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1.  Effect of hydrogen sulfide on inflammatory cytokines in acute myocardial ischemia injury in rats 
Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors.
PMCID: PMC4316979  PMID: 25667680
hydrogen sulfide; acute myocardial ischemia; rat; inflammatory factor
2.  Polymorphism of the low-density lipoprotein receptor-related protein 5 gene and fracture risk 
Several molecular epidemiological studies have been conducted to examine the association between low-density lipoprotein receptor-related proteins (LRP5) Ala1330Val polymorphism and fracture; however, the conclusions remained controversial. We therefore performed an extensive meta-analysis on 10 published studies with 184479 subjects. Electronic databases, including PubMed, Excerpta Medica Database (EMBASE), Cochrane, Elsevier Science Direct and China National Knowledge Infrastructure (CNKI) databases were searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. LRP5 Ala1330Val polymorphism was associated with a significantly increased risk of fracture (OR = 1.10; 95% CI, 1.06-1.14; I2 = 29%). We also found that this polymorphism increased fracture risk in Caucasians. In the subgroup analysis according to gender, women was significantly associated with risk of fracture. In the subgroup analysis by type of fracture, LRP5 Ala1330Val polymorphism showed increased osteoporotic fracture risk. In conclusion, this meta-analysis suggested that an increased risk of fracture was associated with the LRP5 Ala1330Val polymorphism.
PMCID: PMC4307457  PMID: 25664010
Fracture; low-density lipoprotein receptor-related protein; meta-analysis; polymorphism
3.  Optimal single-dose epidural neostigmine for postoperative analgesia after partial hepatectomy 
Indian Journal of Pharmacology  2014;46(6):613-616.
Neostigmine can produce analgesia by acting on the spinal cord. This study was to determine the optimal single-dose of epidural neostigmine for postoperative analgesia after partial hepatectomy.
Patients and Methods:
Twenty-six patients undergoing elective partial hepatectomy under general anesthesia combined with epidural block were studied. The dose of epidural neostigmine was determined using Dixon's up-and-down method, starting from neostigmine 100 μg with an interval of 25 μg. Thirty minutes after skin incision, a predetermined dose of neostigmine was injected via the epidural catheter. Each patient received 0.125% bupivacaine and fentanyl 2 μg/ml for patient controlled epidural analgesia (PCEA) after the operation. Assessment of analgesia quality was performed at 8 h and 24 h after the operation.
The ED50 of epidural neostigmine in combination with PCEA for satisfactory analgesia was 226.78 ± 33.20 μg. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg), respectively.
The ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg).
PMCID: PMC4264076  PMID: 25538332
Dixon's up-and-down method; neostigmine; optimal dose; postoperative analgesia; patient controlled epidural analgesia
4.  Real-Time Control of Uni-Directional Liquid Spreading on a Half-Cone Nanoshell Array 
Scientific Reports  2014;4:6751.
Half-cone nanoshell arrays, fabricated by a simple and efficient colloidal lithography method, enable uni-directional liquid spreading on their hydrophilic asymmetric nanostructured surface. The preferred direction of the liquid flow is reversed when the surface is made hydrophobic. Accordingly, poly(N-isopropyl-acrylamide) is polymerized onto the surface for in-site controlling the transition of liquid spreading direction via its temperature dependent hydrophobicity. Furthermore, we also explain theoretically, that the spreading direction on hexagonal nanocone arrays is independent of the lattice orientation and only depends on the slanting direction. The insights gained from this work offer new opportunities for smart microfluidics, water harvesting and making use of other wetting conditions on demand.
PMCID: PMC4208037  PMID: 25341416
5.  Layer-dependent Band Alignment and Work Function of Few-Layer Phosphorene 
Scientific Reports  2014;4:6677.
Using first-principles calculations, we study the electronic properties of few-layer phosphorene focusing on layer-dependent behavior of band gap, work function band alignment and carrier effective mass. It is found that few-layer phosphorene shows a robust direct band gap character, and its band gap decreases with the number of layers following a power law. The work function decreases rapidly from monolayer (5.16 eV) to trilayer (4.56 eV), and then slowly upon further increasing the layer number. Compared to monolayer phosphorene, there is a drastic decrease of hole effective mass along the ridge (zigzag) direction for bilayer phosphorene, indicating a strong interlayer coupling and screening effect. Our study suggests that 1). Few-layer phosphorene with a layer-dependent band gap and a robust direct band gap character is promising for efficient solar energy harvest. 2). Few-layer phosphorene outperforms monolayer counterpart in terms of a lighter carrier effective mass, a higher carrier density and a weaker scattering due to enhanced screening. 3). The layer-dependent band edges and work functions of few-layer phosphorene allow for modification of Schottky barrier with enhanced carrier injection efficiency. It is expected that few-layer phosphorene will present abundant opportunities for a plethora of new electronic applications.
PMCID: PMC4202206  PMID: 25327586
6.  Single nucleotide polymorphisms in VEGF gene are associated with an increased risk of osteosarcoma 
We aimed to assess whether the five common SNPs can affect the risk of osteosarcoma, and its association with demographic characteristics of osteosarcoma. 165 osteosarcoma patients and 330 cancer-free controls were enrolled into our study. Five common SNPs in VEGF gene, -2578C/A (rs699947), -1156G/A (rs1570360), +1612G/A (rs10434), +936C/T (rs3025039) and -634G/C (rs2010963), were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Conditional logistic regression analyses found that individuals with AA genotype and A allele of rs699947 were associated with an increased risk of osteosarcoma. Individuals with GG genotype and G allele of rs2010963 were associated with an increased risk of osteosarcoma. By stratified analysis, AA genotype of rs699947 was associated with an increased risk of osteosarcoma in those with shorter age, males and a family history of cancer, and GG genotype of rs2010963 was correlated with an increased risk of osteosarcoma in those with shorter age, females and a family history of cancer. Our study suggests that rs699947 and rs2010963 polymorphisms may play a role in the pathogenesis of osteosarcoma.
PMCID: PMC4270581  PMID: 25550863
Single nucleotide polymorphism; vascular endothelial growth factor; osteosarcoma
7.  Overexpression of hypoxia-inducible factor-1α and vascular endothelial growth factor in sacral giant cell tumors and the correlation with tumor microvessel density 
Although classified as benign, giant cell tumors of the bone (GCTB) may be aggressive, recur and even metastasize to the lungs. In addition, the pathogenesis and histogenesis remain unclear; thus, the driving factors behind the strong tumor growth capacity of GCTB require investigation. In the present study, the expression levels of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), which are promoted by hypoxic conditions, were determined in 22 sacral GCTB samples using immunohistochemistry and western blot analysis. Furthermore, CD34 expression was analyzed using these methods. The correlation between HIF-1α or VEGF expression and the tumor microvessel density (MVD) was then determined. The results demonstrated that HIF-1α, VEGF and CD34 were overexpressed in the 22 sacral GCTB specimens, and overexpression of HIF-1α and VEGF correlated with the tumor MVD. Thus, the present study has provided novel indicators for the tumor growth capacity of GCTBs.
PMCID: PMC4186367  PMID: 25289039
hypoxia inducible factor-1α; vascular endothelial growth factor; sacral giant cell tumors; microvessel density
8.  Induction of human chronic myeloid leukemia K562 cell apoptosis by virosecurinine and its molecular mechanism 
Molecular Medicine Reports  2014;10(5):2365-2371.
Virosecurinine is a major alkaloid of the plant Securinega suffruticosa and has been found to be a potent agent in inducing the differentiation of cancer cells. The present study aimed to investigate the antitumor effects of virosecurinine by inducing the apoptosis of leukemic K562 cells and to examine the underlying mechanisms. K562 cells were treated with different concentrations of virosecurinine (6.25, 12.5, 25, 50, 100 and 200 μmol/l) for 24, 48 and 72 h. The cell counting kit (CCK)-8 method was used to detect the antitumor effect of K562 cells in vitro. Flow cytometry was used to observe the apoptotic ratio and analyze the cell cycle following treatment with virosecurinine in K562 cells. Light and electron microscopy was used to identify morphological alterations in the virosecurinine-treated K562 cells. The mRNA levels of mammalian target of rapamycin (mTOR), SH2 domain-containing inositol-5′-phosphatase 2 (SHIP2), phosphatase and tensin homologue (PTEN) and breakpoint cluster region (BCR)/Abelson (ABL) were detected pre and post-virosecurinine treatment using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The generation depression effects of K562 cells cultured in vitro were detected using CCK-8 technology, which revealed a dose and time-dependent association. The IC50 was 32.984 μmol/l at 48 h. Flow cytometric analysis indicated that treatment with virosecurinine at concentrations of 6.25, 25 and 50 μmol/l increased the apoptotic rate of the K562 cells and caused G1/S phase arrest. RT-qPCR indicated that virosecurinine upregulated the gene expression of PTEN and downregulated the expression of mTOR, SHIP-2 and BCR/ABL in K562 cells. Virosecurinine inhibited the growth and proliferation of the K562 cell lines and induced apoptosis in K562 cells by affecting the expression of mTOR, SHIP2, BCR/ABL and PTEN.
PMCID: PMC4214351  PMID: 25189629
virosecurinine; apoptosis; mammalian target of rapamycin; SH2 domain-containing inositol-5′-phosphatase 2; phosphatase and tensin homologue; breakpoint cluster region/Abelson; chronic myeloid leukemia; K562 cells
9.  Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: Implications for HIV-1-associated neuropathology 
A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its ability to affact NMDAR-mediated excitatory postsynaptic currents (EPSCNMDAR) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSCNMDAR. In contrast, control (untreated) MCM had limited effects on EPSCNMDAR. Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSCNR2AR) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSCNR2BR) for MCM showed significant increased EPSCNR2BR when compared to EPSCNR2AR enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSCNMDAR evoked by stronger stimulations. This suggested that increase in EPSCNMDAR was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3kD) to medium (3-10kD) molecular weight mediated the observed increases in EPSCNMDAR. The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.
PMCID: PMC3740075  PMID: 23660833
HIV-1gp120; Macrophages; NMDA receptors; EPSC; Neurotoxicity
10.  Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance 
Journal of Virology  2014;88(17):9504-9513.
Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ∼1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nanoATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance.
IMPORTANCE The need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART concentrations in such sites enhances viral clearance. The current work uncovers a new mechanism by which nanoART can enhance viral clearance over native drug formulations.
PMCID: PMC4136325  PMID: 24920821
11.  Sick sinus syndrome associated with hypopituitarism: a case report and literature review 
Journal of Biomedical Research  2014;28(5):429-432.
Though an association between autoimmune diseases and sick sinus syndrome has been reported, there has been no report on the association of hypopituitarism and sick sinus syndrome. Herein, we provide the first case report of hypopituitarism accompanying sick sinus syndrome in a 51-year-old woman presented to our hospital with syncope due to cardiac arrest. The patient was successfully managed by pacemaker installation and hormone replacement therapy.
PMCID: PMC4197395  PMID: 25332716
sick sinus syndrome; hypopituitarism; obstetrical hemorrhage; Sheehan's syndorome
12.  Characterization of a Multiresistant Mosaic Plasmid from a Fish Farm Sediment Exiguobacterium sp. Isolate Reveals Aggregation of Functional Clinic-Associated Antibiotic Resistance Genes 
The genus Exiguobacterium can adapt readily to, and survive in, diverse environments. Our study demonstrated that Exiguobacterium sp. strain S3-2, isolated from marine sediment, is resistant to five antibiotics. The plasmid pMC1 in this strain carries seven putative resistance genes. We functionally characterized these resistance genes in Escherichia coli, and genes encoding dihydrofolate reductase and macrolide phosphotransferase were considered novel resistance genes based on their low similarities to known resistance genes. The plasmid G+C content distribution was highly heterogeneous. Only the G+C content of one block, which shared significant similarity with a plasmid from Exiguobacterium arabatum, fit well with the mean G+C content of the host. The remainder of the plasmid was composed of mobile elements with a markedly lower G+C ratio than the host. Interestingly, five mobile elements located on pMC1 showed significant similarities to sequences found in pathogens. Our data provided an example of the link between resistance genes in strains from the environment and the clinic and revealed the aggregation of antibiotic resistance genes in bacteria isolated from fish farms.
PMCID: PMC3911065  PMID: 24362420
13.  Concomitant depletion of PTEN and p27 and overexpression of cyclin D1 may predict a worse prognosis for patients with post-operative stage II and III colorectal cancer 
Oncology Letters  2014;8(4):1543-1550.
Prognostic markers for colorectal cancer (CRC) have not yet been fully investigated. Phosphatase and tensin homolog (PTEN), p27 and Cyclin D1 play significant roles in tumorigenesis and cell cycle regulation, and therefore require evaluation for their prognostic value in this disease. The aim of the present study was to assess the prognostic value of the single and combined expression of PTEN, p27 and Cyclin D1 in CRC patients. Protein expression levels of PTEN, p27 and Cyclin D1 were examined by immunohistochemistry from 61 patients with CRC in either stage II or III. In the CRC tissues, the frequencies of PTEN(−), p27(−) and Cyclin D1(+) expression were 42.62% (26/61), 32.79% (20/61) and 45.90% (28/61), respectively. Depletion of PTEN and p27 was more common with respect to stage III, low grade and lymph node metastasis compared with stage II, moderate grade and no lymph node metastasis (P<0.05). Cyclin D1-positive expression was frequently detected in CRC of stage III, with lymph node metastasis and deeper invasion (P<0.05). The depletion of PTEN was significantly correlated with the loss of p27 (P<0.001) and with the increased expression of Cyclin D1 (P<0.001). PTEN(−) and/or p27(−) expression was significantly correlated with Cyclin D1(+) expression (P<0.05). Combined PTEN(−)/p27(−)/Cyclin D1(+) expression was correlated with a significant decrease in overall survival time (P<0.05). Combined p27(−) and Cyclin D1(+) expression indicated a worse overall survival time than other combined expression patterns. These findings indicate that the single expression of PTEN(−), p27(−) and Cyclin D1(+) and the combined detection of p27(−) and Cyclin D1(+) may be used as prognostic markers for overall survival time in CRC.
PMCID: PMC4156215  PMID: 25202365
colorectal cancer; prognosis; PTEN; p27; cyclin D1
14.  A Bond-order Theory on the Phonon Scattering by Vacancies in Two-dimensional Materials 
Scientific Reports  2014;4:5085.
We theoretically investigate the phonon scattering by vacancies, including the impacts of missing mass and linkages () and the variation of the force constant of bonds associated with vacancies () by the bond-order-length-strength correlation mechanism. We find that in bulk crystals, the phonon scattering rate due to change of force constant is about three orders of magnitude lower than that due to missing mass and linkages . In contrast to the negligible in bulk materials, in two-dimensional materials can be 3–10 folds larger than . Incorporating this phonon scattering mechanism to the Boltzmann transport equation derives that the thermal conductivity of vacancy defective graphene is severely reduced even for very low vacancy density. High-frequency phonon contribution to thermal conductivity reduces substantially. Our findings are helpful not only to understand the severe suppression of thermal conductivity by vacancies, but also to manipulate thermal conductivity in two-dimensional materials by phononic engineering.
PMCID: PMC4035577  PMID: 24866858
15.  CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer’s disease 
Neurobiology of aging  2012;34(4):1060-1068.
Neuroinflammation affects the pathobiology of Alzheimer’s disease (AD). Notably, beta-amyloid (Aβ) deposition induces microglial activation and the subsequent production of pro-inflammatory neurotoxic factors. In maintaining brain homeostasis, microglia plasticity also enables phenotypic transition between toxic and trophic activation states. One important control for such cell activation is through the CC-chemokine ligand 2 (CCL2) and its receptor, the CC-chemokine receptor 2 (CCR2). Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood brain barrier. However, how CCL2-CCR2 signaling contributes to AD pathogenesis is not well understood. To this end, we report that CCL2 deficiency influences behavioral abnormalities and disease progression in Aβ precursor protein/presenilin-1 double-transgenic mice. Here, increased cortical and hippocampal Aβ deposition is coincident with the formulation of Aβ oligomers. Deficits in peripheral Aβ clearance and in scavenger, neuroprogenitor and microglial cell functions are linked to deficient Aβ uptake. All can serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis.
PMCID: PMC4011558  PMID: 23040664
Chemokine; Microglia; Phagocytosis; Memory function; Neurogenesis
16.  Comparison of the Inhibitory Potential of Bavachalcone and Corylin against UDP-Glucuronosyltransferases 
Bavachalcone and corylin are two major bioactive compounds isolated from Psoralea corylifolia L., which has been widely used as traditional Chinese medicine for many years. As two antibiotic or anticancer drugs, bavachalcone and corylin are used in combination with other drugs; thus it is necessary to evaluate potential pharmacokinetic herb-drug interactions (HDI) of the two bioactive compounds. The aim of the present study was to compare the effects of liver UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT1A7, UGT1A8, UGT 1A10, and UGT2B4 inhibited by bavachalcone and corylin. 4-Methylumbelliferone (4-MU) was used as a nonspecific “probe” substrate. Bavachalcone had stronger inhibition on UGT1A1 and UGT1A7 than corylin which did not inhibit UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A10, and UGT2B4. Data fitting using Dixon and Lineweaver-Burk plots demonstrated the noncompetitive inhibition of bavachalcone against UGT1A1 and UGT1A7-mediated 4-MU glucuronidation reaction. The values of inhibition kinetic parameters (Ki) were 5.41 μM and 4.51 μM for UGT1A1 and UGT1A7, respectively. The results of present study suggested that there was a possibility of UGT1A1 and UGT1A7 inhibition-based herb-drug interaction associated with bavachalcone and provided the basis for further in vivo studies to investigate the HDI potential between bavachalcone and UGT substrates.
PMCID: PMC4009204  PMID: 24829606
17.  Augmenting Multi-Instance Multilabel Learning with Sparse Bayesian Models for Skin Biopsy Image Analysis 
BioMed Research International  2014;2014:305629.
Skin biopsy images can reveal causes and severity of many skin diseases, which is a significant complement for skin surface inspection. Automatic annotation of skin biopsy image is an important problem for increasing efficiency and reducing the subjectiveness in diagnosis. However it is challenging particularly when there exists indirect relationship between annotation terms and local regions of a biopsy image, as well as local structures with different textures. In this paper, a novel method based on a recent proposed machine learning model, named multi-instance multilabel (MIML), is proposed to model the potential knowledge and experience of doctors on skin biopsy image annotation. We first show that the problem of skin biopsy image annotation can naturally be expressed as a MIML problem and then propose an image representation method that can capture both region structure and texture features, and a sparse Bayesian MIML algorithm which can produce probabilities indicating the confidence of annotation. The proposed algorithm framework is evaluated on a real clinical dataset containing 12,700 skin biopsy images. The results show that it is effective and prominent.
PMCID: PMC3997873  PMID: 24860817
18.  Fcγ Receptor-Mediated Inflammation Inhibits Axon Regeneration 
PLoS ONE  2014;9(2):e88703.
Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.
PMCID: PMC3921223  PMID: 24523933
19.  Complete Genome Sequence of Streptococcus pneumoniae Strain A026, a Clinical Multidrug-Resistant Isolate Carrying Tn2010 
Genome Announcements  2013;1(6):e01034-13.
Streptococcus pneumoniae is a primary cause of bacterial infection in humans. Here, we present the complete genome sequence of S. pneumoniae strain A026, which is a multidrug-resistant strain isolated from cerebrospinal fluid.
PMCID: PMC3861425  PMID: 24336372
20.  Polyhydroxylated Steroids from the South China Sea Soft Coral Sarcophyton sp. and Their Cytotoxic and Antiviral Activities 
Marine Drugs  2013;11(12):4788-4798.
Chemical investigation on the soft coral Sarcophyton sp. collected from the South China Sea yielded three new polyhydroxylated steroids, compounds (1–3), together with seven known ones (4–10). Their structures were established by extensive spectroscopic methods and comparison of their data with those of the related known compounds. All the isolates possessed the 3β,5α,6β-trihydroxylated steroidal nucleus. The cytotoxicities against selected HL-60, HeLa and K562 tumor cell lines and anti-H1N1 (Influenza A virus (IAV)) activities for the isolates were evaluated. Compounds 2, 3 and 5–8 exhibited potent activities against K562 cell lines with IC50 values ranging from 6.4 to 10.3 μM. Compounds 1, 6–8 potently inhibited the growth of HL-60 tumor cell lines, and 6 also showed cytotoxicity towards HeLa cell lines. In addition, preliminary structure-activity relationships for the isolates are discussed. The OAc group at C-11 is proposed to be an important pharmacophore for their cytotoxicities in the 3β,5α,6β-triol steroids. Compounds 4 and 9 exhibited significant anti-H1N1 IAV activity with IC50 values of 19.6 and 36.7 μg/mL, respectively.
PMCID: PMC3877887  PMID: 24317470
soft coral; Sarcophyton sp.; polyhydroxylated steroids; cytotoxicities; anti-H1N1 activity
21.  Impaired Spatial Learning and Memory after Sevoflurane–Nitrous Oxide Anesthesia in Aged Rats Is Associated with Down-Regulated cAMP/CREB Signaling 
PLoS ONE  2013;8(11):e79408.
Neurocognitive deficits arising from anesthetic exposure have recently been debated, while studies have shown that the phosphorylation of cyclic AMP response element-binding protein (CREB) in the hippocampus is critical for long-term memory. To better understand the neural effects of inhalational anesthetics, we studied the behavioral and biochemical changes in aged rats that were exposed to sevoflurane (Sev) and nitrous oxide (N2O) for 4 h. Eighteen-month-old rats were randomly assigned to receive 1.3% sevoflurane and 50% nitrous oxide/50% oxygen or 50% oxygen for 4 h. Spatial learning and memory were tested with the Morris water maze 48 h after exposure, and the results showed that sevoflurane–nitrous oxide exposure induced a significant deficit in spatial learning acquisition and memory retention. Experiments revealed that the cAMP and pCREB levels in the dorsal hippocampus were decreased in rats with anesthetic exposure in comparison with control rats 48 h after anesthesia as well as 15 min after the probe trial, but there were no significant differences in CREB expression. Besides these, the current study also found the DG neurogenesis significantly decreased as well as neuronal loss and neuronal apoptosis increased in the hippocampus of rats exposed to Sev+N2O. The current study demonstrated that down-regulation of cAMP/CREB signaling, decrease of CREB-dependent neurogenesis and neuronal survival in the hippocampus contributed to the neurotoxicity and cognitive dysfunction induced by general anesthesia with sevoflurane–nitrous oxide.
PMCID: PMC3829840  PMID: 24260214
22.  Automated skin biopsy histopathological image annotation using multi-instance representation and learning 
BMC Medical Genomics  2013;6(Suppl 3):S10.
With digitisation and the development of computer-aided diagnosis, histopathological image analysis has attracted considerable interest in recent years. In this article, we address the problem of the automated annotation of skin biopsy images, a special type of histopathological image analysis. In contrast to previous well-studied methods in histopathology, we propose a novel annotation method based on a multi-instance learning framework. The proposed framework first represents each skin biopsy image as a multi-instance sample using a graph cutting method, decomposing the image to a set of visually disjoint regions. Then, we construct two classification models using multi-instance learning algorithms, among which one provides determinate results and the other calculates a posterior probability. We evaluate the proposed annotation framework using a real dataset containing 6691 skin biopsy images, with 15 properties as target annotation terms. The results indicate that the proposed method is effective and medically acceptable.
PMCID: PMC3980401  PMID: 24565115
23.  Calcitonin gene-related peptide stimulates BMP-2 expression and the differentiation of human osteoblast-like cells in vitro 
Acta Pharmacologica Sinica  2013;34(11):1467-1474.
To investigate whether bone morphogenic protein-2 (BMP-2) expression was involved in calcitonin gene-related peptide (CGRP)-induced osteogenesis in human osteoblast-like cells in vitro.
MG-63 osteogenic human osteosarcoma cells were treated with CGRP (10-8 mol/L) for 48 h. Cell cycle phases were determined using flow cytometry assay. The protein levels of BMP-2, ALP, Osteocalcin, ColIa1, CREB, and pCREB were measured with Western blotting, while the mRNA level of BMP-2 was measured with qR-T PCR. The expression of ALP in MG-63 cells was also studied using immunofluorescence staining. The level of cAMP was measured with ELISA assay.
CGRP treatment significantly stimulated proliferation of MG-63 cells, and increased the expression of BMP-2 and the osteogenic proteins ALP, Osteocalcin and ColIa1. Pretreatment with the BMP signaling inhibitor Noggin (100 ng/mL) did not affect CGRP-stimulated proliferation and BMP-2 expression, but abolished the CGRP-induced increases of the osteogenic proteins ALP, Osteocalcin and ColIa1. Furthermore, CGRP treatment markedly increased cAMP level in MG-63 cells, whereas pretreatment with the cAMP pathway inhibitor H89 (5 μmol/L) abolished the CGRP-induced increases of cAMP level and BMP-2 expression.
In MG-63 cells, the BMP pathway is involved in CGRP-induced osteogenic differentiation but not in proliferation, whereas the cAMP/pCREB pathway is involved in the expression of BMP-2.
PMCID: PMC4006471  PMID: 23708553
calcitonin gene-related peptide; Noggin; H89; MG-63 human osteosarcoma cell; osteogenesis; bone morphogenic protein; cAMP/pCREB pathway
24.  Effect of admission time on mortality in an intensive care unit in Mainland China: a propensity score matching analysis 
Critical Care  2013;17(5):R230.
The relationship between admission time and intensive care unit (ICU) mortality is inconclusive and influenced by various factors. This study aims to estimate the effect of admission time on ICU outcomes in a tertiary teaching hospital in China by propensity score matching (PSM) and stratified analysis.
A total of 2,891 consecutive patients were enrolled in this study from 1 January 2009 to 29 December 2011. Multivariate logistic regression and survival analysis were performed in this retrospective study. PSM and stratified analysis were applied for confounding factors, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) score and admission types.
Compared with office hour subgroup (n = 2,716), nighttime (NT, n = 175) subgroup had higher APACHE II scores (14 vs. 8, P < 0.001), prolonged length of stay in the ICU (42 vs. 24 h, P = 0.011), and higher percentages of medical (8.6% vs. 3.3%, P < 0.001) and emergency (59.4% vs. 12.2%, P < 0.001) patients. Moreover, NT admissions were related to higher ICU mortality [odds ratio (OR), 1.725 (95% CI 1.118–2.744), P = 0.01] and elevated mortality risk at 28 days [14.3% vs. 3.2%; OR, 1.920 (95% CI 1.171–3.150), P = 0.01]. PSM showed that admission time remained related to ICU outcome (P = 0.045) and mortality risk at 28 days [OR, 2.187 (95% CI 1.119–4.271), P = 0.022]. However, no mortality difference was found between weekend and workday admissions (P = 0.849), even if weekend admissions were more related to higher APACHE II scores compared with workday admissions.
NT admission was associated with poor ICU outcomes. This finding may be related to shortage of onsite intensivists and qualified residents during NT. The current staffing model and training system should be improved in the future.
PMCID: PMC4055975  PMID: 24112558

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