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1.  Supramolecular nanofibrils inhibit cancer progression in vitro and in vivo 
Advanced healthcare materials  2014;3(8):1217-1221.
The recent discovery of the inverse comorbidity between cancer and Alzheimer’s disease implies that one may use amyloids to inhibit tumors. During the conversion of a dipeptide segment (Phe-Phe) in β-amyloid into a supramolecular hydrogelator, we obtained a small molecule (1) that can self-assembly into nanofibrils via multiple intermolecular hydrogen bonding and aromatic-aromatic interactions. Interestingly, while the monomers of 1 are innocuous, the nanofibrils formed by 1 can selectively inhibit the growth of glioblastoma cells over neuronal cells. To further assess the potential of this small molecular nanofibrils as anti-cancer agent, we exam the biological activity of the nanofibrils and demonstrate that the nanofibrils of 1 efficiently inhibit the progression of cancer cells (e.g., HeLa cells) both in cell assays and on xenograft mice model. This work suggests that nanofibrils derived from core motif of amyloid are effective agents for inhibiting cancer progression. Thus, this work contributes to a new approach that uses supramolecular nanofibrils as de novo molecular amyloids for inhibiting the growth of cancer cells.
doi:10.1002/adhm.201300645
PMCID: PMC4134730  PMID: 24574174
supramolecular; nanofibrils; anticancer; inverse comorbidity; de novo amyloid oligomer
2.  MicroRNA Directly Enhances Mitochondrial Translation during Muscle Differentiation 
Cell  2014;158(3):607-619.
MicroRNAs are well known to mediate translational repression and mRNA degradation in the cytoplasm. Various microRNAs have also been detected in membrane-compartmentalized organelles, but the functional significance has remained elusive. Here we report that miR-1, a microRNA specifically induced during myogenesis, efficiently enters the mitochondria where it unexpectedly stimulates, rather than represses, the translation of specific mitochondrial genome-encoded transcripts. We show that this positive effect requires specific miR:mRNA base-pairing and Ago2, but not its functional partner GW182, which is excluded from the mitochondria. We provide evidence for the direct action of Ago2 in mitochondrial translation by CLIP-seq, functional rescue with mitochondria-targeted Ago2, and selective inhibition of the microRNA machinery in the cytoplasm. These findings unveil a positive function of microRNA in mitochondrial translation and suggest a highly coordinated myogenic program via miR-1 mediated translational stimulation in the mitochondria and repression in the cytoplasm.
doi:10.1016/j.cell.2014.05.047
PMCID: PMC4119298  PMID: 25083871
3.  Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages 
Cell & Bioscience  2015;5:36.
Background
Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined.
Results
Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.
Conclusions
Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.
Electronic supplementary material
The online version of this article (doi:10.1186/s13578-015-0026-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13578-015-0026-x
PMCID: PMC4491253  PMID: 26146544
Hypoxia; TGFß; phospho-SMAD2; SMAD2 degradation; Calpain; Macrophages
4.  Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation 
Molecular and Cellular Biology  2014;35(1):63-75.
l-Arginine and l-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colony-stimulating factor culture system and also facilitated the differentiation of CD8α+ conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation.
doi:10.1128/MCB.00805-14
PMCID: PMC4295380  PMID: 25332236
5.  Draft Genome Sequence of Bacillus coagulans NL01, a Wonderful l-Lactic Acid Producer 
Genome Announcements  2015;3(3):e00635-15.
Here, we report the draft genome sequence of Bacillus coagulans NL01, which could produce high optically pure l-lactic acid using xylose as a sole carbon source. The draft genome is 3,505,081 bp, with 144 contigs. About 3,903 protein-coding genes and 92 rRNAs are predicted from this assembly.
doi:10.1128/genomeA.00635-15
PMCID: PMC4472896  PMID: 26089419
6.  Quantitative analysis of an engineered CO2-fixing Escherichia coli reveals great potential of heterotrophic CO2 fixation 
Background
Production of fuels from the abundant and wasteful CO2 is a promising approach to reduce carbon emission and consumption of fossil fuels. Autotrophic microbes naturally assimilate CO2 using energy from light, hydrogen, and/or sulfur. However, their slow growth rates call for investigation of the possibility of heterotrophic CO2 fixation. Although preliminary research has suggested that CO2 fixation in heterotrophic microbes is feasible after incorporation of a CO2-fixing bypass into the central carbon metabolic pathway, it remains unclear how much and how efficient that CO2 can be fixed by a heterotrophic microbe.
Results
A simple metabolic flux index was developed to indicate the relative strength of the CO2-fixation flux. When two sequential enzymes of the cyanobacterial Calvin cycle were incorporated into an E. coli strain, the flux of the CO2-fixing bypass pathway accounts for 13 % of that of the central carbon metabolic pathway. The value was increased to 17 % when the carbonic anhydrase involved in the cyanobacterial carbon concentrating mechanism was introduced, indicating that low intracellular CO2 concentration is one limiting factor for CO2 fixation in E. coli. The engineered CO2-fixing E. coli with carbonic anhydrase was able to fix CO2 at a rate of 19.6 mg CO2 L−1 h−1 or the specific rate of 22.5 mg CO2 g DCW−1 h−1. This CO2-fixation rate is comparable with the reported rates of 14 autotrophic cyanobacteria and algae (10.5–147.0 mg CO2 L−1 h−1 or the specific rates of 3.5–23.7 mg CO2 g DCW−1 h−1).
Conclusions
The ability of CO2 fixation was created and improved in E. coli by incorporating partial cyanobacterial Calvin cycle and carbon concentrating mechanism, respectively. Quantitative analysis revealed that the CO2-fixation rate of this strain is comparable with that of the autotrophic cyanobacteria and algae, demonstrating great potential of heterotrophic CO2 fixation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-015-0268-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-015-0268-1
PMCID: PMC4475311  PMID: 26097503
Carbon fixation; CO2-fixation rate; Heterotrophic microbe; Carbonic anhydrase; Rubisco
7.  Dezocine Prevents Postoperative Hyperalgesia in Patients Undergoing Open Abdominal Surgery 
Objective. Postoperative hyperalgesia is very frequent and hard to treat. Dezocine is widely used and has a modulatory effect for thermal hyperalgesia in animal models. So, this study was designed to investigate the potential role of dezocine in decreasing postoperative hyperalgesia for patients undergoing open abdominal surgery. Methods. This is a randomized, double-blinded, and placebo-controlled trial. 50 patients for elective open gastrectomy were randomly allocated to either a true treatment group (0.15 mg/kg intravenous dezocine at the end of surgery) or a sham treatment group (equivalent volume of saline) in a 1 : 1 ratio. Patients were followed up for 48 hours postoperatively and pain threshold to Von Frey filaments, pain scores, PCIA consumption, rescue analgesics use, sedation score, and occurrence of postoperative nausea and vomiting were recorded. Results. Patients in the true treatment group experienced statistically significantly higher pain threshold on forearm and smaller extent of peri-incisional hyperalgesia than the sham treatment group. Rescue analgesic use, cumulative PCIA consumption, and pain scores were statistically significantly decreased in the true treatment group compared to the sham treatment group. Conclusions. Dezocine offers a significant antihyperalgesic and analgesic effect in patients undergoing elective open gastrectomy for up to 48 hours postoperatively.
doi:10.1155/2015/946194
PMCID: PMC4480811  PMID: 26170890
8.  Using the Fuzzy DEMATEL to Determine Environmental Performance: A Case of Printed Circuit Board Industry in Taiwan 
PLoS ONE  2015;10(6):e0129153.
The method by which high-technology product manufacturers balance profits and environmental performance is of crucial concern for governments and enterprises. To examine the environmental performance of manufacturers, the present study applied Fuzzy-DEMATEL model to examine environmental performance of the PCB industry in Taiwan. Fuzzy theory was employed to examine the environmental performance criteria of manufacturers and analyse fuzzy linguistics. The fuzzy-DEMATEL model was then employed to assess the direction and level of interaction between environmental performance criteria. The core environmental performance criteria which were critical for enhancing environmental performance of the PCB industry in Taiwan were identified and presented. The present study revealed that green design (a1), green material procurement (a2), and energy consumption (b3) constitute crucial reason criteria, the core criteria influencing other criteria, and the driving factors for resolving problems.
doi:10.1371/journal.pone.0129153
PMCID: PMC4459958  PMID: 26052710
9.  Cloning and Iron Transportation of Nucleotide Binding Domain of Cryptosporidium andersoni ATP-Binding Cassette (CaABC) Gene 
Cryptosporidium andersoni ATP-binding cassette (CaABC) is an important membrane protein involved in substrate transport across the membrane. In this research, the nucleotide binding domain (NBD) of CaABC gene was amplified by PCR, and the eukaryotic expression vector of pEGFP-C1-CaNBD was reconstructed. Then, the recombinant plasmid of pEGFP-C1-CaNBD was transformed into the mouse intestinal epithelial cells (IECs) to study the iron transportation function of CaABC. The results indicated that NBD region of CaABC gene can significantly elevate the transport efficiency of Ca2+, Mg2+, K+, and HCO3- in IECs (P<0.05). The significance of this study is to find the ATPase inhibitors for NBD region of CaABC gene and to inhibit ATP binding and nutrient transport of CaABC transporter. Thus, C. andersoni will be killed by inhibition of nutrient uptake. This will open up a new way for treatment of cryptosporidiosis.
doi:10.3347/kjp.2015.53.3.335
PMCID: PMC4510675  PMID: 26174828
Cryptosporidium andersoni; cloning; iron transportation; ATP-binding cassette transporter protein
10.  Supramolecular Hydrogels Made of the Basic Biological Building Blocks 
Chemistry, an Asian journal  2014;9(6):1446-1472.
As a consequence of the self-assembly of small organic molecules in water, supramolecular hydrogels are evolving from serendipitous events during organic synthesis to become a new type of materials that promise increased applications in biomedicine. In this focus review, we describe the recent development on the use of basic biological building blocks for creating molecules that act as hydrogelators and the potential applications of the corresponding hydrogels. After introducing the concept of supramolecular hydrogels and defining the scope of this review, we briefly describe the methods for making and characterizing supramolecular hydrogels. Then, we discuss representative hydrogelators according to the categories of their building blocks, such as amino acids, nucleobases, and saccharides, and highlight the applications of the hydrogels when necessary. Finally, we offer our perspectives and outlooks on this fast-growing field at the interface of organic chemistry, materials, biology, and medicine. By providing a snapshot for chemists, engineers, and medical scientists, we hope that this focus review will contribute to the development of multidisciplinary research on supramolecular hydrogels for a wide range of applications in different fields.
doi:10.1002/asia.201301693
PMCID: PMC4024374  PMID: 24623474
supramolecular; hydrogels; biomedicine; peptides; nucleobase saccharides
11.  DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1 
Let-7 miRNAs act as tumour suppressors by directly binding to the 3′UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response.
doi:10.1111/jcmm.12522
PMCID: PMC4459849  PMID: 25702703
let-7; regulatory loop; cyclin D1; DICER1; cell apoptosis; cancer stem cells
12.  Learning-guided automatic three dimensional synapse quantification for drosophila neurons 
BMC Bioinformatics  2015;16(1):177.
Background
The subcellular distribution of synapses is fundamentally important for the assembly, function, and plasticity of the nervous system. Automated and effective quantification tools are a prerequisite to large-scale studies of the molecular mechanisms of subcellular synapse distribution. Common practices for synapse quantification in neuroscience labs remain largely manual or semi-manual. This is mainly due to computational challenges in automatic quantification of synapses, including large volume, high dimensions and staining artifacts. In the case of confocal imaging, optical limit and xy-z resolution disparity also require special considerations to achieve the necessary robustness.
Results
A novel algorithm is presented in the paper for learning-guided automatic recognition and quantification of synaptic markers in 3D confocal images. The method developed a discriminative model based on 3D feature descriptors that detected the centers of synaptic markers. It made use of adaptive thresholding and multi-channel co-localization to improve the robustness. The detected markers then guided the splitting of synapse clumps, which further improved the precision and recall of the detected synapses. Algorithms were tested on lobula plate tangential cells (LPTCs) in the brain of Drosophila melanogaster, for GABAergic synaptic markers on axon terminals as well as dendrites.
Conclusions
The presented method was able to overcome the staining artifacts and the fuzzy boundaries of synapse clumps in 3D confocal image, and automatically quantify synaptic markers in a complex neuron such as LPTC. Comparison with some existing tools used in automatic 3D synapse quantification also proved the effectiveness of the proposed method.
doi:10.1186/s12859-015-0616-y
PMCID: PMC4445279  PMID: 26017624
Synapse detection; Automatic quantification; 3D confocal image; Model selection; BIOCAT
13.  Evaluation of miR-29c inhibits endotheliocyte migration and angiogenesis of human endothelial cells by suppressing the insulin like growth factor 1 
MicroRNAs, a class of 22-nucleotide non-coding RNAs, modulate gene expression by associating with the 3’-untranslated regions (3’- UTRs) of messenger RNAs (mRNAs). Although multiple miRNAs are known to be regulated during angiogenesis, their individual roles in blood vessel development are still not fully understood. Herein, we investigate the role of miR-29c in regulating cell cycle and angiogenic phenotype of endothelial cells. The results showed that IGF-1 is highly expressed and down-regulated by miR-29c in human umbilical vein endothelial cells (HUVEC). Consistent with this preliminary finding, introduction of exogenous miR-29c or miR-29c inhibitor alters cell cycle progression, proliferation and tube formation of HUVEC, respectively. Furthermore, by using luciferase reporter assay, we find that the expression of IGF-1, a suppressor transcription factor, is directly regulated by miR-29c through 3’-UTR. In addition, we show that the selective inhibition of PI3K/AKT pathway prior to miR-29c stimulation prevents the expression of angiogenesis suppressor miRNAs that are family and cluster specific. As a conclusion, we find that miR-29c plays a significant role in regulating cell cycle, proliferation and angiogenic properties of HUVECs. This function is likely mediated through IGF-1 proteins at the post-transcriptional level. As a novel molecular target, miR-29c may have a potential value in the treatment of angiogenesis-associated diseases, such as cardiovascular diseases and cancers.
PMCID: PMC4494138  PMID: 26175848
miRNA-29c; angiogenesis; endothelial cell; IGF-1
14.  Transcutaneous electrical acupoint stimulation alleviates the hyperandrogenism of polycystic ovarian syndrome rats by regulating the expression of P450arom and CTGF in the ovaries 
The present study was to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS) in alleviating the hyperandrogenism of polycystic ovarian syndrome (PCOS) model rats induced by testosterone propionate and the possible underlying mechanism. Thirty-six female Sprague-Dawley rats were randomly divided into normal control, PCOS model and TEAS groups with twelve rats in each group. The PCOS model rats were established by single injection of testosterone propionate at 9th day after birth, and the status of estrous cyclicity for each rat was observed. When the 8-week TEAS treatment completed, the weight of body, uterus and ovaries of the rats were respectively measured. The serum levels of total testosterone (TT), sex hormone binding globulin (SHBG), androstenedione, luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol (E2) were detected. The mRNA and protein expression levels of aromatase cytochrome P450 (P450arom) and connective tissue growth factor (CTGF) in the ovaries of the rats were respectively measured with real-time quantitative PCR and immunohistochemistry. The TEAS treatment significantly improved the estrous cycles of the PCOS rats and the TEAS group displayed significantly lower average body and ovaries weights than the PCOS model group (P < 0.05). TEAS significantly decreased the serum TT, free androgen index (FAI), androstenedione and LH/FSH levels, and increased the serum FSH levels of the PCOS rats (P < 0.05). The TEAS treatment significantly increased the P450arom mRNA as well as protein expression levels and significantly decreased the CTGF mRNA as well as protein expression levels in the ovaries of the PCOS rats (P < 0.05). We concluded that it is through regulating the P450arom and CTGF expression levels in the ovaries that TEAS significantly alleviates the hyperandrogenism of PCOS rats induced by testosterone propionate.
PMCID: PMC4509271  PMID: 26221326
Transcutaneous electrical acupoint stimulation; polycystic ovarian syndrome; hyperandrogenism; aromatase cytochrome P450; connective tissue growth factor
15.  Mechanisms for U2AF to define 3′ splice sites and regulate alternative splicing in the human genome 
The U2AF heterodimer has been well studied for its role in defining functional 3′ splice sites in pre-mRNA splicing, but many fundamental questions still remain unaddressed regarding the function of U2AF in mammalian genomes. Through genome-wide analysis of U2AF-RNA interactions, we report that U2AF has the capacity to directly define ~88% of functional 3′ splice sites in the human genome, but numerous U2AF binding events also occur in intronic locations. Mechanistic dissection reveals that upstream intronic binding events interfere with the immediate downstream 3′ splice site associated either with the alternative exon, to cause exon skipping, or with the competing constitutive exon, to induce exon inclusion. We further demonstrate partial functional impairment with leukemia-associated mutations in U2AF35, but not U2AF65, in regulated splicing. These findings reveal the genomic function and regulatory mechanism of U2AF in both normal and disease states.
doi:10.1038/nsmb.2906
PMCID: PMC4429597  PMID: 25326705
16.  Characterization of the promoter and extended C-terminal domain of Arabidopsis WRKY33 and functional analysis of tomato WRKY33 homologues in plant stress responses 
Journal of Experimental Botany  2015;66(15):4567-4583.
Highlight
We demonstrate that WRKY33 proteins are evolutionarily conserved and play a critical role in broad plant stress responses. Both C-terminal domain and specific promoter are involved in WRKY33-induced stress tolerance.
Arabidopsis AtWRKY33 plays a critical role in broad plant stress responses. Whether there are evolutionarily conserved homologues of AtWRKY33 in other plants and what make AtWRKY33 such an important protein in plant stress responses are largely unknown. We compared AtWRKY33 with its close homologues to identify AtWRKY33-specific regulatory and structural elements, which were then functionally analysed through complementation. We also performed phylogenetic analysis to identify structural AtWRKY33 homologues in other plants and functionally analysed two tomato homologues through complementation and gene silencing. AtWRKY33 has an extended C-terminal domain (CTD) absent in its close homologue AtWRKY25. Both its CTD and the strong pathogen/stress-responsive expression of AtWRKY33 are necessary to complement the critical phenotypes of atwrky33. Structural AtWRKY33 homologues were identified in both dicot and monocot plants including two (SlWRKY33A and SlWRKY33B) in tomato. Molecular complementation and gene silencing confirmed that the two tomato WRKY genes play a critical role similar to that of AtWRKY33 in plant stress responses. Thus, WRKY33 proteins are evolutionarily conserved with a critical role in broad plant stress responses. Both its CTD and promoter are critical for the uniquely important roles of WRKY33 in plant stress responses.
doi:10.1093/jxb/erv221
PMCID: PMC4507763  PMID: 25969555
Arabidopsis; C-terminal domain; plant stress; promoter; response; tomato; WRKY33.
17.  Microcystins Induces Vascular Inflammation in Human Umbilical Vein Endothelial Cells via Activation of NF-κB 
Mediators of Inflammation  2015;2015:942159.
Microcystins (MCs) produced by toxic cyanobacteria cause serious water pollution and public health hazard to humans and animals. However, direct molecular mechanisms of MC-LR in vascular endothelial cells (ECs) have not been understood yet. In this study, we investigated whether MC-LR induces vascular inflammatory process in cultured human umbilical vein endothelial cells (HUVECs). Our data demonstrated that MC-LR decreased HUVECs proliferation and tube formation and enhanced apoptosis. MC-LR also induced intracellular reactive oxygen species formation (ROS) in HUVECs. The MC-LR directly stimulated phosphorylation of NF-κB. Furthermore, MC-LR also increased cell adhesion molecules (ICAM-1 and VCAM-1) expression in HUVECs. Taken together, the present data suggested that MC-LR induced vascular inflammatory process, which may be closely related to the oxidative stress, NF-κB activation, and cell adhesion molecules expression in HUVECs. Our findings may highlight that MC-LR causes potential damage to blood vessels.
doi:10.1155/2015/942159
PMCID: PMC4438169  PMID: 26063980
18.  Trim9 regulates activity-dependent fine-scale topography in Drosophila 
Current biology : CB  2014;24(9):1024-1030.
SUMMARY
Topographic projection of afferent terminals into two-dimensional maps in the central nervous system (CNS) is a general strategy used by the nervous system to encode the locations of sensory stimuli. In vertebrates, it is known that while guidance cues are critical for establishing a coarse topographic map, neural activity directs fine-scale topography between adjacent afferent terminals [1–4]. However, the molecular mechanism underlying activity-dependent regulation of fine-scale topography is poorly understood. Molecular analysis of the spatial relationship between adjacent afferent terminals requires reliable localization of the presynaptic terminals of single neurons as well as genetic manipulations with single-cell resolution in vivo. Although both requirements can potentially be met in Drosophila melanogaster [5, 6], no activity-dependent topographic system has been identified in flies [7]. Here we report a topographic system that is shaped by neuronal activity in Drosophila. With this system, we found that topographic separation of the presynaptic terminals of adjacent nociceptive neurons requires different levels of Trim9, an evolutionarily conserved signaling molecule [8–11]. Neural activity regulates Trim9 protein levels to direct fine-scale topography of sensory afferents. This study offers both a novel mechanism by which neural activity directs fine-scale topography of axon terminals and a new system to study this process at single-neuron resolution.
doi:10.1016/j.cub.2014.03.041
PMCID: PMC4030378  PMID: 24746793
19.  MicroRNA301 is a potential diagnostic biomarker for hepatocellular cancer 
We explored microRNA301 diagnosis value in hepatocellular cancer (HCC), attempting to provide novel insights for early detection, effective prevention, and timely treatment. 42 patients with HCC and 38 controls composed of 9 liver cirrhosis (LC), 9 chronic hepatitis B (CHB) and 20 healthy individuals were investigated in the study. Serum microRNA301 expression levels were detected using fluorescent quantitative polymerase chain reaction (FQ-PCR) technology. ROC curve was performed to evaluate diagnosis value of microRNA301. Meanwhile, the correlations of microRNA301 levels with clinical characteristics were also analyzed. Significantly up-regulated expression of serum microRNA301 was seen in HCC patients compared with the controls (P < 0.05). We also noted that level changes of microRNA301 were associated with differentiation, alpha fetoprotein (AFP), portal vein-emboli and HasAg (P < 0.05), rather than age, gender and tumor size. Based on the area under ROC curve of 0.880, the critical value of microRNA301 was 2.3530 and the sensitivity and specificity were 88.1% and 70.3%, respectively. The results of this study revealed that microRNA301 might function as a potential diagnostic biomarker for HCC.
PMCID: PMC4503142  PMID: 26191271
Hepatocellular cancer; MicroRNA301; diagnosis
20.  Lysine biotinylation and methionine oxidation in the heat shock protein HSP60 synergize in the elimination of reactive oxygen species in human cell cultures† 
Previous studies suggest that the number of proteins containing covalently bound biotin is larger than previously thought. Here, we report the identity of some of these proteins. Using mass spectrometry we discovered 108 novel biotinylation sites in the human embryonic kidney HEK293 cell proteome; members of the heat shock protein (HSP) superfamily were overrepresented among the novel biotinylated proteins. About half of the biotinylated proteins also displayed various degrees of methionine oxidation, which is known to play an important role in the defense against reactive oxygen species; for biotinylated HSPs, the percent of methionine sulfoxidation approached 100%. Protein structure analysis suggests that methionine sulfoxides localize in close physical proximity to the biotinylated lysines on the protein surface. Mass spectrometric analysis revealed that between 1 and 5 of the methionine residues in the C-terminal KEEKDPGMGAMGGMGGGMGGGMF motif are oxidized in HSP60. The likelihood of methionine sulfoxidation is higher if one of the adjacent lysine residues is biotinylated. Knockdown of HSP60 caused a 60% increase in the level of reactive oxygen species in fibroblasts cultured in biotin-sufficient medium. When HEK293 cells were transferred from biotin-sufficient medium to biotin-free medium, the level of reactive oxygen species increased by >9 times compared with baseline controls and a time-response relationship was evident. High levels of methionine sulfoxidation coincided with cell cycle arrest in the G0/G1 and S phases in biotin-depleted cells. We conclude that biotinylation of lysines synergizes with sulfoxidation of methionines in heat-shock proteins such as HSP60 in the defense against reactive oxygen species.
doi:10.1016/j.jnutbio.2013.12.008
PMCID: PMC3959574  PMID: 24582286
biotin; heat shock proteins; methionine oxidation; reactive oxygen species
21.  Evaluation of miR-29c inhibits endotheliocyte migration and angiogenesis of human endothelial cells by suppressing the insulin like growth factor 1 
MicroRNAs, a class of 22-nucleotide non-coding RNAs, modulate gene expression by associating with the 3’-untranslated regions (3’-UTRs) of messenger RNAs (mRNAs). Although multiple miRNAs are known to be regulated during angiogenesis, their individual roles in blood vessel development are still not fully understood. Herein, we investigate the role of miR-29c in regulating cell cycle and angiogenic phenotype of endothelial cells. The results showed that IGF-1 is highly expressed and down-regulated by miR-29c in human umbilical vein endothelial cells (HUVEC). Consistent with this preliminary finding, introduction of exogenous miR-29c or miR-29c inhibitor alters cell cycle progression, proliferation and tube formation of HUVEC, respectively. Furthermore, by using luciferase reporter assay, we find that the expression of IGF-1, a suppressor transcription factor, is directly regulated by miR-29c through 3’-UTR. In addition, we show that the selective inhibition of PI3K/AKT pathway prior to miR-29c stimulation prevents the expression of angiogenesis suppressor miRNAs that are family and cluster specific. As a conclusion, we find that miR-29c plays a significant role in regulating cell cycle, proliferation and angiogenic properties of HUVECs. This function is likely mediated through IGF-1 proteins at the post-transcriptional level. As a novel molecular target, miR-29c may have a potential value in the treatment of angiogenesis-associated diseases, such as cardiovascular diseases and cancers.
PMCID: PMC4448189  PMID: 26045889
miRNA-29c; angiogenesis; endothelial cell; IGF-1
22.  Complete Genome Sequences of One Human Respiratory Syncytial Antigenic Group A Virus from China and Its Four Mouse-Adapted Isolates 
Genome Announcements  2015;3(2):e00062-15.
In this study, one human respiratory syncytial antigenic group A virus (HRSV-A-GZ08-0) and its four BALB/c mouse-adapted isolates were sequenced and elucidated. Nineteen nucleotides were mutated between HRSV-A-GZ08-0 and the four mouse-adapted isolates.
doi:10.1128/genomeA.00062-15
PMCID: PMC4358386  PMID: 25744999
23.  High sensitivity C-reactive protein (Hs-CRP) remains highly stable in long-term archived human serum 
Clinical biochemistry  2013;47(0):315-318.
Background
The stability of biomarkers in stored biomedical samples is crucial, especially when storage is for extended periods of time. High-sensitivity CRP (Hs-CRP) is a biomarker of low grade inflammation that is extensively used to identify and study cardiovascular and/or inflammatory processes in clinical care and large epidemiologic studies. Therefore, assessing Hs-CRP stability in archived samples at a given temperature is important to insure precision of measurements over time and the validity of studies using archived samples.
Methods
We evaluated the stability of Hs-CRP in 30 randomly selected human serum samples by measuring Hs-CRP concentrations in freshly collected sample [Hs-CRP (0)] and in the same set of samples after 7–11 years of storage at −80°C [Hs-CRP (LT)].
Results
Hs-CRP did not significantly change up to 11 years of storage at −80°C as shown by a negligible median difference between Hs-CRP (0) and Hs-CRP (LT), delta(Hs-CRP (0)- Hs-CRP (LT)=−0.01, p=0.45. There was a good concordance and agreement between Hs-CRP (0) and Hs-CRP (LT) as measured respectively by Lin's coefficient of correlation (ρC= 0.98) and Bland-Altman analysis (mean difference=−0.02, 95% CI [−0.04–0.0045] p=0.107). In addition, the data also suggest that the time elapsed between collection and Hs-CRP measurement does not affect Hs-CRP stability over time when samples are kept under the appropriate conditions.
Conclusions
Long-term storage at −80°C for up to 11 years did not significantly affect the stability of serum Hs-CRP. Given the cost and time for collecting fresh samples, this observation represents an important finding for biomedical research and clinical care.
doi:10.1016/j.clinbiochem.2013.12.014
PMCID: PMC3991112  PMID: 24373927
C-reactive protein; archived samples; long-term storage; stability; biomedical research
24.  Aromatic-Aromatic Interactions Enhance Interfiber Contacts for Enzymatic Formation of A Spontaneously Aligned Supramolecular Hydrogel 
Anisotropy or alignment is a critical feature of functional soft materials in living organisms, but it remains a challenge for spontaneously generating anisotropic gel materials. Here we report a molecular design that increases intermolecular aromatic-aromatic interactions of hydrogelators during enzymatic hydrogelation for spontaneously forming an anisotropic hydrogel. This process, relying on both aromatic-aromatic interactions and enzyme catalysis, results in spontaneously aligned supramolecular nanofibers as the matrices of a monodomain hydrogel that exhibits significant birefringence. This work, as the first example of monodomain hydrogels formed via an enzymatic reaction, illustrates a new biomimetic approach for generating aligned anisotropic soft materials.
doi:10.1021/ja4127399
PMCID: PMC3986011  PMID: 24512553
25.  A naphthalene-containing amino acid enables hydrogelation of a conjugate of nucleobase-saccharideamino acids 
Here we report the first example of a hydrogelator made of the conjugate of nucleobase-saccharide-amino acids by incorporating L-3-(2-naphthyl)-alanine to the conjugate, which illustrates a facile and effective method for generating bioactive and functional hydrogelators from the basic biological building blocks.
doi:10.1039/c3cc48946a
PMCID: PMC3974899  PMID: 24412974

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