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1.  Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate 
Wang, X | Li, H | Zheng, A | Yang, L | Liu, J | Chen, C | Tang, Y | Zou, X | Li, Y | Long, J | Liu, J | Zhang, Y | Feng, Z
Cell Death & Disease  2014;5(11):e1521-.
Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.
doi:10.1038/cddis.2014.473
PMCID: PMC4260731  PMID: 25393477
2.  Cloning, expression and location of RNase9 in human epididymis 
Liu, J | Li, JY | Wang, HY | Zhang, CL | Li, N | Lin, YQ | Liu, J | Wang, WT
BMC Research Notes  2008;1:111.
Background
Mammalian spermatozoa become fully motile and fertile during transit through the luminal fluid of the epididymis. At least 200 proteins are present in the epididymal lumen, but the potential roles of these luminal proteins in male fertility are unknown. Investigation of the function of these proteins will elucidate the mechanism of sperm maturation, and also provide new drug targets for male contraception. We cloned RNase9 from a human epididymis cDNA library for characterization and analysis of its functions.
Findings
It was predicted that human RNase9 gene was located on chromosome 14q11.2 and encoded a 205 amino acids protein with a signal peptide of 26 amino acids at the N-terminus. The protein had eight conserved cysteine residues characteristic of the RNase A family members and several potential post-translational modification sites.
At the transcriptional level, RNase9 was expressed in a wide variety of tissues, and the expression was higher in men than in boys. RNase9 was localized to the post-equatorial region of the sperms' head. Immunofluorescence staining showed that RNase9 protein was present mostly in the epithelium of the epididymal tubule. Recombinant RNase9 had no ribonuclease activity. In addition, RNase9 had no detectable effect on sperm motility and fertilization as demonstrated by blocking spermatozoa with anti-RNase9 polyclonal serum.
Conclusion
RNase9 is expressed in a wide variety of tissues. It is located on the post-equatorial region of the sperm head and the epithelium of epididymal tubule. Although RNase9 belongs to the RNase A family, it has no ribonuclease activity.
doi:10.1186/1756-0500-1-111
PMCID: PMC2669477  PMID: 18992174
3.  Point and deletion mutations eliminate one or both methyl group transfers catalysed by the yeast TRM1 encoded tRNA (m22G26)dimethyltransferase. 
Nucleic Acids Research  1998;26(22):5102-5108.
Guanosine at position 26 in eukaryotic tRNAs is usually modified to N2 , N2 -dimethylguanosine (m22G26). In Saccharomyces cerevisiae , this reaction is catalysed by the TRM1 encoded tRNA (m22G26)dimethyltransferase. As a prerequisite for future studies, the yeast TRM1 gene was expressed in Escherichia coli and the His-tagged Trm1 protein (rTrm1p) was extensively purified. rTrm1p catalysed both the mono- and dimethylation of G26 in vivo in Escherichia coli tRNA and in vitro in yeast trm1 mutant tRNA. The TRM1 gene from two independent wild-type yeast strains differed at 14 base positions causing two amino acid exchanges . Exchange of the original Ser467 for Leu caused a complete loss of enzyme activity in vitro against trm1 yeast tRNA. Comparatively short N- or C-terminal deletions from the 570 amino acid long Trm1 polypeptide decreased or eliminated the enzyme activity, as did some point mutations within these regions. This indicated that the protein is not a two domain peptide with the enzyme activity localised to one of the domains, but rather that both ends of the polypeptide seem to interact to influence the conformation of those parts that make up the RNA-binding site and/or the active site of the enzyme.
PMCID: PMC147968  PMID: 9801306
4.  TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis 
The New England journal of medicine  2015;372(4):341-350.
BACKGROUND
Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.
METHODS
We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions.
RESULTS
We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.
CONCLUSIONS
Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.
doi:10.1056/NEJMoa1406829
PMCID: PMC4326244  PMID: 25564734
5.  Real-space anisotropic dielectric response in a multiferroic skyrmion lattice 
Scientific Reports  2015;5:8318.
A magnetic skyrmion lattice is a microstructure consisting of hexagonally aligned skyrmions. While a skyrmion as a topologically protected carrier of information promises a number of applications, an easily accessible probe of the skyrmion and skyrmion lattice at mesoscopic scale is of significance. It is known that neutron scattering, Lorentz transmission electron microscopy, and spin-resolved STM as effective probes of skyrmions have been established. In this work, we propose that the spatial contour of dielectric permittivity in a skyrmion lattice with ferromagnetic interaction and in-plane (xy) Dzyaloshinskii-Moriya (DM) interaction can be used to characterize the skyrmion lattice. The phase field and Monte Carlo simulations are employed to develop the one-to-one correspondence between the magnetic skyrmion lattice and dielectric dipole lattice, both exhibiting the hexagonal symmetry. Under excitation of in-plane electric field in the microwave range, the dielectric permittivity shows the dumbbell-like pattern with the axis perpendicular to the electric field, while it is circle-like for the electric field along the z-axis. The dependences of the spatial contour of dielectric permittivity on external magnetic field along the z-axis and dielectric frequency dispersion are discussed.
doi:10.1038/srep08318
PMCID: PMC4321174  PMID: 25661786
6.  Skyrmion-skyrmion and skyrmion-edge repulsions in skyrmion-based racetrack memory 
Scientific Reports  2015;5:7643.
Magnetic skyrmions are promising for building next-generation magnetic memories and spintronic devices due to their stability, small size and the extremely low currents needed to move them. In particular, skyrmion-based racetrack memory is attractive for information technology, where skyrmions are used to store information as data bits instead of traditional domain walls. Here we numerically demonstrate the impacts of skyrmion-skyrmion and skyrmion-edge repulsions on the feasibility of skyrmion-based racetrack memory. The reliable and practicable spacing between consecutive skyrmionic bits on the racetrack as well as the ability to adjust it are investigated. Clogging of skyrmionic bits is found at the end of the racetrack, leading to the reduction of skyrmion size. Further, we demonstrate an effective and simple method to avoid the clogging of skyrmionic bits, which ensures the elimination of skyrmionic bits beyond the reading element. Our results give guidance for the design and development of future skyrmion-based racetrack memory.
doi:10.1038/srep07643
PMCID: PMC4284505  PMID: 25560935
7.  Effect of Different Inclusion Level of Condensed Distillers Solubles Ratios and Oil Content on Amino Acid Digestibility of Corn Distillers Dried Grains with Solubles in Growing Pigs 
The purpose of this experiment was to determine and compare the digestibility of crude protein (CP) and amino acids (AA) in full-oil (no oil extracted) and de-oiled (oil extracted) corn distillers dried grains with solubles (DDGS) with different condensed distillers solubles (CDS) ratios. Six barrows (29.6±2.3 kg) fitted with ileal T-cannula were allotted into a 6×6 Latin square design. Each period was comprised of a 5-d adaption period followed by a 2-d collection of ileal digesta. The five test diets contained 62% DDGS as the sole source of AA. A nitrogen-free diet was used to measure the basal endogenous losses of CP and AA. Chromic oxide (0.3%) was used as an index in each diet. The results showed that CP and AA were very similar in 5 DDGS, but the standardized ileal digestibility (SID) of lysine (from 56.16% to 71.15%) and tryptophan (from 54.90% to 68.38%) had the lowest values and largest variation within the essential AA, which suggests reduced availability of AA and different levels of Maillard reactions in the five DDGS. The apparent ileal digestibility and SID of CP and most of AA in full-oil DDGS (sources 1 and 2) were greater (p<0.05) than de-oiled DDGS (sources 3, 4, and 5). Comparing the AA SID in the 5 DDGS, full-oil with low CDS ratio DDGS (source 1) had non-significantly higher values (p >0.05) than full-oil with high CDS ratio DDGS (source 2); however, the SID of most AA of de-oiled with low CDS ratios DDGS (source 3) were non-significantly lower (p>0.05) than de-oiled with high CDS ratio DDGS (source 4); and the de-oiled DDGS with middle CDS ratio (source 5) but with different drying processing had the lowest SID AA values. In conclusion, de-oiled DDGS had lower SID of CP and AA than full-oil DDGS; a higher CDS ratio tended to decrease the SID of AA in full-oil DDGS but not in de-oiled DDGS; and compared with CDS ratio, processing, especially drying, may have more of an effect on AA digestibility of DDGS.
doi:10.5713/ajas.14.0161
PMCID: PMC4283178  PMID: 25557681
Amino Acid Digestibility; Condensed Distillers Solubles Ratio; Corn Distillers Dried Grains with Solubles; Full-oil and De-oiled; Growing Pigs; Processing
8.  Determination and Prediction of the Amino Acid Digestibility of Sunflower Seed Meals in Growing Pigs 
This experiment was conducted to evaluate the chemical composition and amino acid (AA) digestibility of sunflower seed meal (SFSM) and to use this data to develop prediction equations for estimating AA digestibility for growing pigs. Ten SFSM were collected from five provinces in China. Twelve barrows (38.8±4.6 kg), fitted with ileal T-cannula were allotted into two 6×6 Latin square designs. Each of six experimental periods comprised a 5-d adaption period followed by a 2-d collection of ileal digesta. The ten test diets contained 50% SFSM as the sole source of AA. Another nitrogen-free diet was used to measure the basal endogenous losses of crude protein (CP) and AA. Chromic oxide (0.3%) was used as an inert marker in each diet. There was considerable variation (CV>10%) among the ten SFSM in chemical composition (dry matter [DM]). The concentration of CP and ether extract (EE) ranged from 29.33% to 39.09% and 0.88% to 11.33%, respectively. Crude fibre (CF), neutral detergent fibre and acid detergent fibre ranged from 21.46% to 36.42%, 38.15% to 55.40%, and 24.59% to 37.34%, respectively. There was variation among the ten SFSM in apparent ileal digestibility (AID) and standardized ileal digestibility (SID) for lysine and threonine, which ranged from 63.16 to 79.21 and 55.19% to 72.04% for AID and 67.03% to 82.07% and 61.97% to 77.01% for SID, respectively. The variation in CP and methionine ranged from 60.13% to 74.72% and 74.79% to 88.60% for AID and 66.70% to 79.31% and 77.16% to 90.27% for SID, respectively. Methionine was a good indicator to predict AA digestibility. These results indicate that conventional chemical composition of SFSM was variable (CV>10%) among the ten SFSM (DM). The results of AID, SID and prediction equations could be used to evaluate the digestibility of SFSM in growing pigs.
doi:10.5713/ajas.14.0109
PMCID: PMC4283192  PMID: 25557679
Sunflower Seed Meal; Chemical Composition; Amino Acid Digestibility; Growing Pigs; Prediction Equations
9.  Basal Ganglia Surface Morphology and the Effects of Stimulant Medications in Youth with Attention-Deficit/Hyperactivity Disorder 
The American journal of psychiatry  2010;167(8):977-986.
Objective
Disturbances in the basal ganglia portions of Cortico-Striato-Thalamo-Cortical (CSTC) circuits likely contribute to the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). This study examines the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD.
Design
We examined 104 individuals (47 with combined-type ADHD and 57 controls) aged 7 to 18 years, in a cross-sectional case-control study using anatomical magnetic resonance imaging. We measured conventional volumes and the surface morphology for the basal ganglia.
Results
Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei that were localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the CSTC circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe were their ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared to those with ADHD who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to controls. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons.
Conclusion
These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia of children with ADHD and suggest that stimulants may “normalize” morphological features of the basal ganglia in children with ADHD.
doi:10.1176/appi.ajp.2010.09091259
PMCID: PMC4254769  PMID: 20595414
10.  Controlling spin-dependent tunneling by bandgap tuning in epitaxial rocksalt MgZnO films 
Scientific Reports  2014;4:7277.
Widespread application of magnetic tunnel junctions (MTJs) for information storage has so far been limited by the complicated interplay between tunnel magnetoresistance (TMR) ratio and the product of resistance and junction area (RA). An intricate connection exists between TMR ratio, RA value and the bandgap and crystal structure of the barrier, a connection that must be unravelled to optimise device performance and enable further applications to be developed. Here, we demonstrate a novel method to tailor the bandgap of an ultrathin, epitaxial Zn-doped MgO tunnel barrier with rocksalt structure. This structure is attractive due to its good Δ1 spin filtering effect, and we show that MTJs based on tunable MgZnO barriers allow effective balancing of TMR ratio and RA value. In this way spin-dependent transport properties can be controlled, a key challenge for the development of spintronic devices.
doi:10.1038/srep07277
PMCID: PMC4250913  PMID: 25451163
11.  MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways 
Wu, N | Lin, X | Zhao, X | Zheng, L | Xiao, L | Liu, J | Ge, L | Cao, S
British Journal of Cancer  2013;109(11):2853-2863.
Background:
We have recently identified miR-125b upregulation in glioblastoma (GMB). The aim of this study is to determine the correlation between miR-125b expression and malignant grades of glioma and the genes targeted by miR-125b.
Methods:
Real-time PCR was employed to measure the expression level of miR-125b. Cell viability was evaluated by cell growth and colony formation in soft-agar assays. Cell apoptosis was determined by Hoechst 33342 staining and AnnexinV-FITC assay. The Luciferase assay was used to confirm the actual binding sites of p38MAPK mRNA. Western blot was used to detect the gene expression level.
Results:
The expression level of miR-125b is positively correlated with the malignant grade of glioma. Ectopic expression of miR-125b promotes the proliferation of GMB cells. Knockdown of endogenous miR-125b inhibits cell proliferation and promotes cell apoptosis. Further studies reveal that p53 is regulated by miR-125b. However, downregulation of the endogenous miR-125b also results in p53-independent apoptotic pathway leading to apoptosis in p53 mutated U251 cells and p53 knockdown U87 cells. Moreover, p38MAPK is also regulated by miR-125b and downregulation of miR-125b activates the p38MAPK-induced mitochondria apoptotic pathway.
Conclusion:
High-level expression of miR-125b is associated with poor outcomes of GMB. MiR-125b may have an oncogenic role in GMB cells by promoting cell proliferation and inhibiting apoptosis.
doi:10.1038/bjc.2013.672
PMCID: PMC3844918  PMID: 24169356
microRNA; miR-125b; glioblastoma; cell apoptosis; p53; p38MAPK
12.  SLC3A1 and SLC7A9 Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System 
Background
Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds.
Hypothesis/Objectives
To determine urinary cystine concentrations, inheritance and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds.
Animals
Mixed and purebred Labrador Retrievers (n=6), Australian Cattle Dogs (6), Miniature Pinschers (4) and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs.
Methods
Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA.
Results
In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed specific DNA tests were developed, but the prevalence of each mutation remains unknown.
Conclusions and clinical importance
These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds.
doi:10.1111/jvim.12176
PMCID: PMC3946761  PMID: 24001348
Metabolic disease; urolithiasis; nephropathy; hereditary disease
13.  The N-terminal region of p27 inhibits HIF-1α protein translation in ribosomal protein S6-dependent manner by regulating PHLPP-Ras-ERK-p90RSK axis 
Zhang, D | Liu, J | Mi, X | Liang, Y | Li, J | Huang, C
Cell Death & Disease  2014;5(11):e1535-.
P27 was identified as a tumor suppressor nearly two decades, being implicated in cell-cycle control, differentiation, senescence, apoptosis and motility. Our present study, for the first time to the best of our knowledge, revealed a potential role of p27 in inhibiting S6-mediated hypoxia-inducible factor-1α (HIF-1α) protein translation, which contributed to the protection from environmental carcinogen (sodium arsenite)-induced cell transformation. Our findings showed that depletion of p27 expression by knockout and knockdown approaches efficiently enhanced S6 phosphorylation in arsenite response via overactivating Ras/Raf/MEK/ERK pathway, which consequently resulted in the stimulation of p90RSK (90 kDa ribosomal S6 kinase), a direct kinase for S6 phosphorylation. Although PI3K/AKT pathway was also involved in S6 activation, blocking AKT and p70S6K activation did not attenuate arsenite-induced S6 activation in p27−/− cells, suggesting p27 specifically targeted Ras/ERK pathway rather than PI3K/AKT pathway for inhibition of S6 activation in response to arsenite exposure. Further functional studies found that p27 had a negative role in cell transformation induced by chronic low-dose arsentie exposure. Mechanistic investigations showed that HIF-1α translation was upregulated in p27-deficient cells in an S6 phosphorylation-dependent manner and functioned as a driving force in arsenite-induced cell transformation. Knockdown of HIF-1α efficiently reversed arsenite-induced cell transformation in p27-depleted cells. Taken together, our findings provided strong evidence showing that by targeting Ras/ERK pathway, p27 provided a negative control over HIF-1α protein synthesis in an S6-dependent manner, and abrogated arsenite-induced cell transformation via downregulation of HIF-1α translation.
doi:10.1038/cddis.2014.496
PMCID: PMC4260754  PMID: 25412313
14.  Coupled ferroelectric polarization and magnetization in spinel FeCr2S4 
Scientific Reports  2014;4:6530.
One of the core issues for multiferroicity is the strongly coupled ferroelectric polarization and magnetization, while so far most multiferroics have antiferromagnetic order with nearly zero magnetization. Magnetic spinel compounds with ferrimagnetic order may be alternative candidates offering large magnetization when ferroelectricity can be activated simultaneously. In this work, we investigate the ferroelectricity and magnetism of spinel FeCr2S4 in which the Fe2+ sublattice and Cr3+ sublattice are coupled in antiparallel alignment. Well defined ferroelectric transitions below the Fe2+ orbital ordering termperature Too = 8.5 K are demonstrated. The ferroelectric polarization has two components. One component arises mainly from the noncollinear conical spin order associated with the spin-orbit coupling, which is thus magnetic field sensitive. The other is probably attributed to the Jahn-Teller distortion induced lattice symmetry breaking, occuring below the orbital ordering of Fe2+. Furthermore, the coupled ferroelectric polarization and magnetization in response to magnetic field are observed. The present work suggests that spinel FeCr2S4 is a multiferroic offering both ferroelectricity and ferrimagnetism with large net magnetization.
doi:10.1038/srep06530
PMCID: PMC4185382  PMID: 25284432
15.  Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity 
British Journal of Cancer  2013;109(6):1599-1608.
Background:
Squamous cell lung cancer (SqCC) is the second most common type of lung cancer in the United States. Previous studies have used gene-expression data to classify SqCC samples into four subtypes, including the primitive, classical, secretory and basal subtypes. These subtypes have different survival outcomes, although it is unknown whether these molecular subtypes predict response to therapy.
Methods:
Here, we analysed RNAseq data of 178 SqCC tumour samples and characterised the features of the different SqCC subtypes to define signature genes and pathway alterations specific to each subtype. Further, we compared the gene-expression features of each molecular subtype to specific time points in models of airway development. We also classified SqCC-derived cell lines and their reported therapeutic vulnerabilities.
Results:
We found that the primitive subtype may come from a later stage of differentiation, whereas the basal subtype may be from an early time. Most SqCC cell lines responded to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), whereas the basal-type cell line EBC-1 was sensitive to three other drugs (PF2341066, AZD6244 and PD-0325901).
Conclusion:
Compared with the other three subtypes of cell lines, the secretory-type cell lines were significantly less sensitive to the five most effective drugs, possibly because of their low proliferation activity. We provide a bioinformatics framework to explore drug repurposing for cancer subtypes based on the available genomic profiles of tumour samples, normal cell types, cancer cell lines and data of drug sensitivity in cell lines.
doi:10.1038/bjc.2013.452
PMCID: PMC3776976  PMID: 24002593
squamous cell lung cancer subtypes; gene expression; RNAseq; microarray; signature genes; cells of origin; representative cell line; drug sensitivity; classification
16.  Remodeling characteristics and biomechanical properties of a crosslinked versus a non-crosslinked porcine dermis scaffolds in a porcine model of ventral hernia repair 
Purpose
The objective of this study was to evaluate the histologic remodeling profile and biomechanical properties of the porcine abdominal wall after repair with HDMI-crosslinked (Permacol®) or non-crosslinked (Strattice®) porcine dermis in a porcine model of ventral hernia repair.
Methods
Bilateral incisional hernias were created in Yucatan minipigs and repaired after 21 days. The repair site, including mesh and abdominal wall, was harvested after 1, 6, and 12 months and subjected to histologic analysis and uniaxial testing. Native abdominal wall without mesh was also subjected to uniaxial tensile testing.
Results
Permacol® demonstrated significant improvement over time in every remodeling category except scaffold degradation, while remodeling characteristics of Strattice® remained relatively unchanged over time for every category except fibrous encapsulation and neovascularization. However, remodeling scores for Strattice® were already significantly higher after just 1 month compared to Permacol® in the categories of cellular infiltration, ECM deposition, and neovascularization, providing evidence of earlier remodeling of the non-crosslinked grafts compared to the crosslinked grafts. The tensile strength and stiffness of both crosslinked and non-crosslinked graft-tissue composites were greater than the tensile strength and stiffness of the native porcine abdominal wall in the very early post-operative period (1 month), but there was no difference in tensile strength or stiffness by the end of the study period (12 months).
Conclusions
HDMI collagen crosslinking of porcine dermis scaffolds reduces the early histologic remodeling profile but does not significantly impact the tensile strength or stiffness of the graft-tissue composites in a porcine model of ventral hernia repair.
doi:10.1007/s10029-013-1070-2
PMCID: PMC3883946  PMID: 23483265
Biologic mesh; Crosslinking; Porcine; Remodeling; Tensile strength; Ventral hernia repair
17.  Role of leptin receptor gene polymorphisms in susceptibility to the development of essential hypertension: a case–control association study in a Northern Han Chinese population 
Journal of human hypertension  2014;28(9):551-556.
In order to explore the potential association between the leptin receptor (LEPR) gene polymorphisms and essential hypertension (EH) risk in the Northern Han Chinese population, we recruited 823 hypertensive subjects and 491 healthy control subjects from the Northern Han Chinese. Genotyping was performed to identify the Lys109Arg, Gln223Arg and Lys656Asn polymorphisms of the LEPR gene. Significant associations were found in a dominant genetic model ([GG+AG] vs AA), P=0.007, odds ratio (OR)=3.697, 95% confidence interval (CI) 1.442–9.482), and in homozygote comparison (GG vs AA, P=0.005, OR=3.890, 95% CI 1.501–10.077) for the Gln223Arg polymorphism. No significant association could be found between Lys109Arg or Lys656Asn polymorphism and EH risk. Linkage disequilibrium was detected between the Lys109Arg and Gln223Arg polymorphisms, and haplotype analyses identified that the G-A haplotype was a protective haplotype for EH. Our studies demonstrated that the LEPR Gln223Arg polymorphism had an important role in a patient's susceptibility to EH in the Northern Han Chinese population.
doi:10.1038/jhh.2013.149
PMCID: PMC4133281  PMID: 24522342
leptin receptor; polymorphism; essential hypertension; Chinese; linkage disequilibrium; haplotypes
18.  Effects of Aspergillus Oryzae Culture and 2-Hydroxy-4-(Methylthio)-Butanoic Acid on In vitro Rumen Fermentation and Microbial Populations between Different Roughage Sources 
An in vitro experiment was conducted to evaluate the effects of Aspergillus oryzae culture (AOC) and 2-hydroxy-4-(methylthio)-butanoic acid (HMB) on rumen fermentation and microbial populations between different roughage sources. Two roughage sources (Chinese wild rye [CWR] vs corn silage [CS]) were assigned in a 2×3 factorial arrangement with HMB (0 or 15 mg) and AOC (0, 3, or 6 mg). Gas production (GP), microbial protein (MCP) and total volatile fatty acid (VFA) were increased in response to addition of HMB and AOC (p<0.01) for the two roughages. The HMB and AOC showed inconsistent effects on ammonia-N with different substrates. For CWR, neither HMB nor AOC had significant effect on molar proportion of individual VFA. For CS, acetate was increased (p = 0.02) and butyrate was decreased (p<0.01) by adding HMB and AOC. Increase of propionate was only occurred with AOC (p<0.01). Populations of protozoa (p≤0.03) and fungi (p≤0.02) of CWR were differently influenced by HMB and AOC. Percentages of F. succinogenes, R. albus, and R. flavefaciens (p<0.01) increased when AOC was added to CWR. For CS, HMB decreased the protozoa population (p = 0.01) and increased the populations of F. succinogenes and R. albus (p≤0.03). Populations of fungi, F. succinogenes (p = 0.02) and R. flavefacien (p = 0.03) were increased by adding AOC. The HMB×AOC interactions were noted in MCP, fungi and R. flavefacien for CWR and GP, ammonia-N, MCP, total VFA, propionate, acetate/propionate (A/P) and R. albus for CS. It is inferred that addition of HMB and AOC could influence rumen fermentation of forages by increasing the number of rumen microbes.
doi:10.5713/ajas.2013.13742
PMCID: PMC4150195  PMID: 25178372
Aspergillus Oryzae; 2-Hydroxy-4-(Methylthio)-Butanoic Acid; Chinese Wild Rye; Corn Silage; In vitro Rumen Fermentation; Microbial Population
19.  β2-AR-HIF-1α: A Novel Regulatory Axis for Stress-Induced Pancreatic Tumor Growth and Angiogenesis 
Shan, T. | Ma, J. | Ma, Q. | Guo, K. | Guo, J. | Li, X. | Li, W. | Liu, J. | Huang, C. | Wang, F. | Wu, E.
Current molecular medicine  2013;13(6):1023-1034.
The purpose of this study was to test the hypothesis that chronic stress in a negative social and psychological state plays a critical role in pancreatic cancer development and progression. In this study, we created a new stress model system to determine the effects of chronic stress on pancreatic cancer progression. Here, we show that chronic stress not only causes depression in mice, most likely attributed to an elevated level of epinephrine, but also induces pancreatic cancer progression. We provide evidence that the pancreatic cancer progression induced by chronic stress could be blocked to a significant degree by β2-AR inhibitor ICI118 551 or HIF-1α inhibitor 2-methoxyestradiol. Moreover, establishment of pancreatic cancer in mice exposed to chronic stress was accompanied by up-regulation of the expression of MMP-2, MMP-9, and VEGF, mediated by a HIF-1α-dependent β-AR signaling pathway. Our data suggest that the β2-AR-HIF-1α axis regulates stress-induced pancreatic tumor growth and angiogenesis. This study may have a therapeutic or preventive potential for the patients with pancreatic cancer who are especially prone to psychosocial stress challenges.
PMCID: PMC4104615  PMID: 23745588
Angiogenesis; β2-AR; HIF-1α; pancreatic cancer; regulatory axis; stress
21.  Should both iodised and non-iodised salt be made available in Chinese cities? A cross-sectional survey 
Yu, J | Liu, P | Liu, Y | Liu, S J | Sun, D J
BMJ Open  2014;4(7):e005397.
Objective
To contribute evidence relevant to the policy of supplying iodised salt (IS), non-iodised salt (NIS) or both in Chinese cities.
Design
Subnational telephone interview survey.
Setting
China.
Participants
Totally, 24 557 telephone numbers were dialled and 4833 citizens accepted the telephone interview. The telephone numbers were randomly selected by random digit dialling and a Mitofsky-Waksberg two-stage sampling method in 17 capital cities and 6 coastal cities from 17 iodine deficiency disorder (IDD)-eliminated provinces (municipalities).
Results
The 4833 citizens finished the telephone interview. Among them, 3738 (77.3%) citizens chose IS, 481 (10%) citizens chose NIS, and the others chose both IS and NIS. The citizens’ awareness rates of IDD and IDD preventive measures were 68.7% and 62.5%, respectively.
Conclusions
It is not a suitable time to supply IS and NIS simultaneously in the developed cities of China, but a pilot project may be conducted in the cities where IDD has been sustainably eliminated, there is strong awareness of IDD and the population can make informed decisions regarding IS. IDD health education should be further strengthened, especially regarding the potential for IQ damage.
doi:10.1136/bmjopen-2014-005397
PMCID: PMC4120298  PMID: 25015474
telephone interview; iodized salt; non-iodized salt; knowledge-attitude-practice; iodine deficiency disorders
22.  Temporal Multiscale Approach for Nanocarrier Motion with Simultaneous Adhesion and Hydrodynamic Interactions in Targeted Drug Delivery 
We present a fluctuating hydrodynamics approach and a hybrid approach combining fluctuating hydrodynamics with generalized Langevin dynamics to resolve the motion of a nanocarrier when subject to both hydrodynamic interactions and adhesive interactions. Specifically, using these approaches, we compute equilibrium probability distributions at constant temperature as well as velocity autocorrelation functions of the nanocarrier subject to thermal motion in a quiescent Newtonian fluid medium, when tethered by a harmonic spring force mimicking a tether due to a single receptor-ligand bond. We demonstrate that the thermal equipartition of translation, rotation, and spring degrees of freedom are preserved by our formalism while simultaneously resolving the nature of the hydrodynamic correlations. Additionally, we evaluate the potential of mean force (or free energy density) along a specified reaction coordinate to faciltate extensive conformational sampling of the nanocarrier motion. We show that our results are in excellent agreement with analytical results and Monte Carlo simulations, thereby validating our methodologies. The frameworks we have presented provide a comprehensive platform for temporal multiscale modeling of hydrodynamic and microscopic interactions mediating nanocarrier motion and adhesion in vascular targeted drug delivery.
doi:10.1016/j.jcp.2012.10.026
PMCID: PMC3706300  PMID: 23853388
23.  Correlation between microRNA-34a levels and lens opacity severity in age-related cataracts 
Eye  2013;27(7):883-888.
Purpose
MicroRNA 34a (miR-34a) is involved in regulating tissue senescence. However, the role of miR-34a in age-related cataracts is unclear. In this study, we evaluated the correlations among the severity of lens opacity, patient age, and miR-34a expression level in the lens epithelium of age-related cataracts for clarifying the role of miR-34a in the lens senescence.
Methods
This study was carried as a case control study in the Department of Ophthalmology, Taipei Veterans General Hospital, Taiwan. We recorded age of each patient at the time of their cataract surgery and information regarding lens opacity according to a modified version of the Lens Opacities Classification System III. Correlations among age, lens opacity, and miR-34a expression levels were evaluated.
Results
This study evaluated 110 patients with a mean age of 73.19 years (SD±10.2). Older patients had higher nuclear cataract (NC), cortical (C), and posterior subcapsular cataract (P) scores (one-way analysis of variance (ANOVA), P<0.05). miR-34a expression levels were significantly different between each age group (ANOVA post hoc Bonferroni's test, P<0.001), and there were moderate correlations between high NC, C, and P cataract scores and high miR-34a levels (Pearson correlation coefficient; R=0.606, 0.575, and 0.515, respectively).
Conclusions
The current study demonstrated positive correlations between high miR-34a levels and high lens opacity severity in NC, C, or P cataracts. These results suggest that miR-34a expression has a role in lens senescence.
doi:10.1038/eye.2013.90
PMCID: PMC3709404  PMID: 23661155
aging; cataract; microRNA; senescence
24.  Comparison of line-scanned and point-scanned dual-axis confocal microscope performance 
Optics letters  2013;38(24):5280-5283.
The point-scanned dual-axis confocal (PS-DAC) microscope has been shown to exhibit a superior capability to reject out-of-focus and multiply scattered light in comparison to its conventional single-axis counterpart. However, the slow frame rate (typically < 5 Hz) resulting from point-by-point data collection makes these systems vulnerable to motion artifacts. While video-rate point-scanned confocal microscopy is possible, a line-scanned dual-axis confocal (LS-DAC) microscope provides a simpler means of achieving high-speed imaging through line-by-line data collection, but sacrifices contrast due to a loss of confocality along one dimension. Here we evaluate the performance tradeoffs between a LS-DAC and PS-DAC microscope with identical spatial resolutions. Characterization experiments of the LS-DAC and PS-DAC microscopes with tissue phantoms, in reflectance mode, are shown to match results from Monte-Carlo scattering simulations of the systems. Fluorescence images of mouse brain vasculature, obtained using resolution-matched LS-DAC and PS-DAC microscopes, demonstrate the comparable performance of LS-DAC and PS-DAC microscopy at shallow depths.
PMCID: PMC4077180  PMID: 24322237
25.  High Energy Product Developed from Cobalt Nanowires 
Scientific Reports  2014;4:5345.
Cobalt nanowires with high aspect ratio have been synthesized via a solvothermal chemical process. Based on the shape anisotropy and orientation of the nanowire assemblies, a record high room-temperature coercivity of 10.6 kOe has been measured in Co nanowires with a diameter of about 15 nm and a mean length of 200 nm. As a result, energy product of the wires reaches 44 MGOe. It is discovered that the morphology uniformity of the nanowires is the key to achieving the high coercivity and high energy density. Nanowires of this type are ideal building blocks for future bonded, consolidated and thin film magnets with high energy density and high thermal stability.
doi:10.1038/srep05345
PMCID: PMC4061547  PMID: 24939036

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