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1.  Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls 
Neuropsychopharmacology  2012;38(4):683-689.
The SNP rs2958182 was reported to be significantly associated with schizophrenia (SCZ) in Han Chinese. This study examined this SNP's associations with cognitive functions in 580 SCZ patients and 498 controls. Cognitive functions were assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-RC), the Attention Network Task (ANT), the Stroop task, the dot pattern expectancy (DPX), task and the N-back working memory task. Results showed significant or marginally significant interaction effects between genotype and diagnosis status on IQ (P=0.011) and attention-related tasks (ie, the forward digit span of WAIS-RC, P=0.005; the ANT conflict effect; P=0.020, and its ratios over mean reaction time (RT), P=0.036; the Stroop conflict effect, P=0.032, and its ratios over mean RT, P=0.062; and the DPX task's error rate under the BX condition, P<0.001, and the error rate of BX minus the error rate of AY (BX−AY), P=0.002). There were no such interaction effects on the measures of working memory (all P-values >0.05). Further analysis of the significant genotype-by-diagnosis interactions showed that the risk (T) allele was associated with better performance on cognitive tasks in patients but with worse performance in controls. These results seem to indicate that the association between this SNP and selected cognitive functions may be of an inverted U-shaped pattern. Future research is needed to replicate these results and to explore the biochemical mechanisms behind this association.
PMCID: PMC3572466  PMID: 23249814
schizophrenia; attention; working memory; TCF4; polymorphism; biological psychiatry; cognition; intermediate phenotype; molecular genetics; psychiatry & behavioral sciences; schizophrenia; antipsychotics
2.  Ochracenoids A and B, Guaiazulene-Based Analogues from Gorgonian Anthogorgia ochracea Collected from the South China Sea 
Marine Drugs  2014;12(3):1569-1579.
Two new guaiazulene-based analogues, ochracenoids A (1) and B (2), along with four known analogues (3–6), were isolated from the gorgonian Anthogorgia ochracea collected from the South China Sea. The planar structures of the new compounds were elucidated by comprehensive spectroscopic data. The absolute configuration of 1 was determined as 3R by the comparison of TDDFT calculated electronic circular dichroism with its experimental spectrum. Compound 1 is a rare guaiazulene-based analogue possessing a unique C16 skeleton. The possible generation process of 1 through an intermolecular one-carbon-transfer reaction was also discussed. Compound 2 was previously described as a presumed intermediate involved in the biogenesis of anthogorgienes A and I. Compound 3 exhibited antiproliferative effects on the embryo development of zebrafish Danio rerio.
PMCID: PMC3967227  PMID: 24637960
gorgonian; Anthogorgia ochracea; guaiazulene-based analogue; antiproliferative effect; zebrafish embryo
3.  Use of Synthetic Isoprenoids to Target Protein Prenylation and Rho GTPases in Breast Cancer Invasion 
PLoS ONE  2014;9(2):e89892.
Dysregulation of Ras and Rho family small GTPases drives the invasion and metastasis of multiple cancers. For their biological functions, these GTPases require proper subcellular localization to cellular membranes, which is regulated by a series of post-translational modifications that result in either farnesylation or geranylgeranylation of the C-terminal CAAX motif. This concept provided the rationale for targeting farnesyltransferase (FTase) and geranylgeranyltransferases (GGTase) for cancer treatment. However, the resulting prenyl transferase inhibitors have not performed well in the clinic due to issues with alternative prenylation and toxicity. As an alternative, we have developed a unique class of potential anti-cancer therapeutics called Prenyl Function Inhibitors (PFIs), which are farnesol or geranyl-geraniol analogs that act as alternate substrates for FTase or GGTase. Here, we test the ability of our lead PFIs, anilinogeraniol (AGOH) and anilinofarnesol (AFOH), to block the invasion of breast cancer cells. We found that AGOH treatment effectively decreased invasion of MDA-MB-231 cells in a two-dimensional (2D) invasion assay at 100 µM while it blocked invasive growth in three-dimensional (3D) culture model at as little as 20 µM. Notably, the effect of AGOH on 3D invasive growth was phenocopied by electroporation of cells with C3 exotransferase. To determine if RhoA and RhoC were direct targets of AGOH, we performed Rho activity assays in MDA-MB-231 and MDA-MB-468 cells and found that AGOH blocked RhoA and RhoC activation in response to LPA and EGF stimulation. Notably, the geranylgeraniol analog AFOH was more potent than AGOH in inhibiting RhoA and RhoC activation and invasive growth. Interestingly, neither AGOH nor AFOH impacted 3D growth of MCF10A cells. Collectively, this study demonstrates that AGOH and AFOH dramatically inhibit breast cancer invasion, at least in part by blocking Rho function, thus, suggesting that targeting prenylation by using PFIs may offer a promising mechanism for treatment of invasive breast cancer.
PMCID: PMC3935959  PMID: 24587105
4.  Systematic Review of Evidence-Based Guidelines on Medication Therapy for Upper Respiratory Tract Infection in Children with AGREE Instrument 
PLoS ONE  2014;9(2):e87711.
To summarize recommendations of existing guidelines on the treatment of upper respiratory tract infections (URTIs) in children, and to assess the methodological quality of these guidelines.
We searched seven databases and web sites of relevant academic agencies. Evidence-based guidelines on pediatric URTIs were included. AGREE II was used to assess the quality of these guidelines. Two researchers selected guidelines independently and extracted information on publication years, institutions, target populations, recommendations, quality of evidence, and strength of recommendations. We compared the similarities and differences of recommendations and their strength. We also analyzed the reasons for variation.
Thirteen guidelines meeting our inclusion criteria were included. Huge differences existed among these 13 guidelines concerning the categorization of evidence and recommendations. Nearly all of these guidelines lacked the sufficient involvement of stake holders. Further, the applicability of these guidelines still needs to be improved. In terms of recommendations, penicillin and amoxicillin were suggested for group A streptococcal pharyngitis. Amoxicillin and amoxicillin-clavulanate were recommended for acute bacterial rhinosinusitis (ABRS). An observation of 2–3 days prior to antibiotic therapy initiation for mild acute otitis media (AOM) was recommended with amoxicillin as the suggested first choice agent. Direct evidence to support strong recommendations on the therapy for influenza is still lacking. In addition, the antimicrobial durations for pharyngitis and ABRS were still controversial. No consensus was reached for the onset of antibiotics for ABRS in children.
Future guidelines should use a consistent grading system for the quality of evidence and strength of recommendations. More effort needs to be paid to seek the preference of stake holders and to improve the applicability of guidelines. Further, there are still areas in pediatric URTIs that need more research.
PMCID: PMC3930557  PMID: 24586287
5.  Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells 
Oncogene  2012;32(32):3754-3764.
Rho signaling is increasingly recognized to contribute to invasion and metastasis. In this study, we discovered that metastasis-associated protein S100A4 interacts with the Rho binding domain (RBD) of Rhotekin, thus connecting S100A4 to the Rho pathway. GST pull-down and immunoprecipitation assays demonstrated that S100A4 specifically and directly binds to Rhotekin RBD, but not other Rho effector RBDs. S100A4 binding to Rhotekin is calcium-dependent and uses residues distinct from those bound by active Rho. Interestingly, we found that S100A4 and Rhotekin can form a complex with active RhoA. Using RNAi, we determined that suppression of both S100A4 and Rhotekin leads to loss of Rho-dependent membrane ruffling in response to EGF, an increase in contractile F-actin “stress” fibers, and blocked invasive growth in three-dimensional culture. Accordingly, our data suggest that interaction of S100A4 and Rhotekin permits S100A4 to complex with RhoA and switch Rho function from stress fiber formation to membrane ruffling to confer an invasive phenotype.
PMCID: PMC3525797  PMID: 22964635
Rho; Rhotekin; S100A4/metastasin; lamellipodia; invasive growth
6.  Draft Genome Sequence of the Filamentous Cyanobacterium Leptolyngbya sp. Strain Heron Island J, Exhibiting Chromatic Acclimation 
Genome Announcements  2014;2(1):e01166-13.
Leptolyngbya sp. strain Heron Island is a cyanobacterium exhibiting chromatic acclimation. However, this strain has strong interactions with other bacteria, making it impossible to obtain axenic cultures for sequencing. A protocol involving an analysis of tetranucleotide frequencies, G+C content, and BLAST searches has been described for separating the cyanobacterial scaffolds from those of its cooccurring bacteria.
PMCID: PMC3916487  PMID: 24503993
7.  Spinal cord quantitative MRI discriminates between disability levels in multiple sclerosis 
Neurology  2013;80(6):540-547.
The clinicoradiologic paradox, or disconnect between clinical and radiologic findings, is frequently encountered in multiple sclerosis (MS), particularly in the spinal cord (SC), where lesions are expected to cause clinical impairment. We aimed to assess whether quantitative diffusion tensor and magnetization transfer imaging measures in the SC can distinguish MS cases of comparable lesion burdens with high and low disability.
One hundred twenty-four patients with MS underwent 3-T cervical SC MRI and were categorized into 4 subgroups according to SC lesion count and disability level. Regions of interest circumscribed the SC cross-section axially between C3 and C4. Cross-sectional area, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ⊥), parallel diffusivity (λ‖), and magnetization transfer ratio (MTR) were calculated. Differences between patient subgroups were assessed using t tests and linear regression.
FA, MD, λ⊥, λ‖, MTR, and SC cross-sectional area were more abnormal in the high- vs low-disability subgroup of patients with low lesion counts (p < 0.05). MRI measures (except λ‖ and MTR) were more abnormal in the high- vs low-disability subgroup of patients with high lesion counts (p < 0.05). In age- and sex-adjusted comparisons of high- vs low-disability subgroups, all MRI measures retained differences in the low-lesion subgroup, except λ‖, whereas only FA, MD, and λ⊥ retained differences in the high-lesion subgroup.
In this cross-sectional study of patients with MS, quantitative MRI reflects clinically relevant differences beyond what can be detected by conventional MRI. Our findings support the utility of quantitative MRI in clinical settings, where accurate measurement of disease burden is becoming increasingly critical for assessing treatment efficacy.
PMCID: PMC3589285  PMID: 23325903
8.  HIV-1 Genetic Characteristics and Transmitted Drug Resistance among Men Who Have Sex with Men in Kunming, China 
PLoS ONE  2014;9(1):e87033.
Yunnan has been severely affected by HIV/AIDS in China. Recently, the reported prevalence of HIV-1 among men who have sex with men (MSM) in Yunnan was high in China. To monitor dynamic HIV-1 epidemic among Yunnan MSM, HIV-1 genetic characteristics and transmitted drug resistance (TDR) were investigated.
Blood samples from 131 newly HIV-1 diagnosed MSM were continuously collected at fixed sites from January 2010 to December 2012 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.
Multiple genotypes were identified among MSM in Kunming, including CRF01_AE (64.9%), CRF07_BC (25.2%), unique recombinant forms (URFs, 5.3%), subtype B (3.1%) and CRF08_BC (1.5%). CRF01_AE and CRF07_BC were the predominant strains. The mean of genetic distance within CRF01_AE were larger than that within CRF07_BC. The estimated introducing time of CRF01_AE in Yunnan MSM (1996.9) is earlier than that of CRF07_BC (2002.8). In this study, subtype B was first identified in Yunnan MSM. CRF08_BC seems to be the distinctive strain in Yunnan MSM, which was seldom found among MSM outside Yunnan. The proportion of URFs increased, which further contributed to genetic diversity among MSM. Strikingly, genetic relatedness was found among these strains with MSM isolates from multiple provinces, which suggested that a nationwide transmission network may exist. TDR-associated mutations were identified in 4.6% individuals. The multivariate analysis revealed that non-native MSM and divorced/widowed MSM were independently associated with a higher TDR rate.
This work revealed diverse HIV-1 genetics, national transmission networks and a baseline level of TDR in MSM. These findings enhance our understanding of the distribution and evolution of HIV-1 in MSM, and are valuable for developing HIV prevention strategies for MSM.
PMCID: PMC3906090  PMID: 24489829
9.  Association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) Polymorphisms and Graves' Disease Risk: A Meta-Analysis of 11 Case-Control Studies 
PLoS ONE  2014;9(1):e86077.
Data on the association between the interleukin-1 (IL-1) gene polymorphisms and Graves' disease (GD) risk were conflicting. A meta-analysis was undertaken to assess this association.
We searched for case-control studies investigating the association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk. We extracted data using standardized forms and calculated odds ratios (OR) with 95% confidence intervals (CI).
A total of 11 case-control studies were included in this meta-analysis. Available data indicated that the IL1B (-511) polymorphism was associated with GD risk in the overall populations (Caucasians and Asians) in homozygote model (TT vs. CC, OR = 0.86, 95% CI: 0.76–0.97, Pz = 0.015), but not in dominant and recessive models (TT+TC vs. CC: OR = 0.95, 95% CI: 0.81–1.12, Pz = 0.553 and TT vs. TC+CC: OR = 0.82, 95% CI: 0.60–1.12, Pz = 0.205, respectively). No association between the IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk was found in the overall populations in any of the genetic models. In subgroup analyses according to ethnicity, the IL1B (-511) polymorphism was associated with GD risk in Asians in recessive and homozygote models (TT vs. TC+CC: OR = 0.68, 95% CI: 0.55–0.84, Pz<0.001 and TT vs. CC: OR = 0.81, 95% CI: 0.70–0.93, Pz = 0.003, respectively), but not in dominant model (TT+TC vs. CC: OR = 0.92, 95% CI: 0.77–1.11, Pz = 0.389). No association between the IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk was indicated in Asians, and we found no association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk in Caucasians in any of the genetic models.
The IL1B (-511) polymorphism, but not the IL1B (+3954) and IL1RN (VNTR) polymorphisms was associated with GD risk in Asians. There was no association between these polymorphisms and GD risk in Caucasians.
PMCID: PMC3897612  PMID: 24465880
Optical coherence tomography (OCT) of the macular cube has become an increasingly important tool for investigating and managing retinal pathology. One important new area of investigation is the analysis of anatomic variably across a population. Such an analysis on the retina requires the construction of a normalized space, which is generally created through deformable registration of each subject into a common template. Unfortunately, state-of-the-art 3D registration tools fail to adequately spatially normalize retinal OCT images. This work proposes a new deformable registration algorithm for OCT images using the similarity between pairs of A-mode scans. First, a retinal OCT specific affine step is presented, which uses automated landmarks to perform global translations and individual rescaling of all the subject’s A-mode scans. Then, a deformable registration using regularized one-dimensional radial basis functions is applied to further align the retinal layers. Results on 15 subjects show the improved accuracy of this approach in comparison to state of the art methods with respect to registration for labeling. Additional results show the ability to generate stereotaxic spaces for retinal OCT.
PMCID: PMC3892764  PMID: 24443687
Optical coherence tomography; registration
11.  B=Basal Cell Carcinoma: Stressful Life Events and the Tumor Environment 
Archives of general psychiatry  2012;69(6):618-626.
Child emotional maltreatment can result in lasting immune dysregulation that may be heightened in the context of more recent life stress. Basal cell carcinoma (BCC) is the most common skin cancer, and the immune system plays a prominent role in tumor appearance and progression.
To address relationships among recent severe life events, childhood parental emotional maltreatment, depression, and messenger RNA (mRNA) coding for immune markers associated with BCC tumor progression/regression.
University medical center
We collected information about early parent-child experiences, severe life events in the last year as assessed by the Life Events and Difficulties Schedule (LEDS), depression, and mRNA for immune markers associated with BCC tumor progression/regression from BCC tumor patients.
91 BCC patients (ages 23–92) who had all had a previous BCC tumor.
Main Outcome Measures
The expression of four BCC tumor mRNA markers (CD25, CD3ε, ICAM-1, and CD68) that have been linked to BCC tumor progression/regression were assessed in BCC tumor biopsies.
Both maternal and paternal emotional maltreatment interacted with the occurrence of severe life events to predict the local immune response to the tumor (adjusted p=0.009, p=0.03, respectively). Among BCC patients who had experienced a severe life event within the past year, those who were emotionally maltreated by their mothers (p=0.007) or fathers (p=0.02) as children had a poorer immune response to the BCC tumor. Emotional maltreatment was unrelated to BCC immune responses among those who did not experience a severe life event. Depressive symptoms were not associated with the local tumor immune response.
Troubled early parent-child relationships, in combination with a severe life event in the past year, predicted immune responses to a BCC tumor. The immunoreactivity observed in BCCs and the surrounding stroma reflects an anti-tumor-specific immune response that can be altered by stress.
PMCID: PMC3890083  PMID: 22664550
12.  Phosphorylation at tyrosine 114 of Proliferating Cell Nuclear Antigen (PCNA) is required for adipogenesis in response to high fat diet 
Clonal proliferation is an obligatory component of adipogenesis. Although several cell cycle regulators are known to participate in the transition between pre-adipocyte proliferation and terminal adipocyte differentiation, how the core DNA synthesis machinery is coordinately regulated in adipogenesis remains elusive. PCNA (proliferating cell nuclear antigen) is an indispensable component for DNA synthesis during proliferation. Here we show that PCNA is subject to phosphorylation at the highly conserved tyrosine residue 114 (Y114). Replacing the Y114 residue with phenylalanine (Y114F), which is structurally similar to tyrosine but cannot be phosphorylated, does not affect normal animal development. However, when challenged with high fat diet, mice carrying homozygous Y114F alleles (PCNAF/F) are resistant to adipose tissue enlargement in comparison to wild-type (WT) mice. Mouse embryonic fibroblasts (MEFs) harboring WT or Y114F mutant PCNA proliferate at similar rates. However, when subjected to adipogenesis induction in culture, PCNAF/F MEFs are not able to re-enter the cell cycle and fail to form mature adipocytes, while WT MEFs undergo mitotic clonal expansion in response to the adipogenic stimulation, accompanied by enhanced Y114 phosphorylation of PCNA, and differentiate to mature adipocytes. Consistent with the function of Y114 phosphorylation in clonal proliferation in adipogenesis, fat tissues isolated from WT mice contain significantly more adipocytes than those isolated from PCNAF/F mice. This study identifies a critical role for PCNA in adipose tissue development, and for the first time identifies a role of the core DNA replication machinery at the interface between proliferation and differentiation.
PMCID: PMC3724334  PMID: 23201573
PCNA; tyrosine phosphorylation; adipogenesis; proliferation
13.  Cleavage of Anti-apoptotic Bcl-2 Family Members After TCR Stimulation Contributes to the Decision Between T Cell Activation and Apoptosis 
Engagement of the TCR induces activation-induced cell death (AICD) of T cells that have been previously stimulated. However, a portion of these T cells can survive and undergo further activation. The molecular mechanism that decides whether a T cell will live or die after TCR re-engagement is unclear. We found that crosslinking of TCR in pre-activated primary mouse T cells led to the cleavage of anti-apoptotic Bcl-2 and Bcl-xL in dying cells. Cleavage-resistant Bcl-2 and Bcl-xL were more efficient than their wild type counterparts in the inhibition of apoptosis in primary mouse T cells and in the H9 T cell line after TCR crosslinking. In contrast, the surviving T cells after TCR re-engagement displayed up-regulation of Bcl-xL, while knockdown of Bcl-xL promoted AICD. This indicates that caspase-mediated cleavage of anti-apoptotic Bcl-2 or Bcl-xL facilitates AICD in T cells, whereas up-regulation of Bcl-xL promotes T cell survival and allows further T cell activation. Our data suggest that cleavage of anti-apoptotic Bcl-2 and Bcl-xL contributes to the decision between T cell activation and apoptosis after TCR re-engagement.
PMCID: PMC3529753  PMID: 23203923
14.  Analyses of Programmed Cell Death in Dendritic Cells 
PMCID: PMC3576849  PMID: 23397388
15.  Optimization and effects of different culture conditions on growth of Halomicronema hongdechloris – a filamentous cyanobacterium containing chlorophyll f 
A chlorophyll f containing cyanobacterium, Halomicronema hongdechloris (H. hongdechloris) was isolated from a stromatolite cyanobacterial community. The extremely slow growth rate of H. hongdechloris has hindered research on this newly isolated cyanobacterium and the investigation of chlorophyll f-photosynthesis. Therefore, optimizing H. hongdechloris culture conditions has become an essential requirement for future research. This work investigated the effects of various culture conditions, essential nutrients and light environments to determine the optimal growth conditions for H. hongdechloris and the biosynthetic rate of chlorophyll f. Based on the total chlorophyll concentration, an optimal growth rate of 0.22 ± 0.02 day-1(doubling time: 3.1 ± 0.3 days) was observed when cells were grown under continuous illumination with far-red light with an intensity of 20 μE at 32°C in modified K + ES seawater (pH 8.0) with additional nitrogen and phosphor supplements. High performance liquid chromatography on H. hongdechloris pigments confirmed that chlorophyll a is the major chlorophyll and chlorophyll f constitutes ~10% of the total chlorophyll from cells grown under far-red light. Fluorescence confocal image analysis demonstrated changes of photosynthetic membranes and the distribution of photopigments in response to different light conditions. The total photosynthetic oxygen evolution yield per cell showed no changes under different light conditions, which confirms the involvement of chlorophyll f in oxygenic photosynthesis. The implications of the presence of chlorophyll f in H. hongdechloris and its relationship with the ambient light environment are discussed.
PMCID: PMC3934312  PMID: 24616731
cyanobacteria; chlorophyll a; chlorophyll f; Halomicronema hongdechloris (H. hongdechloris); light; photopigments
16.  Bcl-2 expression predicts sensitivity to chemotherapy in breast cancer: a systematic review and meta-analysis 
Numerous studies have yielded inconclusive results regarding the relationship between anti-apoptotic protein Bcl-2 expression and the sensitivity to chemotherapy in the patients with breast cancer. The purpose of the current study was therefore to elaborate their relationship.
Methods, findings
A total of 23 previously published eligible studies involving 2,467 cases were identified and included in this meta-analysis. Negative Bcl-2 expression was associated with good chemotherapy response in breast cancer patients (total objective response [OR]: risk ratio [RR] = 1.16, 95% confidence interval [CI] = 1.02-1.32, p = 0.026; total complete response [CR]: RR = 1.67, 95% CI = 1.24-2.24, p = 0.001; pathological CR: RR = 1.92, 95% CI = 1.38-2.69, p < 0.001). In further stratified analyses, this association remained for sub-groups of response in neoadjuvant chemotherapy setting, especially pathological CR. Besides, negative Bcl-2 expression was significantly associated with good OR and pathological CR in anthracycline-based chemotherapy subgroup. Furthermore, there were significant links between negative Bcl-2 expression and taxane-based chemotherapy with pathological CR, but not OR.
The results of the present meta-analysis suggest that Bcl-2 expression is a predictive factor for chemotherapy sensitivity in breast cancer patients. They could also potentially benefit further clinical treatment for breast cancers.
PMCID: PMC3922829  PMID: 24370277
Bcl-2; Breast cancer; Chemotherapy; Response
17.  Low Pressure Radio-Frequency Oxygen Plasma Induced Oxidation of Titanium – Surface Characteristics and Biological Effects 
PLoS ONE  2013;8(12):e84898.
This research was designed to investigate the effects of low pressure radio-frequency (RF) oxygen plasma treatment (OPT) on the surface of commercially pure titanium (CP-Ti) and Ti6Al4V. Surface topography, elemental composition, water contact angle, cell viability, and cell morphology were surveyed to evaluate the biocompatibility of titanium samples with different lengths of OP treating time.
Materials and Methods
CP-Ti and Ti6Al4V discs were both classified into 4 groups: untreated, treated with OP generated by using oxygen (99.98%) for 5, 10, and 30 min, respectively. After OPT on CP-Ti and Ti6Al4V samples, scanning probe microscopy, X-ray photoelectron spectrometry (XPS), and contact angle tests were conducted to determine the surface topography, elemental composition and hydrophilicity, respectively. The change of surface morphology was further studied using sputtered titanium on silicon wafers. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and F-actin immunofluorescence stain were performed to investigate the viability and spreading behavior of cultivated MG-63 cells on the samples.
The surface roughness was most prominent after 5 min OPT in both CP-Ti and Ti6Al4V, and the surface morphology of sputtered Ti sharpened after the 5 min treatment. From the XPS results, the intensity of Ti°, Ti2+, and Ti3+ of the samples’ surface decreased indicating the oxidation of titanium after OPT. The water contact angles of both CP-Ti and Ti6Al4V were increased after 5 min OPT. The results of MTT assay demonstrated MG-63 cells proliferated best on the 5 min OP treated titanium sample. The F-actin immunofluorescence stain revealed the cultivated cell number of 5 min treated CP-Ti/Ti6Al4V was greater than other groups and most of the cultivated cells were spindle-shaped.
Low pressure RF oxygen plasma modified both the composition and the morphology of titanium samples’ surface. The CP-Ti/Ti6Al4V treated with 5 min OPT displayed the roughest surface, sharpest surface profile and best biocompatibility.
PMCID: PMC3873422  PMID: 24386433
18.  The multiple roles for Sox2 in stem cell maintenance and tumorigenesis 
Cellular signalling  2013;25(5):10.1016/j.cellsig.2013.02.013.
The Sry-containing protein Sox2 initially was known to regulate the self-renewal of the mouse and human embryonic stem cells (ESCs). It is also important for the maintenance of stem cells in multiple adult tissues including the brain and trachea, and it is one of the key transcription factors for establishing induced pluripotent stem cells. Recently, overexpression and gene amplification of Sox2 has been associated with the development of squamous cell carcinoma in multiple tissues such as the lung and esophagus. These different roles for Sox2 involve a complicated regulatory networks consisting of microRNAs, kinases and signaling molecules. While the levels of Sox2 are modulated transcriptionally and transnationally, post-translational modification is also important for the various functions of Sox2. In clinics, high levels of Sox2 are correlated with poor prognosis and increased proliferation of cancer stem cells. Therefore targeting Sox2 can be potentially explored for new therapeutic avenue to treat cancers. This review will focus on the different roles for Sox2 in stem cell maintenance and its oncogenic roles in the context of signal transcription and microRNA regulation. We will also review the main upstream and downstream targets of Sox2, which can be potentially used as therapeutic measures to treat cancer with abnormal levels of Sox2
PMCID: PMC3871517  PMID: 23416461
Sox2; signal transduction; cancer therapy
19.  Joint conditional Gaussian graphical models with multiple sources of genomic data 
Frontiers in Genetics  2013;4:294.
It is challenging to identify meaningful gene networks because biological interactions are often condition-specific and confounded with external factors. It is necessary to integrate multiple sources of genomic data to facilitate network inference. For example, one can jointly model expression datasets measured from multiple tissues with molecular marker data in so-called genetical genomic studies. In this paper, we propose a joint conditional Gaussian graphical model (JCGGM) that aims for modeling biological processes based on multiple sources of data. This approach is able to integrate multiple sources of information by adopting conditional models combined with joint sparsity regularization. We apply our approach to a real dataset measuring gene expression in four tissues (kidney, liver, heart, and fat) from recombinant inbred rats. Our approach reveals that the liver tissue has the highest level of tissue-specific gene regulations among genes involved in insulin responsive facilitative sugar transporter mediated glucose transport pathway, followed by heart and fat tissues, and this finding can only be attained from our JCGGM approach.
PMCID: PMC3865369  PMID: 24381584
Gaussian graphical models; gene networks; GGMs; conditional GGMs; joint sparsity
20.  Development of a DNA Microarray for Molecular Identification of All 46 Salmonella O Serogroups 
Applied and Environmental Microbiology  2013;79(11):3392-3399.
Salmonella is a major cause of food-borne disease in many countries. Serotype determination of Salmonella is important for disease assessment, infection control, and epidemiological surveillance. In this study, a microarray system that targets the O antigen-specific genes was developed for simultaneously detecting and identifying all 46 Salmonella O serogroups. Of these, 40 serogroups can be confidently identified, and the remaining 6, in three pairs (serogroups O67 and B, E1 and E4, and A and D1), need to be further distinguished from each other using PCR methods or conventional serotyping methods. The microarray was shown to be highly specific when evaluated against 293 Salmonella strains, 186 Shigella strains, representative Escherichia coli strains, and 10 strains of other bacterial species. The assay correctly identified 288 (98%) of the Salmonella strains. The detection sensitivity was determined to be 50 ng genomic DNA per sample. By testing simulated samples in a tomato background, 2 to 8 CFU per gram inoculated could be detected after enrichment. This newly developed microarray assay is the first molecular protocol that can be used for the comprehensive detection and identification of all 46 Salmonella O serogroups. Compared to the traditional serogrouping method, the microarray provides a reliable, high-throughput, and sensitive approach that can be used for rapid identification of multiple Salmonella O serogroups simultaneously.
PMCID: PMC3648052  PMID: 23524674
21.  The S40 residue in HIV-1 Gag p6 impacts local and distal budding determinants, revealing additional late domain activities 
Retrovirology  2013;10:143.
HIV-1 budding is directed primarily by two motifs in Gag p6 designated as late domain-1 and −2 that recruit ESCRT machinery by binding Tsg101 and Alix, respectively, and by poorly characterized determinants in the capsid (CA) domain. Here, we report that a conserved Gag p6 residue, S40, impacts budding mediated by all of these determinants.
Whereas budding normally results in formation of single spherical particles ~100 nm in diameter and containing a characteristic electron-dense conical core, the substitution of Phe for S40, a change that does not alter the amino acids encoded in the overlapping pol reading frame, resulted in defective CA-SP1 cleavage, formation of strings of tethered particles or filopodia-like membrane protrusions containing Gag, and diminished infectious particle formation. The S40F-mediated release defects were exacerbated when the viral-encoded protease (PR) was inactivated or when L domain-1 function was disrupted or when budding was almost completely obliterated by the disruption of both L domain-1 and −2. S40F mutation also resulted in stronger Gag-Alix interaction, as detected by yeast 2-hybrid assay. Reducing Alix binding by mutational disruption of contact residues restored single particle release, implicating the perturbed Gag-Alix interaction in the aberrant budding events. Interestingly, introduction of S40F partially rescued the negative effects on budding of CA NTD mutations EE75,76AA and P99A, which both prevent membrane curvature and therefore block budding at an early stage.
The results indicate that the S40 residue is a novel determinant of HIV-1 egress that is most likely involved in regulation of a critical assembly event required for budding in the Tsg101-, Alix-, Nedd4- and CA N-terminal domain affected pathways.
PMCID: PMC3907034  PMID: 24257210
HIV-1; Alix; Tsg101; Nedd4; CA NTD; Viral particle maturation; Protease; Viral budding
22.  Epitope analysis of anti-myeloperoxidase antibodies in propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis 
Arthritis Research & Therapy  2013;15(6):R196.
Increasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.
Six recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.
Compared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P = 0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P < 0.001; 41.2% versus 14.1%, P = 0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P < 0.001].
Linear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.
PMCID: PMC3979166  PMID: 24252385
23.  An investigation of economic costs of schizophrenia in two areas of China 
Schizophrenia is a severe psychotic disorder characterized by significant disturbances in thinking, perception, emotions and behavior. Even if it is not a very frequent disorder, but it is the most burdensome and costly illnesses worldwide. The total population was approximate 1.3 billion and there are approximate 8 million schizophrenic patients in China. Despite the wide-ranging financial and social burdens associated with schizophrenia, but there have been few cost-of-illness studies of this illness in China.
To evaluate the economic cost of schizophrenic patients in China.
356 schizophrenic patients who met with DSM-IV criteria were enrolled and investigated with the Economic Burden Questionnaire(EBQ), 299 schizophrenic patients completed the study for 12 months. All the data were combined and classified by researcher. EBQ include all kinds of cost such as direct cost, indirect cost and total cost as well. It was filled in by patients and their close caregivers. Comparison of cost was made between not only out-patients and in-patients but also urban patients and rural patients. Multiple stepwise regression analysis was made to identify the main influence factors of total cost.
(i) The per case per annum total costs, direct costs and indirect costs of schizophrenia amounted to US$2586.21, US$862.81(33.4%) and US$1723.40(66.6%) respectively. The per case total cost, direct cost and direct medical cost of in-patients were more higher than out-patients (P < 0.05). (ii) There was significant difference in per case per annum total cost, direct cost, direct medical cost, cost due to lost working-days and disability between urban and rural schizophrenic patients (P < 0.05), the former is higher than the latter. (iii) The results of multivariate stepwise regression analysis show that five variables were significantly correlated with higher cost: professional status(cadre), diagnostic subtype(residual schizophrenia), urban or rural patients(urban patients), in-patients or out-patients(in-patients) and researcher centre(southern center). The standardized regression coefficient were 0.308, 0.218, 0.212, 0.156 and 0.149 respectively, the correlation of determination R square was 0.2741, F = 15.651, P < 0.0000. These characteristics explain 27.41% of the variability in the total cost.
(i) Economic cost of schizophrenia were serious, we must pay close attention to it. (ii) The indirect cost are the majority of the total cost. The cost of urban patients are more higher than the cost of rural patients, the cost of in-patients are more higher than the cost of out-patients.
PMCID: PMC3843524  PMID: 24237846
Schizophrenia; Economic burden; Economic cost
24.  Voxel-Wise Displacement as Independent Features in Classification of Multiple Sclerosis 
Proceedings of SPIE  2013;8669:10.1117/12.2007150.
We present a method that utilizes registration displacement fields to perform accurate classification of magnetic resonance images (MRI) of the brain acquired from healthy individuals and patients diagnosed with multiple sclerosis (MS). Contrary to standard approaches, each voxel in the displacement field is treated as an independent feature that is classified individually. Results show that when used with a simple linear discriminant and majority voting, the approach is superior to using the displacement field with a single classifier, even when compared against more sophisticated classification methods such as adaptive boosting, random forests, and support vector machines. Leave-one-out cross-validation was used to evaluate this method for classifying images by disease, MS subtype (Acc: 77%–88%), and age (Acc: 96%–100%).
PMCID: PMC3824253  PMID: 24236227
Image registration; Magnetic resonance imaging; Classification; Multiple Sclerosis
25.  Regulation of Basal Lateral Membrane Mobility and Permeability to Divalent Cations by Membrane Associated-Protein Kinase C 
PLoS ONE  2013;8(11):e80291.
Biological membrane stabilization is essential for maintenance of cellular homeostasis, functionality and appropriate response to various stimuli. Previous studies have showed that accumulation of PKCs in the cell membrane significantly downregulates the membrane fluidity and Ca2+ influxes through the membranes in activated cells. In addition, membrane-inserted form of PKCs has been found in a variety of resting mammalian cells and tissues. This study is aimed to investigate possible role of the endogenous membrane-associated PKCs in the modulation of basal membrane fluidity. Here, we showed that interfering PKC expression by chronic activation of PKC with phorbol myristate acetate (PMA) or shRNA targeting at PKCα lowered the levels of PKCα in cytosol, peripheral membrane and integral membrane pools, while short-term activation of PKC with PMA induced accumulation of PKCα in the membrane pool accompanied by a dramatic decrease in the cytosol fraction. The lateral membrane mobility increased or decreased in accordance with the abundance alterations in the membrane-associated PKCα by these treatments. In addition, membrane permeability to divalent cations including Ca2+, Mn2+ and Ba2+ were also potentiated or abrogated along with the changes in PKC expression on the plasma membrane. Membrane stabilizer ursodeoxycholate abolished both of the enhanced lateral membrane mobility and permeability to divalent cations due to PKCα deficiency, whereas Gö6983, a PKC antagonist, or Gd3+ and 2-aminoethyoxydipheyl borne, two Ca2+ channels blockers, showed no effect, suggesting that this PKC-related regulation is independent of PKC activation or a modulation of specific divalent cation channel. Thus, these data demonstrate that the native membrane-associated PKCα is involved in the maintenance of basal membrane stabilization in resting cells.
PMCID: PMC3832666  PMID: 24260363

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