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1.  Effect of 2, 5-Substituents on the Stability of Cyclic Nitrone Superoxide Spin Adducts: A Density Functional Theory Approach 
Free radical research  2010;44(7):751-778.
To design efficient spin traps for superoxide radicals, interest in the elucidation of substituent effects on the stability of superoxide spin adducts has become a necessary priority. In the present study, five cyclic nitrone superoxide spin adducts, i.e. DMPO-OOH, M3PO-OOH, EMPO-OOH, DEPMPO-OOH, and DEPDMPO-OOH, were chosen as model compounds to investigate the effect of 2,5-subsitituents on their stability, through structural analysis and decay thermodynamics using density functional theory (DFT) calculations. Analysis of the optimized geometries reveals that none of the previously proposed stabilizing factors, including intramolecular H-bonds, intramolecular nonbonding interactions, bulky steric protection, nor the C(2)–N(1) bond distance can be used to clearly explain the effect of 2,5-substituents on the stability of the spin adducts. Additionally the effect of the 2,5-substituents on the stability of the superoxide spin adducts cannot be simply clarified by Milliken charges on both atoms (nitroxyl nitrogen and nitroxyl oxygen). Subsequent study found that spin densities on the nitroxyl nitrogen and oxygen are well correlated with the half-life times of the spin adducts, and consequently are the proper parameters to characterize the effect of 2,5-substituents on their stability. Examination of the decomposition thermodynamics further supports the effect of the substituents on the persistence of cyclic nitrone superoxide spin adducts.
doi:10.3109/10715761003758130
PMCID: PMC3074479  PMID: 20370568
2.  Tension Sensing Nanoparticles for Mechano-imaging at the Living Non-living Interface 
Studying chemo-mechanical coupling at interfaces is important for fields ranging from lubrication and tribology to microfluidics and cell biology. Several polymeric macro- and microscopic systems and cantilevers have been developed to image forces at interfaces, but few materials are amenable for molecular tension sensing. To address this issue, we have developed a gold nanoparticle sensor for molecular tension-based fluorescence microscopy (MTFM). As a proof of concept, we imaged the tension exerted by integrin receptors at the interface between living cells and a substrate with high spatial (<1 μm) resolution, at 100 ms acquisition times, and with molecular specificity. We report integrin tension values ranging from 1 to 15 pN and a mean of ~1 pN within focal adhesions. Through the use of a conventional fluorescence microscope, this method demonstrates a force sensitivity that is three orders of magnitude greater than is achievable by traction force microscopy or PDMS micro-post arrays,1 which are the standard in cellular biomechanics.
doi:10.1021/ja401494e
PMCID: PMC3630457  PMID: 23495954
3.  Morphology, Molecular Genetics, and Bioacoustics Support Two New Sympatric Xenophrys Toads (Amphibia: Anura: Megophryidae) in Southeast China 
PLoS ONE  2014;9(4):e93075.
Given their recent worldwide declines and extinctions, characterization of species-level diversity is of critical importance for large-scale biodiversity assessments and conservation of amphibians. This task is made difficult by the existence of cryptic species complexes, species groups comprising closely related and morphologically analogous species. The combination of morphology, genetic, and bioacoustic analyses permits robust and accurate species identification. Using these methods, we discovered two undescribed Xenophrys species, namely Xenophrys lini sp. nov. and Xenophrys cheni sp. nov. from the middle range of Luoxiao Mountains, southeast China. These two new species can be reliably distinguished from other known congeners by morphological and morphometric differences, distinctness in male advertisement calls, and substantial genetic distances (>3.6%) based on the mitochondrial 16s and 12s rRNA genes. The two new species, together with X. jinggangensis, are sympatric in the middle range of Luoxiao Mountains but may be isolated altitudinally and ecologically. Our study provides a first step to help resolve previously unrecognized cryptic biodiversity and provides insights into the understanding of Xenophrys diversification in the mountain complexes of southeast China.
doi:10.1371/journal.pone.0093075
PMCID: PMC3979665  PMID: 24714161
4.  Epoxyeicosatrienoic Acids Attenuating Hypotonic-Induced Apoptosis of IMCD Cells via γ-ENaC Inhibition 
PLoS ONE  2014;9(4):e94400.
Inner medulla collecting duct (IMCD) cells are the key part for urinary concentration. Hypotonic stress may trigger apoptosis of IMCD cells and induce renal injury. Epoxyeicosatrienoic acids (EETs) play an important role in anti-apoptosis, but their roles in hypotonic-induced apoptosis of IMCD cells are still unclear. Here we found increasing exogenous 11, 12-EET or endogenous EETs with Ad-CMV-CYP2C23-EGFP transfection decreased apoptosis of IMCD cells induced by hypotonic stress. Moreover, up-regulation of γ-ENaC induced by hypotonic stress was abolished by elevation of exogenous or endogenous EETs. Collectively, this study illustrated that EETs attenuated hypotonic-induced apoptosis of IMCD cells, and that regulation of γ-ENAC may be a possible mechanism contributing to the anti-apoptotic effect of EETs in response to hypotonic stress.
doi:10.1371/journal.pone.0094400
PMCID: PMC3979856  PMID: 24713619
5.  Finite element analysis of the pelvis after modular hemipelvic endoprosthesis reconstruction 
International Orthopaedics  2013;37(4):653-658.
Purpose
The aim of this study was to investigate the biomechanics of the pelvis reconstructed with a modular hemipelvic prosthesis using finite element (FE) analysis.
Methods
A three-dimensional FE model of the postoperative pelvis was developed and input into the Abaqus FEA software version 6.7.1. Mesh refinement tests were then performed and a force of 500 N was applied at the lamina terminalis of the fifth lumbar vertebra along the longitudinal axis of the normal pelvis and the postoperative pelvis for three positions: sitting, standing on two feet, and standing on the foot of the affected side. Stress distribution analysis was performed between the normal pelvis and postoperative pelvis at these three static positions.
Results
In the normal pelvis, stress distribution was concentrated on the superior area of the acetabulum, arcuate line, sacroiliac joint, sacral midline and, in particular, the superior area of the greater sciatic notch. In the affected postoperative hemipelvis, stress distribution was concentrated on the proximal area of the pubic plate, the top of the acetabular cup, the connection between the CS-fixator and acetabular cup and the fixation between the prosthesis and sacroiliac joint.
Conclusions
Stress distribution of the postoperative pelvis was similar to the normal pelvis at three different static positions. Reconstruction with a modular hemipelvic prosthesis yielded good biomechanical characteristics.
doi:10.1007/s00264-012-1756-6
PMCID: PMC3609974  PMID: 23318936
6.  A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization 
Nature structural & molecular biology  2013;20(10):1191-1198.
Germline mis-sense mutations affecting a single BRCA2 allele predispose humans to cancer. Here, we identify a protein-targeting mechanism disrupted by the cancer-associated mutation, BRCA2D2723H that controls the nuclear localization of BRCA2 and its cargo, the recombination enzyme RAD51. A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mis-localization of mutant BRCA2 inhibits the nuclear retention of RAD51, by exposing a similar NES in RAD51 usually obscured by the BRCA2-RAD51 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 in the nucleus. Interestingly, BRCA2D2723H decreases RAD51 nuclear retention even when wildtype BRCA2 is present. Our findings suggest a mechanism for regulation of the nucleo-cytoplasmic distribution of BRCA2 and RAD51, and for its impairment by a heterozygous disease-associated mutation.
doi:10.1038/nsmb.2666
PMCID: PMC3796201  PMID: 24013206
BRCA2; RAD51; nuclear localization; protein targeting; cancer predisposition; germline mutation
7.  FOXP3 Regulates Sensitivity of Cancer Cells to Irradiation by Transcriptional Repression of BRCA1 
Cancer research  2013;73(7):10.1158/0008-5472.CAN-12-2481.
FOXP3 is an X-linked tumor suppressor gene and a master regulator in T regulatory cell function. This gene has been found to be mutated frequently in breast and prostate cancers and to inhibit tumor cell growth, but its functional significance in DNA repair has not been studied. We found that FOXP3 silencing stimulates homologous recombination-mediated DNA repair and also repair of γ-irradiation-induced DNA damage. Expression profiling and chromatin-immunoprecipitation analyses revealed that FOXP3 regulated the BRCA1-mediated DNA repair program. Among 48 FOXP3-regulated DNA repair genes, BRCA1 and 12 others were direct targets of FOXP3 transcriptional control. Site-specific interaction of FOXP3 with the BRCA1 promoter repressed its transcription. Somatic FOXP3 mutants identified in breast cancer samples had reduced BRCA1 repressor activity, while FOXP3 silencing and knock-in of a prostate cancer-derived somatic FOXP3 mutant increased the radioresistance of cancer cells. Together our findings provide a missing link between FOXP3 function and DNA repair programs.
doi:10.1158/0008-5472.CAN-12-2481
PMCID: PMC3815443  PMID: 23319807
8.  Antagonistic Action of Bacillus subtilis Strain SG6 on Fusarium graminearum 
PLoS ONE  2014;9(3):e92486.
Fusarium graminearum causes Fusarium head blight (FHB), a devastating disease that leads to extensive yield and quality loss of wheat and barley. Bacteria isolated from wheat kernels and plant anthers were screened for antagonistic activity against F. graminearum. Based on its in vitro effectiveness, strain SG6 was selected for characterization and identified as Bacillus subtilis. B. subtilis SG6 exhibited a high antifungal effect on the mycelium growth, sporulation and DON production of F. graminearum with the inhibition rate of 87.9%, 95.6% and 100%, respectively. In order to gain insight into biological control effect in situ, we applied B. subtilis SG6 at anthesis through the soft dough stage of kernel development in field test. It was revealed that B. subtilis SG6 significantly reduced disease incidence (DI), FHB index and DON (P≤0.05). Further, ultrastructural examination shows that B. subtilis SG6 strain induced stripping of F. graminearum hyphal surface by destroying the cellular structure. When hypha cell wall was damaged, the organelles and cytoplasm inside cell would exude, leading to cell death. The antifungal activity of SG6 could be associated with the coproduction of chitinase, fengycins and surfactins.
doi:10.1371/journal.pone.0092486
PMCID: PMC3961383  PMID: 24651513
9.  Tomographic imaging via spectral encoding of spatial frequency 
Optics Express  2013;21(6):7488-7504.
Three-dimensional optical tomographic imaging plays an important role in biomedical research and clinical applications. We introduce spectral tomographic imaging (STI) via spectral encoding of spatial frequency principle that not only has the capability for visualizing the three-dimensional object at sub-micron resolution but also providing spatially-resolved quantitative characterization of its structure with nanoscale accuracy for any volume of interest within the object. The theoretical basis and the proof-of-concept numerical simulations are presented to demonstrate the feasibility of spectral tomographic imaging.
doi:10.1364/OE.21.007488
PMCID: PMC3635700  PMID: 23546131
(170.6960) Tomography; (110.6955) Tomographic imaging; (110.1758) Computational imaging; (300.6300) Spectroscopy, Fourier transforms
10.  Bone plate composed of a ternary nano-hydroxyapatite/polyamide 66/glass fiber composite: biomechanical properties and biocompatibility 
An ideal bone plate for internal fixation of bone fractures should have good biomechanical properties and biocompatibility. In this study, we prepared a new nondegradable bone plate composed of a ternary nano-hydroxyapatite/polyamide 66/glass fiber (n-HA/PA66/GF) composite. A breakage area on the n-HA/PA66/GF plate surface was characterized by scanning electron microscopy. Its mechanical properties were investigated using bone-plate constructs and biocompatibility was evaluated in vitro using bone marrow-derived mesenchymal stem cells. The results confirmed that adhesion between the n-HA/PA66 matrix and the glass fibers was strong, with only a few fibers pulled out at the site of breakage. Fractures fixed by the n-HA/PA66/GF plate showed lower stiffness and had satisfactory strength compared with rigid fixation using a titanium plate. Moreover, the results with regard to mesenchymal stem cell morphology, MTT assay, Alizarin Red S staining, enzyme-linked immunosorbent assay, and reverse transcription polymerase chain reaction for alkaline phosphatase and osteocalcin showed that the n-HA/PA66/GF composite was suitable for attachment and proliferation of mesenchymal stem cells, and did not have a negative influence on matrix mineralization or osteogenic differentiation of mesenchymal stem cells. These observations indicate that the n-HA/PA66/GF plate has good biomechanical properties and biocompatibility, and may be considered a new option for internal fixation in orthopedic surgery.
doi:10.2147/IJN.S57353
PMCID: PMC3962318  PMID: 24669191
nano-hydroxyapatite; polyamide; glass fiber; biomechanics; biocompatibility
11.  SoyFN: a knowledge database of soybean functional networks 
Many databases for soybean genomic analysis have been built and made publicly available, but few of them contain knowledge specifically targeting the omics-level gene–gene, gene–microRNA (miRNA) and miRNA–miRNA interactions. Here, we present SoyFN, a knowledge database of soybean functional gene networks and miRNA functional networks. SoyFN provides user-friendly interfaces to retrieve, visualize, analyze and download the functional networks of soybean genes and miRNAs. In addition, it incorporates much information about KEGG pathways, gene ontology annotations and 3′-UTR sequences as well as many useful tools including SoySearch, ID mapping, Genome Browser, eFP Browser and promoter motif scan. SoyFN is a schema-free database that can be accessed as a Web service from any modern programming language using a simple Hypertext Transfer Protocol call. The Web site is implemented in Java, JavaScript, PHP, HTML and Apache, with all major browsers supported. We anticipate that this database will be useful for members of research communities both in soybean experimental science and bioinformatics.
Database URL: http://nclab.hit.edu.cn/SoyFN
doi:10.1093/database/bau019
PMCID: PMC3949006  PMID: 24618044
12.  Impact of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells 
JAMA ophthalmology  2014;132(2):226-228.
doi:10.1001/jamaophthalmol.2013.6030
PMCID: PMC3945104  PMID: 24357250
13.  Genome Sequence of Luteimonas huabeiensis HB-2, a Novel Species of Luteimonas with High Oil Displacement Efficiency 
Genome Announcements  2014;2(2):e00152-14.
Luteimonas huabeiensis HB-2 is a novel and newly isolated strain, which shows a superior property of oil displacement. Here, we present a 4.3-Mb assembly of its genome. The key genes for phospholipid and fatty acid metabolism were annotated, which are crucial for crude oil emulsification and recovery.
doi:10.1128/genomeA.00152-14
PMCID: PMC3945508  PMID: 24604652
14.  FOXP3: Genetic and Epigenetic Implications for Autoimmunity 
Journal of autoimmunity  2013;41:72-78.
FOXP3 plays an essential role in the maintenance of self-tolerance and, thus, in preventing autoimmune diseases. Inactivating mutations of FOXP3 cause immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. FOXP3-expressing regulatory T cells attenuate autoimmunity as well as immunity against cancer and infection. More recent studies demonstrated that FOXP3 is an epithelial cell-intrinsic tumor suppressor for breast, prostate, ovary and other cancers. Corresponding to its broad function, FOXP3 regulates a broad spectrum of target genes. While it is now well established that FOXP3 binds to and regulates thousands of target genes in mouse and human genomes, the fundamental mechanisms of its broad impact on gene expression remain to be established. FOXP3 is known to both activate and repress target genes by epigenetically regulating histone modifications of target promoters. In this review, we first focus on germline mutations found in the FOXP3 gene among IPEX patients, then outline possible molecular mechanisms by which FOXP3 epigenetically regulates its targets. Finally, we discuss clinical implications of the function of FOXP3 as an epigenetic modifier. Accumulating results reveal an intriguing functional convergence between FOXP3 and inhibitors of histone deacetylases. The essential epigenetic function of FOXP3 provides a foundation for experimental therapies against autoimmune diseases.
doi:10.1016/j.jaut.2012.12.004
PMCID: PMC3622774  PMID: 23313429
15.  Cytopenia and Autoimmune Diseases: a Vicious Cycle fueled by mTOR Dysregulation in Hematopoietic Stem Cells 
Journal of autoimmunity  2013;41:182-187.
A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases.
doi:10.1016/j.jaut.2012.12.011
PMCID: PMC3622805  PMID: 23375848
Cytopenia; homeostatic proliferation; CD24; mTOR; hematopoietic stem cells; autoimmune diseases; inflammatory cytokines; rapamycin
16.  Negative Pressure Wound Therapy Decreases Mortality in a Murine Model of Burn-Wound Sepsis Involving Pseudomonas aeruginosa Infection 
PLoS ONE  2014;9(2):e90494.
Background
The colonization of burn wounds by Pseudomonas aeruginosa can lead to septic shock, organ injuries, and high mortality rates. We hypothesized that negative pressure wound therapy (NPWT) would decrease invasion and proliferation of P. aeruginosa within the burn wound and reduce mortality.
Methods
Thermal injuries were induced in anesthetized mice, and P. aeruginosa was applied to the wound surface for 24 h. After removing the burn eschar and debridement, the animals were subjected to either NPWT or wet-to-dry (WTD) treatment protocols. The bacterial loads on the wound surface were assessed during 7 d of treatment, as were the concentrations of inflammatory cytokines in the peripheral blood samples. Survival was monitored daily for 14 d after burn induction. Finally, samples of wounded skin, lung, liver, and kidney were collected and subjected to histopathological examination.
Results
Applying P. aeruginosa to the burn wound surface led to sepsis. During early stages of treatment, NPWT reduced the mortality of the septic animals and levels of P. aeruginosa within the burn wound compared with WTD-treated animals. Circulating levels of cytokines and cytoarchitectural abnormalities were also significantly reduced via NPWT.
Conclusions
Our data indicate that NPWT inhibits the invasion and proliferation of P. aeruginosa in burn-wounded tissue and decreases early mortality in a murine model of burn-wound sepsis. These therapeutic benefits likely result from the ability of NPWT to decrease bacterial proliferation on the wound surface, reduce cytokine serum concentrations, and prevent damage to internal organs.
doi:10.1371/journal.pone.0090494
PMCID: PMC3938770  PMID: 24587379
17.  Involvement of KLF11 in Hepatic Glucose Metabolism in Mice via Suppressing of PEPCK-C Expression 
PLoS ONE  2014;9(2):e89552.
Background
Abnormal hepatic gluconeogenesis is related to hyperglycemia in mammals with insulin resistance. Despite the strong evidences linking Krüppel-like factor 11 (KLF11) gene mutations to development of Type 2 diabetes, the precise physiological functions of KLF11 in vivo remain largely unknown.
Results
In current investigation, we showed that KLF11 is involved in modulating hepatic glucose metabolism in mice. Overexpression of KLF11 in primary mouse hepatocytes could inhibit the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase (cytosolic isoform, PEPCK-C) and peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), subsequently decreasing the cellular glucose output. Diabetic mice with overexpression of KLF11 gene in livers significantly ameliorated hyperglycemia and glucose intolerance; in contrast, the knockdown of KLF11 expression in db/m and C57BL/6J mice livers impaired glucose tolerance.
Conclusions
Our data strongly indicated the involvement of KLF11 in hepatic glucose homeostasis via modulating the expression of PEPCK-C.
doi:10.1371/journal.pone.0089552
PMCID: PMC3935883  PMID: 24586865
18.  Inferring consistent functional interaction patterns from natural stimulus FMRI data 
NeuroImage  2012;61(4):987-999.
There has been increasing interest in how the human brain responds to natural stimulus such as video watching in the neuroimaging field. Along this direction, this paper presents our effort in inferring consistent and reproducible functional interaction patterns under natural stimulus of video watching among known functional brain regions identified by task-based fMRI. Then, we applied and compared four statistical approaches, including Bayesian network modeling with searching algorithms: greedy equivalence search (GES), Peter and Clark (PC) analysis, independent multiple greedy equivalence search (IMaGES), and the commonly used Granger causality analysis (GCA), to infer consistent and reproducible functional interaction patterns among these brain regions. It is interesting that a number of reliable and consistent functional interaction patterns were identified by the GES, PC and IMaGES algorithms in different participating subjects when they watched multiple video shots of the same semantic category. These interaction patterns are meaningful given current neuroscience knowledge and are reasonably reproducible across different brains and video shots. In particular, these consistent functional interaction patterns are supported by structural connections derived from diffusion tensor imaging (DTI) data, suggesting the structural underpinnings of consistent functional interactions. Our work demonstrates that specific consistent patterns of functional interactions among relevant brain regions might reflect the brain's fundamental mechanisms of online processing and comprehension of video messages.
doi:10.1016/j.neuroimage.2012.01.142
PMCID: PMC3929522  PMID: 22440644
Natural stimulus fMRI; DTI; Functional interaction
19.  A New Expanded Mixed Element Method for Convection-Dominated Sobolev Equation 
The Scientific World Journal  2014;2014:297825.
We propose and analyze a new expanded mixed element method, whose gradient belongs to the simple square integrable space instead of the classical H(div; Ω) space of Chen's expanded mixed element method. We study the new expanded mixed element method for convection-dominated Sobolev equation, prove the existence and uniqueness for finite element solution, and introduce a new expanded mixed projection. We derive the optimal a priori error estimates in L2-norm for the scalar unknown u and a priori error estimates in (L2)2-norm for its gradient λ and its flux σ. Moreover, we obtain the optimal a priori error estimates in H1-norm for the scalar unknown u. Finally, we obtained some numerical results to illustrate efficiency of the new method.
doi:10.1155/2014/297825
PMCID: PMC3948468
20.  Nodal Promotes the Self-Renewal of Human Colon Cancer Stem Cells via an Autocrine Manner through Smad2/3 Signaling Pathway 
BioMed Research International  2014;2014:364134.
Colorectal cancer is one of the most common and fatal tumors. However, molecular mechanisms underlying carcinogenesis of colorectal cancer remain largely undefined. Here, we explored the expression and function of Nodal in colon cancer stem cells (CCSCs). Nodal and its receptors were present in numerous human colorectal cancer cell lines. NODAL and ALK-4 were coexpressed in human colon cancerous tissues, and NODAL, CD24, and CD44, markers for CCSCs, were expressed at higher levels in human colon cancerous tissues than adjacent noncancerous colon tissues. Human CCSCs were isolated by magnetic activated cell sorting using anti-CD24 and anti-CD44. Nodal transcript and protein were hardly detectable in CD44- or CD24-negative human colorectal cancer cell lines, whereas Nodal and its receptors were present in CCSCs. Notably, Nodal facilitated spheroid formation of human CCSCs, and phosphorylation of Smad2 and Smad3 was activated by Nodal in cells of spheres derived from human CCSCs. Collectively, these results suggest that Nodal promotes the self-renewal of human CCSCs and mediate carcinogenesis of human colorectal cancer via an autocrine manner through Smad2/3 pathway. This study provides a novel insight into molecular mechanisms controlling fate of human CCSCs and offers new targets for gene therapy of human colorectal cancer.
doi:10.1155/2014/364134
PMCID: PMC3947734
21.  Detecting and understanding genetic and structural features in HIV-1 B subtype V3 underlying HIV-1 co-receptor usage 
Bioinformatics  2013;29(4):451-460.
Motivation: To define V3 genetic elements and structural features underlying different HIV-1 co-receptor usage in vivo.
Results: By probabilistically modeling mutations in the viruses isolated from HIV-1 B subtype patients, we present a unique statistical procedure that would first identify V3 determinants associated with the usage of different co-receptors cooperatively or independently, and then delineate the complicated interactions among mutations functioning cooperatively. We built a model based on dual usage of CXCR4 and CCR5 co-receptors. The molecular basis of our statistical predictions is further confirmed by phenotypic and molecular modeling analyses. Our results provide new insights on molecular basis of different HIV-1 co-receptor usage. This is critical to optimize the use of genotypic tropism testing in clinical practice and to obtain molecular-implication for design of vaccine and new entry-inhibitors.
Contact: jing.zhang.jz349@yale.edu or cf.perno@uniroma2.it
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt002
PMCID: PMC3570207  PMID: 23297034
22.  Transmission-Blocking Antibodies against Mosquito C-Type Lectins for Dengue Prevention 
PLoS Pathogens  2014;10(2):e1003931.
C-type lectins are a family of proteins with carbohydrate-binding activity. Several C-type lectins in mammals or arthropods are employed as receptors or attachment factors to facilitate flavivirus invasion. We previously identified a C-type lectin in Aedes aegypti, designated as mosquito galactose specific C-type lectin-1 (mosGCTL-1), facilitating the attachment of West Nile virus (WNV) on the cell membrane. Here, we first identified that 9 A. aegypti mosGCTL genes were key susceptibility factors facilitating DENV-2 infection, of which mosGCTL-3 exhibited the most significant effect. We found that mosGCTL-3 was induced in mosquito tissues with DENV-2 infection, and that the protein interacted with DENV-2 surface envelop (E) protein and virions in vitro and in vivo. In addition, the other identified mosGCTLs interacted with the DENV-2 E protein, indicating that DENV may employ multiple mosGCTLs as ligands to promote the infection of vectors. The vectorial susceptibility factors that facilitate pathogen invasion may potentially be explored as a target to disrupt the acquisition of microbes from the vertebrate host. Indeed, membrane blood feeding of antisera against mosGCTLs dramatically reduced mosquito infective ratio. Hence, the immunization against mosGCTLs is a feasible approach for preventing dengue infection. Our study provides a future avenue for developing a transmission-blocking vaccine that interrupts the life cycle of dengue virus and reduces disease burden.
Author Summary
Dengue virus (DENV), a mosquito-borne flavivirus, is currently the most significant arbovirus afflicting tropical and sub-tropical countries worldwide. No vaccine or therapeutics are available, and dengue has rapidly spread over the last decade. Therefore, additional strategies to combat dengue are urgently needed. In this study, we characterized multiple C-type lectins as susceptibility factors for dengue infection in A. aegypti. These mosGCTLs directly interacted with dengue virus in vitro and in vivo. The combination of antisera against multiple mosGCTLs efficiently reduced DENV-2 infection after a blood meal, suggesting that it is feasible to develop a mosGCTL-based transmission-blocking vaccine to interrupt the life cycle of dengue virus and control disease burden in nature. This study substantially extends our understanding of dengue replication in vectors and provides a research avenue by which the development of therapeutics for preventing the dissemination of mosquito-borne viral diseases can be pursued in the future.
doi:10.1371/journal.ppat.1003931
PMCID: PMC3923773  PMID: 24550728
23.  Posterior short segment pedicle screw fixation and TLIF for the treatment of unstable thoracolumbar/lumbar fracture 
Background
Currently, Posterior Short Segment Pedicle Screw Fixation is a popular procedure for treating unstable thoracolumbar/lumbar burst fracture. But progressive kyphosis and a high rate of hardware failure because of lack of the anterior column support remains a concern. The efficacy of different methods remains debatable and each technique has its advantages and disadvantages.
Methods
A consecutive series of 20 patients with isolated thoracolumbar/lumbar burst fractures were treated by posterior short segment pedicle screw fixation and transforaminal thoracolumbar/lumbar interbody fusion (TLIF) between January 2005 and December 2007. All patients were followed up for a minimum of 2 years. Demographic data, neurologic status, anterior vertebral body heights, segmental Cobb angle and treatment-related complications were evaluated.
Results
The mean operative time was 167 minutes (range, 150–220). Blood loss was 450 ~ 1200 ml, an average of 820 ml. All patients recovered with solid fusion of the intervertebral bone graft, without main complications like misplacement of the pedicle screw, nerve or vessel lesion or hard ware failure. The post-operative radiographs demonstrated a good fracture reduction and it was well maintained until the bone graft fusion. Neurological recovery of one to three Frankel grade was seen in 14 patients with partial neurological deficit, three grades of improvement was seen in one patient, two grades of improvement was observed in 6 patients and one grade of improvement was found in 6 patients. All the 6 patients with no paraplegia on admission remained neurological intact, and in one patient with Frankel D on admission no improvement was observed.
Conclusion
Posterior short-segment pedicle fixation in conjunction with TLIF seems to be a feasible option in the management of selected thoracolumbar/lumbar burst fractures, thereby addressing all the three columns through a single approach with less trauma and good results.
doi:10.1186/1471-2474-15-40
PMCID: PMC3930337  PMID: 24517217
Short segment fixation; Thoracic vertebrae; Lumbar vertebrae; Unstable burst fractures; Pedicle screw; TLIF
24.  Investigation of nanoscale structural alterations of cell nucleus as an early sign of cancer 
BMC Biophysics  2014;7:1.
Background
The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 – 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis.
Results
Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations – spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis.
Conclusions
The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.
doi:10.1186/2046-1682-7-1
PMCID: PMC3928095  PMID: 24507508
25.  Study of Burn Scar Extraction Automatically Based on Level Set Method using Remote Sensing Data 
PLoS ONE  2014;9(2):e87480.
Burn scar extraction using remote sensing data is an efficient way to precisely evaluate burn area and measure vegetation recovery. Traditional burn scar extraction methodologies have no well effect on burn scar image with blurred and irregular edges. To address these issues, this paper proposes an automatic method to extract burn scar based on Level Set Method (LSM). This method utilizes the advantages of the different features in remote sensing images, as well as considers the practical needs of extracting the burn scar rapidly and automatically. This approach integrates Change Vector Analysis (CVA), Normalized Difference Vegetation Index (NDVI) and the Normalized Burn Ratio (NBR) to obtain difference image and modifies conventional Level Set Method Chan-Vese (C-V) model with a new initial curve which results from a binary image applying K-means method on fitting errors of two near-infrared band images. Landsat 5 TM and Landsat 8 OLI data sets are used to validate the proposed method. Comparison with conventional C-V model, OSTU algorithm, Fuzzy C-mean (FCM) algorithm are made to show that the proposed approach can extract the outline curve of fire burn scar effectively and exactly. The method has higher extraction accuracy and less algorithm complexity than that of the conventional C-V model.
doi:10.1371/journal.pone.0087480
PMCID: PMC3913612  PMID: 24503563

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