisms responsible for embryo abortion during the nut development stage. Genomic information for C. heterophylla Fisch is not available; therefore, data related to transcriptome and gene expression profiling of developing and abortive ovules are needed.
Methodology/Principal Findings
In this study, de novo transcriptome sequencing and RNA-seq analysis were conducted using short-read sequencing technology (Illumina HiSeq 2000). The results of the transcriptome assembly analysis revealed genetic information that was associated with the fruit development stage. Two digital gene expression libraries were constructed, one for a full (normally developing) ovule and one for an empty (abortive) ovule. Transcriptome sequencing and assembly results revealed 55,353 unigenes, including 18,751 clusters and 36,602 singletons. These results were annotated using the public databases NR, NT, Swiss-Prot, KEGG, COG, and GO. Using digital gene expression profiling, gene expression differences in developing and abortive ovules were identified. A total of 1,637 and 715 unigenes were significantly upregulated and downregulated, respectively, in abortive ovules, compared with developing ovules. Quantitative real-time polymerase chain reaction analysis was used in order to verify the differential expression of some genes.
Conclusions/Significance
The transcriptome and digital gene expression profiling data of normally developing and abortive ovules in hazelnut provide exhaustive information that will improve our understanding of the molecular mechanisms of abortive ovule formation in hazelnut.
doi:10.1371/journal.pone.0122072
PMCID: PMC4383543  PMID: 25836368
19.  A Genome Scan for Selection Signatures in Pigs 
PLoS ONE  2015;10(3):e0116850.
Identifying signatures of selection can provide a straightforward insight into the mechanism of artificial selection and further uncover the causal genes related to the phenotypic variation. Based on Illumina Porcine60KSNP chip data, four complementary methods, Long-Range Haplotype (LRH), Tajima’s D, Cross Population Extend Haplotype Homozygosity Test (XPEHH) and FST, were implemented in this study to detect the selection signatures in the whole genome of one typical Chinese indigenous breed, Rongchang, one Chinese cultivated breed, Songliao, and two western breeds, Landrace and Yorkshire. False Discovery Rate (FDR) was implemented to control the false positive rates. In our study, a total of 159, 127, 179 and 159 candidate selection regions with average length of 0.80 Mb, 0.73 Mb, 0.78 Mb and 0.73 Mb were identified in Landrace, Rongchang, Songliao and Yorkshire, respectively, that span approximately 128.00 Mb, 92.38 Mb, 130.30 Mb and 115.40 Mb and account for approximately 3.74–5.33% of genome across all autosomes. The selection regions of 11.52 Mb shared by Landrace and Yorkshire were the longest when chosen pairs from the pool of the four breeds were examined. The overlaps between Yorkshire and Songliao, approximately 9.20 Mb, were greater than those of Yorkshire and Rongchang. Meanwhile, the overlaps between Landrace and Songliao were greater than those of Landrace and Rongchang but less than those of Songliao and Ronchang. Bioinformatics analysis showed that the genes/QTLs relevant to fertility, coat color, and ear morphology were found in candidate selection regions. Some genes, such as LEMD3, MC1R, KIT, TRHR etc. that were reported under selection, were confirmed in our study, and this analysis also demonstrated the diversity of breeds.
doi:10.1371/journal.pone.0116850
PMCID: PMC4355907  PMID: 25756180
20.  Treatment of acutely ruptured wide-necked intracranial aneurysms using self-expanding stent 
Objectives: To evaluate the effectiveness and safety of self-expanding stent in treatment of acutely ruptured wide-necked intracranial aneurysms in the acute stage. Method: Treatment of 38 patients with self-expanding stent was retrospectively analyzed. Results: From January 2009 to May 2014, a total of 38 patients with 44 acutely ruptured wide-necked intracranial aneurysms were embolized with self-expanding stents at our center. Immediate post-operative imaging demonstrated that the aneurysms were densely packed in 17 patients, subtotally embolized in 2 patients, and subtotally embolized with residual aneurysm necks in 19 patients. At discharge, the patients were assessed for prognosis and the results revealed nerve dysfunction in 3 patients (7.9%), coma in 6 patients (15.8%), hospital death in 1 case (2.6%). Twenty-eight (73.7%) patients were asymptomatic at discharge. Ten of the 38 patients were followed up by angiography for a period of 3.7 months on average, which showed complete occlusion in 9 patients (90%), remnant aneurysm necks in 1 patient (10%), and no recanalization was observed in all the followed-up patients. Stent related complications also were recorded. Conclusion: Stent-assisted coiling is effective in treating acutely ruptured wide-necked intracranial aneurysms. Angiographic investigation and clinical follow-up is needed for evaluation of long-term clinical outcomes.
PMCID: PMC4358577  PMID: 25785122
Ruptured intracranial aneurysms; wide-necked aneurysms; self-expandable stent; coiling
21.  The enhancement of radiosensitivity in human esophageal squamous cell carcinoma cells by zoledronic acid and its potential mechanism 
Cytotechnology  2013;66(1):17-25.
Esophageal squamous cell carcinoma (ESCC) has a low 5-year patient survival rate. Radiotherapy, as a preoperative or postoperative treatment of surgery, has a crucial role in improving local control and survival of ESCC. Various chemotherapeutic and biologic agents have been used as radio-sensitizers in combination with radiotherapy. Here, we demonstrate that zoledronic acid (ZOL) has a radio-sensitizing effect on ESCC cells. Exposure of ESCC cancer cells to ZOL plus radiation resulted in increased cell death through arresting the cell cycle between S and G2/M phases. ZOL appeared to inhibit proliferation, tube formation and invasion of endothelial cells. These anti-angiogenetic effects were more marked concurrently with irradiation. In addition, synergistic suppressive effects on VEGF expression were observed after combined treatment. Our data suggest that the combination of ZOL and radiation is a promising therapeutic strategy to enhance radiation therapy for ESCC patients.
doi:10.1007/s10616-012-9532-4
PMCID: PMC3886539  PMID: 23334334
ESCC; Bisphosphonate; Radiosensitivity; Combined effect
22.  Targeted resequencing of GWAS loci reveals novel genetic variants for milk production traits 
BMC Genomics  2014;15(1):1105.
Background
Genome wide association study (GWAS) has been proven to be a powerful tool for detecting genomic variants associated with complex traits. However, the specific genes and causal variants underlying these traits remain unclear.
Results
Here, we used target-enrichment strategy coupled with next generation sequencing technique to study target regions which were found to be associated with milk production traits in dairy cattle in our previous GWAS. Among the large amount of novel variants detected by targeted resequencing, we selected 200 SNPs for further association study in a population consisting of 2634 cows. Sixty six SNPs distributed in 53 genes were identified to be associated significantly with on milk production traits. Of the 53 genes, 26 were consistent with our previous GWAS results. We further chose 20 significant genes to analyze their mRNA expression in different tissues of lactating cows, of which 15 were specificly highly expressed in mammary gland.
Conclusions
Our study illustrates the potential for identifying causal mutations for milk production traits using target-enrichment resequencing and extends the results of GWAS by discovering new and potentially functional mutations.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1105) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1105
PMCID: PMC4377845  PMID: 25510969
Genetic variants; Milk production traits; Targeted resequencing
23.  Genome-wide patterns of copy number variation in the diversified chicken genomes using next-generation sequencing 
BMC Genomics  2014;15(1):962.
Background
Copy number variation (CNV) is important and widespread in the genome, and is a major cause of disease and phenotypic diversity. Herein, we performed a genome-wide CNV analysis in 12 diversified chicken genomes based on whole genome sequencing.
Results
A total of 8,840 CNV regions (CNVRs) covering 98.2 Mb and representing 9.4% of the chicken genome were identified, ranging in size from 1.1 to 268.8 kb with an average of 11.1 kb. Sequencing-based predictions were confirmed at a high validation rate by two independent approaches, including array comparative genomic hybridization (aCGH) and quantitative PCR (qPCR). The Pearson’s correlation coefficients between sequencing and aCGH results ranged from 0.435 to 0.755, and qPCR experiments revealed a positive validation rate of 91.71% and a false negative rate of 22.43%. In total, 2,214 (25.0%) predicted CNVRs span 2,216 (36.4%) RefSeq genes associated with specific biological functions. Besides two previously reported copy number variable genes EDN3 and PRLR, we also found some promising genes with potential in phenotypic variation. Two genes, FZD6 and LIMS1, related to disease susceptibility/resistance are covered by CNVRs. The highly duplicated SOCS2 may lead to higher bone mineral density. Entire or partial duplication of some genes like POPDC3 may have great economic importance in poultry breeding.
Conclusions
Our results based on extensive genetic diversity provide a more refined chicken CNV map and genome-wide gene copy number estimates, and warrant future CNV association studies for important traits in chickens.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-962) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-962
PMCID: PMC4239369  PMID: 25378104
Copy number variation; Whole genome sequencing; aCGH; Genetic diversity; Chicken
24.  Functional aging in the nervous system contributes to age-dependent motor activity decline in C. elegans 
Cell metabolism  2013;18(3):10.1016/j.cmet.2013.08.007.
Aging is characterized by a progressive decline in multiple physiological functions (i.e. functional aging). As animals age, they exhibit a gradual loss in motor activity, but the underlying mechanisms remain unclear. Here we approach this question in C. elegans by functionally characterizing its aging nervous system and muscles. We find that motor neurons exhibit a progressive functional decline, beginning in early life. Surprisingly, body-wall muscles, which are previously thought to undergo functional aging, do not manifest such a decline until mid-late life. Notably, motor neurons first develop a deficit in synaptic vesicle fusion followed by that in quantal size and vesicle docking/priming, revealing specific functional deteriorations in synaptic transmission. Pharmacological stimulation of synaptic transmission can improve motor activity in aged animals. These results uncover a critical role for the nervous system in age-dependent motor activity decline in C. elegans and provide insights into how functional aging occurs in this organism.
doi:10.1016/j.cmet.2013.08.007
PMCID: PMC3811915  PMID: 24011074
25.  A Multiple-SNP Approach for Genome-Wide Association Study of Milk Production Traits in Chinese Holstein Cattle 
PLoS ONE  2014;9(8):e99544.
The multiple-SNP analysis has been studied by many researchers, in which the effects of multiple SNPs are simultaneously estimated and tested in a multiple linear regression. The multiple-SNP association analysis usually has higher power and lower false-positive rate for detecting causative SNP(s) than single marker analysis (SMA). Several methods have been proposed to simultaneously estimate and test multiple SNP effects. In this research, a fast method called MEML (Mixed model based Expectation-Maximization Lasso algorithm) was developed for simultaneously estimate of multiple SNP effects. An improved Lasso prior was assigned to SNP effects which were estimated by searching the maximum joint posterior mode. The residual polygenic effect was included in the model to absorb many tiny SNP effects, which is treated as missing data in our EM algorithm. A series of simulation experiments were conducted to validate the proposed method, and the results showed that compared with SMMA, the new method can dramatically decrease the false-positive rate. The new method was also applied to the 50k SNP-panel dataset for genome-wide association study of milk production traits in Chinese Holstein cattle. Totally, 39 significant SNPs and their nearby 25 genes were found. The number of significant SNPs is remarkably fewer than that by SMMA which found 105 significant SNPs. Among 39 significant SNPs, 8 were also found by SMMA and several well-known QTLs or genes were confirmed again; furthermore, we also got some positional candidate gene with potential function of effecting milk production traits. These novel findings in our research should be valuable for further investigation.
doi:10.1371/journal.pone.0099544
PMCID: PMC4141689  PMID: 25148050

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