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1.  Exploration on the Underlying Mechanism of Female Predominance in Spasmodic Dysphonia: An Anatomical Study of Nodose Ganglion in Rats 
To study the gender differences of amount of neurons in the nodose ganglions of rats. Fourteen Sprague–Dawley rats (7 males and 7 females) were selected. Bilateral nodose ganglions were dissected and serial sections of nodose ganglion were cut in a cryostat, followed by Cresyl-violet staining for neurons. Eight to ten consecutive sections from mid-portion of each nodose ganglion sample, which represent the most neuron number per section, were counted and averaged. Gender difference in the amount of neurons in the nodose ganglions was compared. No gender difference of neuron numbers was found in either side of nodose ganglion (p > 0.05). However, average neuron number of nodose ganglions on the left side of male (654 ± 60) and female (616 ± 37) were significantly more than that on the right side of male (470 ± 22) and female (453 ± 40) respectively (p < 0.05). There is no gender difference in total neuron number of nodose ganglions between male and female rat. However, the neuron number in the left nodose ganglion is greater than that in the right one. The difference may be due to the fact that left and right nodose ganglion is receiving different visceral sensory impulses separately, which is associated with different physiological functions. Further work should be carried out with retrograde tracing on neurons of nodose ganglions in an animal model, which are directly related to laryngeal sensory transmission, in order to determine the gender difference in the neuron number and morphology related to laryngeal functions.
doi:10.1007/s12070-012-0572-z
PMCID: PMC3938708  PMID: 24605297
Nodose ganglion; Neuron; Gender difference; Animal model; Cell counting; Spasmodic dysphonia
2.  Smad2 and Smad4 regulate TGF-β-mediated Il9 gene expression via EZH2 displacement* 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(10):10.4049/jimmunol.1300433.
IL-9 is a pro-allergic cytokine produced by a newly proposed T helper cell subset TH9. TH9 cells can be generated by treatment of naïve T cells with TGF-β and IL-4 in vitro. But how TGF-β signaling regulates TH9 differentiation is still not clear. Here we demonstrate that Smad2 and Smad4, two transcriptional factors activated by TGF-β signaling, are required for TH9 differentiation in vitro. Deficiency of Smad2 or Smad4 in T cells resulted in impaired IL-9 expression, which was coincident with enrichment of repressive chromatin modification H3K27Me3 and enhanced EZH2 binding to the Il9 locus. Pharmacologic inhibition of EZH2 partially rescued IL-9 production in Smad deficient TH9 cells. Smad proteins may displace EZH2 directly from Il9 locus since Smad2 and Smad4 can bind EZH2. Our data shed light on the molecular mechanisms underlying TH9 cell differentiation, revealing that TGF-β-Smad2/4 signaling pathway regulates IL-9 production through an epigenetic mechanism.
doi:10.4049/jimmunol.1300433
PMCID: PMC3842015  PMID: 24108699
3.  Epigenetic Regulation of TSP1/TGFβ/SMAD3 Autocrine Loop Determines Benign Tumor Stem Cell Fate in Ossifying Fibroma 
Cell stem cell  2013;13(5):10.1016/j.stem.2013.08.010.
Summary
Abnormal stem cell function contributes to tumorigenesis of many malignant tumors, but until now, the role of stem cells in benign tumor formation has remained elusive. Here we show that ossifying fibroma (OF) contains mesenchymal stem cells (OFMSCs), capable of generating OF-like tumor xenografts. Mechanistically, enhanced TGFβ signaling induces aberrant proliferation and deficient osteogenesis of OFMSCs via Notch and BMP signaling pathways, respectively. The elevated TGFβ activity is tightly regulated by JHDM1D-mediated epigenetic regulation of thrombospondin-1 (TSP1), forming a JHDM1D/TSP1/TGFβ/SMAD3 autocrine loop. Inhibition of TGFβ signaling in OFMSCs can rescue their abnormal osteogenic differentiation and elevated cell proliferation. Furthermore, normal MSCs, by chronic activation of TGFβ, can be converted to OF-like MSCs via establishment of the JHDM1D/TSP1/TGFβ/SMAD3 autocrine loop. These results reveal a novel mechanism of epigenetic regulation of TGFβ signaling in MSCs that determines benign tumor phenotype in OF neoplasm.
doi:10.1016/j.stem.2013.08.010
PMCID: PMC3861239  PMID: 24209761
4.  Smad3 Signaling Activates Bone Marrow-Derived Fibroblasts in Renal Fibrosis 
Recent studies have demonstrated that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblasts in the kidney are incompletely understood. Since TGF-β1/Smad3 signaling has been shown to play an important role in the pathogenesis of kidney fibrosis, we investigated the role of Smad3 in the activation of bone marrow-derived fibroblasts in the kidney following obstructive injury using Smad3 knockout mice and Smad3 null monocytes. Compared with wild-type mice, Smad3-knockout mice accumulated significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury. Furthermore, Smad3 knockout mice exhibited less myofibroblast activation and expressed less α-SMA in the obstructed kidney. Consistent with these findings, genetic deletion of Smad3 reduced total collagen deposition and suppressed expression of extracellular matrix proteins. Moreover, wild-type mice engrafted with Smad3−/− bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3+/+ bone marrow cells. In cultured monocytes, TGF-β1 induced phosphorylation of Smad3 and Smad3 deficiency abolished TGF-β1-induced expression of α-SMA and extracellular matrix proteins. Taken together, our results demonstrate that Smad3 signaling plays an essential role in the activation of bone marrow-derived fibroblasts in the kidney during the pathogenesis of renal fibrosis.
doi:10.1038/labinvest.2014.43
PMCID: PMC4006302  PMID: 24614197
Cytokine; Bone marrow-derived cells; Fibroblasts; Renal Fibrosis; Extracellular matrix; Chronic kidney disease
5.  TGF-β induction of FGF-2 expression in stromal cells requires integrated smad3 and MAPK pathways 
Transforming Growth Factor-β (TGF-β) regulates the reactive stroma microenvironment associated with most carcinomas and mediates expression of many stromal derived factors important for tumor progression, including FGF-2 and CTGF. TGF-β is over-expressed in most carcinomas, and FGF-2 action is important in tumor-induced angiogenesis. The signaling mechanisms of how TGF-β regulates FGF-2 expression in the reactive stroma microenvironment are not understood. Accordingly, we have assessed key signaling pathways that mediate TGF-β1-induced FGF-2 expression in prostate stromal fibroblasts and mouse embryo fibroblasts (MEFs) null for Smad2 and Smad3. TGF-β1 induced phosphorylation of Smad2, Smad3, p38 and ERK1/2 proteins in both control MEFs and prostate fibroblasts. Of these, Smad3, but not Smad2 was found to be required for TGF-β1 induction of FGF-2 expression in stromal cells. ChIP analysis revealed a Smad3/Smad4 complex was associated with the -1.9 to -2.3 kb upstream proximal promoter of the FGF-2 gene, further suggesting a Smad3-specific regulation. In addition, chemical inhibition of p38 or ERK1/2 MAPK activity also blocked TGF-β1-induced FGF-2 expression in a Smad3-independent manner. Conversely, inhibition of JNK signaling enhanced FGF-2 expression. Together, these data indicate that expression of FGF-2 in fibroblasts in the tumor stromal cell microenvironment is coordinately dependent on both intact Smad3 and MAP kinase signaling pathways. These pathways and key downstream mediators of TGF-β action in the tumor reactive stroma microenvironment, may evolve as putative targets for therapeutic intervention.
PMCID: PMC4219310  PMID: 25374926
Tumor microenvironment; TGF-β; signaling pathway; FGF-2; promoter regulation
6.  Two-Year Predictors of Runaway and Homeless Episodes Following Shelter Services among Substance Abusing Adolescents 
Journal of adolescence  2013;36(5):787-795.
Given high levels of health and psychological costs associated with the family disruption of homelessness, identifying predictors of runaway and homeless episodes is an important goal. The current study followed 179 substance abusing, shelter-recruited adolescents who participated in a randomized clinical trial. Predictors of runaway and homeless episodes were examined over a two year period. Results from the hierarchical linear modeling analysis showed that family cohesion and substance use, but not family conflict or depressive symptoms, delinquency, or school enrollment predicted future runaway and homeless episodes. Findings suggest that increasing family support, care and connection and reducing substance use are important targets of intervention efforts in preventing future runaway and homeless episodes amongst a high risk sample of adolescents.
doi:10.1016/j.adolescence.2013.06.007
PMCID: PMC3768003  PMID: 24011094
runaway shelter services; runaway and homeless adolescents; recidivism; substance abuse; family
7.  Imported Malaria in China, 2012 
Emerging Infectious Diseases  2014;20(10):1778-1780.
doi:10.3201/eid2010.140595
PMCID: PMC4193180  PMID: 25279813
malaria; imported malaria; parasites; Plasmodium species; workers; China
8.  Nanouric acid or nanocalcium phosphate as central nidus to induce calcium oxalate stone formation: a high-resolution transmission electron microscopy study on urinary nanocrystallites 
Purpose
This study aimed to accurately analyze the relationship between calcium oxalate (CaOx) stone formation and the components of urinary nanocrystallites.
Method
High-resolution transmission electron microscopy (HRTEM), selected area electron diffraction, fast Fourier transformation of HRTEM, and energy dispersive X-ray spectroscopy were performed to analyze the components of these nanocrystallites.
Results
The main components of CaOx stones are calcium oxalate monohydrate and a small amount of dehydrate, while those of urinary nanocrystallites are calcium oxalate monohydrate, uric acid, and calcium phosphate. The mechanism of formation of CaOx stones was discussed based on the components of urinary nanocrystallites.
Conclusion
The formation of CaOx stones is closely related both to the properties of urinary nanocrystallites and to the urinary components. The combination of HRTEM, fast Fourier transformation, selected area electron diffraction, and energy dispersive X-ray spectroscopy could be accurately performed to analyze the components of single urinary nanocrystallites. This result provides evidence for nanouric acid and/or nanocalcium phosphate crystallites as the central nidus to induce CaOx stone formation.
doi:10.2147/IJN.S66000
PMCID: PMC4172125  PMID: 25258530
nanocrystallites; calcium oxalate stones; heterogeneous nucleation; HRTEM; EDS
9.  Multiscale geometric modeling of macromolecules II: Lagrangian representation 
Journal of computational chemistry  2013;34(24):10.1002/jcc.23364.
Geometric modeling of biomolecules plays an essential role in the conceptualization of biolmolecular structure, function, dynamics and transport. Qualitatively, geometric modeling offers a basis for molecular visualization, which is crucial for the understanding of molecular structure and interactions. Quantitatively, geometric modeling bridges the gap between molecular information, such as that from X-ray, NMR and cryo-EM, and theoretical/mathematical models, such as molecular dynamics, the Poisson-Boltzmann equation and the Nernst-Planck equation. In this work, we present a family of variational multiscale geometric models for macromolecular systems. Our models are able to combine multiresolution geometric modeling with multiscale electrostatic modeling in a unified variational framework. We discuss a suite of techniques for molecular surface generation, molecular surface meshing, molecular volumetric meshing, and the estimation of Hadwiger’s functionals. Emphasis is given to the multiresolution representations of biomolecules and the associated multiscale electrostatic analyses as well as multiresolution curvature characterizations. The resulting fine resolution representations of a biomolecular system enable the detailed analysis of solvent-solute interaction, and ion channel dynamics, while our coarse resolution representations highlight the compatibility of protein-ligand bindings and possibility of protein-protein interactions.
doi:10.1002/jcc.23364
PMCID: PMC3760017  PMID: 23813599
Variational multiscale modeling; Multiresolution surface; Energy functional; Meshing; Curvature; Electrostatics
10.  A case report on nephrotic syndrome associated with ankylosing spondylitis effectively treated with infliximab 
Renal abnormalities have been reported to occur in patients with ankylosing spondylitis (AS). This study examined a patient who suffered from AS for two years. The 24-hour urine protein of the patient was 4.80 g/day. The result of renal biopsy showed minimal change. The patient was treated with infliximab. After two months, nephrotic syndrome was treated successfully.
PMCID: PMC4211814  PMID: 25356164
Ankylosing spondylitis; nephrotic syndrome; infliximab
11.  Specific Humoral Immune Response Induced by Propionibacterium acnes Can Prevent Actinobacillus pleuropneumoniae Infection in Mice 
Porcine contagious pleuropneumonia, caused by Actinobacillus pleuropneumoniae, has a major impact on economics, ecology, and animal welfare in the pig-rearing industry. Propionibacterium acnes, a facultative anaerobic Gram-positive corynebacterium, exists widely in normal healthy adult animals. We have shown previously that P. acnes can prevent A. pleuropneumoniae infections in mice and pigs. To elucidate the mechanism of this effect and to identify novel A. pleuropneumoniae vaccines, the role of anti-P. acnes antibodies in preventing infection was analyzed by indirect immunofluorescence and opsonophagocytosis assays in vitro. The role of the specific humoral immune response induced by P. acnes was confirmed in a B cell depletion mouse model. The survival rates of mice challenged with A. pleuropneumoniae exhibited a highly significant positive rank correlation with the levels of anti-P. acnes antibodies. The specific antibodies induced by P. acnes had the ability to combine with A. pleuropneumoniae and increase opsonization of A. pleuropneumoniae for phagocytosis. Furthermore, analysis in the murine B cell depletion model confirmed that the humoral immune response induced by P. acnes played an important role in resistance to A. pleuropneumoniae infection. In this study, we further elucidated the reasons that P. acnes can prevent A. pleuropneumoniae infection, which provides useful evidence for the development of heterologous vaccines for the control of porcine contagious pleuropneumonia.
doi:10.1128/CVI.00667-13
PMCID: PMC3957672  PMID: 24429068
12.  Change in Parent- and Child-Reported Internalizing and Externalizing Behaviors among Substance Abusing Runaways: The Effects of Family and Individual Treatments 
Journal of youth and adolescence  2012;42(7):980-993.
Shelter-recruited adolescents are known to have high rates of substance abuse and co-occurring internalizing and externalizing problem behaviors. Many studies have documented these mental health concerns, but only a small number of studies have tested interventions that may be useful for ameliorating these vulnerabilities. The current study compared three empirically supported psychotherapy interventions, Motivational Interviewing (MI), the Community Reinforcement Approach (CRA), and Ecologically-Based Family Therapy (EBFT) with 179 substance abusing runaway adolescents (47% female, 74% minority) and their primary caretaker recruited through a Midwestern runaway crisis shelter. Examining both child and primary caretaker reports, each treatment was associated with significant reductions in internalizing and externalizing behaviors to 24 months post-baseline. However, the trajectory of change differed among the treatments. Adolescents receiving MI showed a quicker reduction in internalizing and externalizing behaviors but also a quicker increase in these behaviors compared to adolescents receiving EBFT, who continued to evidence improvements to 24 months. The findings provide support for continued evaluation of these treatments for use with this vulnerable population of adolescents.
doi:10.1007/s10964-012-9826-z
PMCID: PMC3543760  PMID: 23054350
13.  Aging-Related Geniohyoid Muscle Atrophy Is Related to Aspiration Status in Healthy Older Adults 
Background.
Age-related muscle weakness due to atrophy and fatty infiltration in orofacial muscles may be related to swallowing deficits in older adults. An important component of safe swallowing is the geniohyoid (GH) muscle, which helps elevate and stabilize the hyoid bone, thus protecting the airway. This study aimed to explore whether aging and aspiration in older adults were related to GH muscle atrophy and fatty infiltration.
Method.
Eighty computed tomography scans of the head and neck from 40 healthy older (average age 78 years) and 40 younger adults (average age 32 years) were analyzed. Twenty aspirators and 20 nonaspirators from the 40 older adults had been identified previously. Two-dimensional views in the sagittal and coronal planes were used to measure the GH cross-sectional area and fatty infiltration.
Results.
GH cross-sectional area was larger in men than in women (p < .05). Decreased cross-sectional area was associated with aging (p < .05), and cross-sectional area was significantly smaller in aspirators compared with nonaspirators, but only among the older men (p < .01). Increasing fatty infiltration was associated with aging in the middle (p < .05) and posterior (p < .01) portions of the GH muscle. There was no significant difference in fatty infiltration of the GH muscle among aspirators and nonaspirators.
Conclusion.
GH muscle atrophy was associated with aging and aspiration. Fatty infiltration in the GH muscle was increased with aging but not related to aspiration status. These findings suggest that GH muscle atrophy may be a component of decreased swallowing safety and aspiration in older adults and warrants further investigation.
doi:10.1093/gerona/gls225
PMCID: PMC3732109  PMID: 23112114
Atrophy; Geniohyoid muscle; Older adults; Fatty infiltration; Aspiration; Swallow; CT scans.
14.  COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis 
Nature  2012;493(7431):236-240.
Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer1–4. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire meta-static potential remaisns poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression5, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2)6–9, a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUPTFII as a potential drug target for the intervention of metastatic human prostate cancer.
doi:10.1038/nature11674
PMCID: PMC4022346  PMID: 23201680
15.  Structural and Biochemical Characterization Reveals LysGH15 as an Unprecedented “EF-Hand-Like” Calcium-Binding Phage Lysin 
PLoS Pathogens  2014;10(5):e1004109.
The lysin LysGH15, which is derived from the staphylococcal phage GH15, demonstrates a wide lytic spectrum and strong lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we find that the lytic activity of the full-length LysGH15 and its CHAP domain is dependent on calcium ions. To elucidate the molecular mechanism, the structures of three individual domains of LysGH15 were determined. Unexpectedly, the crystal structure of the LysGH15 CHAP domain reveals an “EF-hand-like” calcium-binding site near the Cys-His-Glu-Asn quartet active site groove. To date, the calcium-binding site in the LysGH15 CHAP domain is unique among homologous proteins, and it represents the first reported calcium-binding site in the CHAP family. More importantly, the calcium ion plays an important role as a switch that modulates the CHAP domain between the active and inactive states. Structure-guided mutagenesis of the amidase-2 domain reveals that both the zinc ion and E282 are required in catalysis and enable us to propose a catalytic mechanism. Nuclear magnetic resonance (NMR) spectroscopy and titration-guided mutagenesis identify residues (e.g., N404, Y406, G407, and T408) in the SH3b domain that are involved in the interactions with the substrate. To the best of our knowledge, our results constitute the first structural information on the biochemical features of a staphylococcal phage lysin and represent a pivotal step forward in understanding this type of lysin.
Author Summary
The staphylococcal phage lysin LysGH15 demonstrates great potential against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the lytic activity of LysGH15 and its CHAP domain is dependent on calcium ions. To elucidate the molecular mechanism, we determined the structures of three individual LysGH15 domains using X-ray crystallography or nuclear magnetic resonance (NMR). The crystal structure unexpectedly reveals an “EF-hand-like” calcium-binding site near the Cys-His-Glu-Asn quartet active site groove in the LysGH15 CHAP domain. Furthermore, the calcium ion plays an important role as a switch that modulates the lytic activity of the CHAP domain. Additionally, structure-guided mutagenesis also confirms that both E282 and the zinc ion play an important role in maintaining the lytic activity of the LysGH15 amidase-2 domain. Moreover, the NMR structure and titration-guided mutagenesis identify residues in the LysGH15 SH3b domain that are involved in the interactions with the substrate. The structure of LysGH15 is the first determined lysin structure from a staphylococcal phage, and these results represent a pivotal step forward in understanding this type of lysin.
doi:10.1371/journal.ppat.1004109
PMCID: PMC4022735  PMID: 24831957
16.  Force-Generation Capacity of Single Vastus Lateralis Muscle Fibers and Physical Function Decline With Age in African Green Vervet Monkeys 
Previous studies on the contractile properties of human myofibrils reported increase, decrease, or no change with aging, perhaps due to the differences in physical activity, diet, and other factors. This study examined physical performance and contractile characteristics of myofibrils of vastus lateralis (VL) muscle in young adult and old African green vervet monkeys. Animals were offered the same diet and lived in the same enclosures during development, so we were able to examine skeletal muscle function in vivo and in vitro with fewer potential confounding factors than are typical in human research studies. Fiber atrophy alone did not account for the age-related differences in specific force and maximal power output. Regression modeling used to identify factors contributing to lower fiber force revealed that age is the strongest predictor. Our results support a detrimental effect of aging on the intrinsic force and power generation of myofilament lattice and physical performance in vervet monkeys.
doi:10.1093/gerona/gls143
PMCID: PMC3566711  PMID: 22923428
Skeletal muscle; Physical function; Monkey; Aging
17.  The Posterior Cricoarytenoid Muscle Is Spared from MuRF1-Mediated Muscle Atrophy in Mice with Acute Lung Injury 
PLoS ONE  2014;9(1):e87587.
Background
Skeletal muscle wasting in acute lung injury (ALI) patients increases the morbidity and mortality associated with this critical illness. The contribution of laryngeal muscle wasting to these outcomes is unknown, though voice impairments and aspiration are common in intensive care unit (ICU) survivors. We evaluated the intrinsic laryngeal abductor (PCA, posterior cricoarytenoid), adductor (CT, cricothyroid) and limb (EDL, extensor digitorum longus) muscles in a mouse model of ALI.
Methods
Escherichia coli lipopolysaccharides were instilled into the lungs of adult male C57Bl6J mice (ALI mice). Limb and intrinsic laryngeal muscles were analyzed for fiber size, type, protein expression and myosin heavy chain (MyHC) composition by SDS-PAGE and mass spectroscopy.
Results
Marked muscle atrophy occurred in the CT and EDL muscles, while the PCA was spared. The E3 ubiquitin ligase muscle ring finger-1 protein (MuRF1), a known mediator of limb muscle atrophy in this model, was upregulated in the CT and EDL, but not in the PCA. Genetic inhibition of MuRF1 protected the CT and EDL from ALI-induced muscle atrophy. MyHC-Extraocular (MyHC-EO) comprised 27% of the total MyHC in the PCA, distributed as hybrid fibers throughout 72% of PCA muscle fibers.
Conclusion
The vocal cord abductor (PCA) contains a large proportion of fibers expressing MyHC-EO and is spared from muscle atrophy in ALI mice. The lack of MuRF1 expression in the PCA suggests a previously unrecognized mechanism whereby this muscle is spared from atrophy. Atrophy of the vocal cord adductor (CT) may contribute to the impaired voice and increased aspiration observed in ICU survivors. Further evaluation of the sparing of muscles involved in systemic wasting diseases may lead to potential therapeutic targets for these illnesses.
doi:10.1371/journal.pone.0087587
PMCID: PMC3909200  PMID: 24498144
18.  Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis 
A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β–induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3–mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β–induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β–induced invasion was not dependent on FOXM1’s transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.
doi:10.1172/JCI71104
PMCID: PMC3904622  PMID: 24382352
19.  Multiscale geometric modeling of macromolecules I: Cartesian representation 
Journal of computational physics  2014;257(Pt A):10.1016/j.jcp.2013.09.034.
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the polarized curvature, for the prediction of protein binding sites.
doi:10.1016/j.jcp.2013.09.034
PMCID: PMC3855405  PMID: 24327772
Protein characterization; Variational multiscale surfaces; Curvature analysis; High order geometric PDEs; Free energy functional; EMDataBank; Protein data bank
20.  Geometric modeling of subcellular structures, organelles, and multiprotein complexes 
SUMMARY
Recently, the structure, function, stability, and dynamics of subcellular structures, organelles, and multi-protein complexes have emerged as a leading interest in structural biology. Geometric modeling not only provides visualizations of shapes for large biomolecular complexes but also fills the gap between structural information and theoretical modeling, and enables the understanding of function, stability, and dynamics. This paper introduces a suite of computational tools for volumetric data processing, information extraction, surface mesh rendering, geometric measurement, and curvature estimation of biomolecular complexes. Particular emphasis is given to the modeling of cryo-electron microscopy data. Lagrangian-triangle meshes are employed for the surface presentation. On the basis of this representation, algorithms are developed for surface area and surface-enclosed volume calculation, and curvature estimation. Methods for volumetric meshing have also been presented. Because the technological development in computer science and mathematics has led to multiple choices at each stage of the geometric modeling, we discuss the rationales in the design and selection of various algorithms. Analytical models are designed to test the computational accuracy and convergence of proposed algorithms. Finally, we select a set of six cryo-electron microscopy data representing typical subcellular complexes to demonstrate the efficacy of the proposed algorithms in handling biomolecular surfaces and explore their capability of geometric characterization of binding targets. This paper offers a comprehensive protocol for the geometric modeling of subcellular structures, organelles, and multiprotein complexes.
doi:10.1002/cnm.2532
PMCID: PMC3568658  PMID: 23212797
macromolecules; geometric modeling; Laplace–Beltrami operator; high-order geometric PDEs; surface meshing; Gaussian curvature; mean curvature
21.  Atmospheric mercury inputs in montane soils increase with elevation: evidence from mercury isotope signatures 
Scientific Reports  2013;3:3322.
The influence of topography on the biogeochemical cycle of mercury (Hg) has received relatively little attention. Here, we report the measurement of Hg species and their corresponding isotope composition in soil sampled along an elevational gradient transect on Mt. Leigong in subtropical southwestern China. The data are used to explain orography-related effects on the fate and behaviour of Hg species in montane environments. The total- and methyl-Hg concentrations in topsoil samples show a positive correlation with elevation. However, a negative elevation dependence was observed in the mass-dependent fractionation (MDF) and mass-independent fractionation (MIF) signatures of Hg isotopes. Both a MIF (Δ199Hg) binary mixing approach and the traditional inert element method indicate that the content of Hg derived from the atmosphere distinctly increases with altitude.
doi:10.1038/srep03322
PMCID: PMC3839031  PMID: 24270081
22.  β3 Integrin Promotes TGF-β1/H2O2/HOCl-Mediated Induction of Metastatic Phenotype of Hepatocellular Carcinoma Cells by Enhancing TGF-β1 Signaling 
PLoS ONE  2013;8(11):e79857.
In addition to being an important mediator of migration and invasion of tumor cells, β3 integrin can also enhance TGF-β1 signaling. However, it is not known whether β3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of β3. Here we report that H2O2 and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-β1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HCC) cells. TGF-β1/H2O2/HOCl, but not TGF-β1 or H2O2/HOCl, induced β3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, β3 in turn promoted TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-β1 signaling. β3 promoted TGF-β1/H2O2/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-β1/H2O2/HOCl-induced expression of α3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, β3 enabled TGF-β1 to augment the promoting effect of H2O2/HOCl on anoikis-resistance of HCC cells. TGF-β1/H2O2/HOCl-induced metastatic phenotype was sufficient for HCC cells to extravasate from circulation and form metastatic foci in an experimental metastasis model in nude mice. Inhibiting the function of β3 could suppress or abrogate the promoting effects of TGF-β1/H2O2/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that β3 could function as a modulator to promote TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting β3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.
doi:10.1371/journal.pone.0079857
PMCID: PMC3832483  PMID: 24260309
23.  Mir-24 Regulates Junctophilin-2 Expression in Cardiomyocytes 
Circulation research  2012;111(7):837-841.
Rationale
Failing cardiomyocytes exhibit decreased efficiency of excitation-contraction (E-C) coupling. The down-regulation of junctophilin-2 (JP2), a protein anchoring the sarcoplasmic reticulum (SR) to T-tubules (TTs), has been identified as a major mechanism underlying the defective E-C coupling. However, the regulatory mechanism of JP2 remains unknown.
Objective
To determine whether microRNAs regulate JP2 expression.
Methods and Results
Bioinformatic analysis predicted two potential binding sites of miR-24 in the 3′-untranslated regions of JP2 mRNA. Luciferase assays confirmed that miR-24 suppressed JP2 expression by binding to either of these sites. In the aortic stenosis model, miR-24 was up-regulated in failing cardiomyocytes. Adenovirus-directed over-expression of miR-24 in cardiomyocytes decreased JP2 expression and reduced Ca2+ transient amplitude and E-C coupling gain.
Conclusions
MiR-24-mediated suppression of JP2 expression provides a novel molecular mechanism for E-C coupling regulation in heart cells, and suggests a new target against heart failure.
doi:10.1161/CIRCRESAHA.112.277418
PMCID: PMC3611051  PMID: 22891046
myocardial contractility; excitation-contraction coupling; heart failure; calcium signaling; heart failure
24.  Myosin Heavy Chain Isoform Expression in the Vastus Lateralis Muscle of Aging African Green Vervet Monkeys 
Experimental Gerontology  2012;47(8):601-607.
Non-human primates (NHP) represent an emerging animal model for the study of physical function, and provide opportunities for exploration of relationships of muscle biomolecular changes with age. One such primate model, the African green vervet monkey, has been used extensively in biomedical research but little is known regarding skeletal muscle composition, expression of myosin heavy chain (MHC) isoforms, and changes with age. In the present study we examined the effects of age on vastus lateralis (VL) muscle fiber-type composition, fiber cross-sectional area (CSA), and MHC isoforms expressed in 4 young and 4 older adult vervet monkeys. Proteomics analysis, using a human and nonhuman primate protein database, showed five MHC isoforms (I, IIA, IIX, IIB, and IIB′) expressed in female vervet VL muscle, which matched the human MHC isoforms. Fast type II fibers predominated and no pure type IIB or IIB′ containing fibers were detected. Hybrid fibers containing IIB/IIB′ MHC decreased in the old vervets. The CSA of both type I and type II fibers was significantly smaller in older vervet while type IIA fibers showed the most severity of atrophy. The decrease of fast MHC and atrophy of muscle fiber with aging recapitulate observations in human VL muscle. These findings, along with its homology of MHC between the vervet and human suggested that the vervet monkey may be a suitable preclinical model for understanding the cellular and molecular basis of sarcopenia and for developing new interventions to ameliorate the impact of disorders that affect skeletal muscle structure and function.
doi:10.1016/j.exger.2012.05.007
PMCID: PMC3389286  PMID: 22617406
myosin heavy chain; aging; non-human primate; vervet
25.  Students’ awareness of malaria at the beginning of national malaria elimination programme in China 
Malaria Journal  2013;12:237.
Background
In the battle against malaria in China, the rate of elementary and high school students’ awareness on malaria knowledge is an important index for malaria elimination, but only rare data is available. This study aimed to investigate the level of malaria awareness in students at elementary and high schools in malaria endemic areas of China, and to provide the baseline information for the malaria elimination.
Methods
This cross-sectional survey was conducted in 20 different malaria-endemic provinces in the first year of China’s National Malaria Elimination Programme (NMEP). A structured questionnaire was administrated to students at elementary and high schools enrolled. A total of 44,519 questionnaires were effective while 1,220 were excluded because of incomplete survey responses.
Results
More than 60% of students were aware of malaria, but only 9,013 of them answered correctly to all five questions, and there were still 1,862 students unaware of malaria. There were significant differences of the awareness of malaria among different age groups, between male and female, between two different education levels.
Discussion
The study reveals that students at elementary and high school levels did not have adequate knowledge of malaria about biology, pathogenicity, transmitting vectors and preventive methods and so on at the beginning of NMEP in China. Further emphasis should be paid on health education campaigns in China to increase students’ public awareness of malaria about vector control, treatment, prevention.
doi:10.1186/1475-2875-12-237
PMCID: PMC3723966  PMID: 23844969
Awareness; Malaria; Students; China

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