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1.  Modulation of Brain Electroencephalography Oscillations by Electroacupuncture in a Rat Model of Postincisional Pain 
The present study aimed to investigate how ongoing brain rhythmical oscillations changed during the postoperative pain and whether electroacupuncture (EA) regulated these brain oscillations when it relieved pain. We established a postincisional pain model of rats with plantar incision to mimic the clinical pathological pain state, tested the analgesic effects of EA, and recorded electroencephalography (EEG) activities before and after the EA application. By analysis of power spectrum and bicoherence of EEG, we found that in rats with postincisional pain, ongoing activities at the delta-frequency band decreased, while activities at theta-, alpha-, and beta-frequency bands increased. EA treatment on these postincisional pain rats decreased the power at high-frequency bands especially at the beta-frequency band and reversed the enhancement of the cross-frequency coupling strength between the beta band and low-frequency bands. After searching for the PubMed, our study is the first time to describe that brain oscillations are correlated with the processing of spontaneous pain information in postincisional pain model of rats, and EA could regulate these brain rhythmical frequency oscillations, including the power and cross-frequency couplings.
PMCID: PMC3655616  PMID: 23710210
2.  Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience 
Science (New York, N.Y.)  2014;344(6181):313-319.
Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (Ih). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger Ih, which was observed in parallel with increased potassium (K+) channel currents. Experimentally enhancing the firing-increasing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice, completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.
PMCID: PMC4334447  PMID: 24744379
3.  The E3 ligase OsPUB15 interacts with the receptor-like kinase PID2 and regulates plant cell death and innate immunity 
BMC Plant Biology  2015;15:49.
Rice blast disease is one of the most destructive diseases of rice worldwide. We previously cloned the rice blast resistance gene Pid2, which encodes a transmembrane receptor-like kinase containing an extracellular B-lectin domain and an intracellular serine/threonine kinase domain. However, little is known about Pid2-mediated signaling.
Here we report the functional characterization of the U-box/ARM repeat protein OsPUB15 as one of the PID2-binding proteins. We found that OsPUB15 physically interacted with the kinase domain of PID2 (PID2K) in vitro and in vivo and the ARM repeat domain of OsPUB15 was essential for the interaction. In vitro biochemical assays indicated that PID2K possessed kinase activity and was able to phosphorylate OsPUB15. We also found that the phosphorylated form of OsPUB15 possessed E3 ligase activity. Expression pattern analyses revealed that OsPUB15 was constitutively expressed and its encoded protein OsPUB15 was localized in cytosol. Transgenic rice plants over-expressing OsPUB15 at early stage displayed cell death lesions spontaneously in association with a constitutive activation of plant basal defense responses, including excessive accumulation of hydrogen peroxide, up-regulated expression of pathogenesis-related genes and enhanced resistance to blast strains. We also observed that, along with plant growth, the cell death lesions kept spreading over the whole seedlings quickly resulting in a seedling lethal phenotype.
These results reveal that the E3 ligase OsPUB15 interacts directly with the receptor-like kinase PID2 and regulates plant cell death and blast disease resistance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0442-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4330927
U-box; E3 ligase; Protein interaction; Blast resistance; Cell death; Rice
4.  Effect of progressive horizontal resistive force on the comfortable walking speed of individuals post-stroke 
Individuals post-stroke select slow comfortable walking speeds (CWS) and the major factors used to select their CWS is unknown.
To determine the extent to which slow CWS post-stroke is achieved through matching a relative force output or targeting a particular walking speed.
Ten neurologically nonimpaired individuals and fourteen chronic stroke survivors with hemiplegia were recruited. Participants were instructed to “walk at the speed that feels most comfortable” on a treadmill against 12 progressively increasing horizontal resistive force levels applied at the pelvis using a robotic system that allowed participant to self-select their walking speed. We compared slope coefficients of the simple linear regressions between the observed normalized force vs. normalized speed relationship in each group to a slope of -1.0 (i.e. ideal slope for a constant relative force output) and 0.0 (i.e. ideal slope for a constant relative speed). We also compared slope coefficients between groups.
The slope coefficients were significantly greater than -1.0 (p < 0.001 for both) and significantly less than 0 (p < 0.001 for both). However, compared with nonimpaired individuals, people post-stroke were less able to maintain their walking speed (p = 0.003).
The results of this study provide evidence for a complex interaction between the regulation of relative force output and intention to move at a particular speed in the selection of the CWS for individuals post-stroke. This would suggest that therapeutic interventions should not only focus on task specific lower-limb strengthening exercises (e.g. walking against resistance), but should also focus on increasing the range of speeds at which people can safely walk.
PMCID: PMC4329221
Locomotion; Post-stroke; Force generation; Comfortable walking speed
5.  Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population 
Chinese journal of cancer  2013;33(2):68-73.
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02–1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17–2.14; OR = 1.51, 95% CI: 1.09–2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interactions with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12–1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
PMCID: PMC3884064  PMID: 23816557
Pancreatic ductal adenocarcinoma; ABO gene; genome-wide association study; genetic variation; haplotype
6.  Assessing winter oilseed rape freeze injury based on Chinese HJ remote sensing data*  
The winter oilseed rape (Brassica napus L.) accounts for about 90% of the total acreage of oilseed rape in China. However, it suffers the risk of freeze injury during the winter. In this study, we used Chinese HJ-1A/1B CCD sensors, which have a revisit frequency of 2 d as well as 30 m spatial resolution, to monitor the freeze injury of oilseed rape. Mahalanobis distance-derived growing regions in a normal year were taken as the benchmark, and a mask method was applied to obtain the growing regions in the 2010–2011 growing season. The normalized difference vegetation index (NDVI) was chosen as the indicator of the degree of damage. The amount of crop damage was determined from the difference in the NDVI before and after the freeze. There was spatial variability in the amount of crop damage, so we examined three factors that may affect the degree of freeze injury: terrain, soil moisture, and crop growth before the freeze. The results showed that all these factors were significantly correlated with freeze injury degree (P<0.01, two-tailed). The damage was generally more serious in low-lying and drought-prone areas; in addition, oilseed rape planted on south- and west-oriented facing slopes and those with luxuriant growth status tended to be more susceptible to freeze injury. Furthermore, land surface temperature (LST) of the coldest day, soil moisture, pre-freeze growth and altitude were in descending order of importance in determining the degree of damage. The findings proposed in this paper would be helpful in understanding the occurrence and severity distribution of oilseed rape freeze injury under certain natural or vegetation conditions, and thus help in mitigation of this kind of meteorological disaster in southern China.
PMCID: PMC4322424  PMID: 25644468
Brassica napus; Freeze injury; Remote sensing; Crop monitoring; HJ-CCD
7.  Associations of the uric acid related genetic variants in SLC2A9 and ABCG2 loci with coronary heart disease risk 
BMC Genetics  2015;16(1):4.
Multiple studies investigated the associations between serum uric acid and coronary heart disease (CHD) risk. However, further investigations still remain to be carried out to determine whether there exists a causal relationship between them. We aim to explore the associations between genetic variants in uric acid related loci of SLC2A9 and ABCG2 and CHD risk in a Chinese population.
A case–control study including 1,146 CHD cases and 1,146 controls was conducted. Association analysis between two uric acid related variants (SNP rs11722228 in SLC2A9 and rs4148152 in ABCG2) and CHD risk was performed by logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Compared with subjects with A allele of rs4148152, those with G allele had a decreased CHD risk and the association remained significant in a multivariate model. However, it altered to null when BMI was added into the model. No significant association was observed between rs11722228 and CHD risk. The distribution of CHD risk factors was not significantly different among different genotypes of both SNPs. Among subjects who did not consume alcohol, the G allele of rs4148152 showed a moderate protective effect. However, no significant interactions were observed between SNP by CHD risk factors on CHD risk.
There might be no association between the two uric acid related SNPs with CHD risk. Further studies were warranted to validate these results.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0162-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4314773  PMID: 25634581
Coronary heart disease; Uric acid; Polymorphism; Gene-environment interaction
8.  Glycomic Signatures on Serum IgGs for Prediction of Postvaccination Response 
Scientific Reports  2015;5:7648.
Millions of individuals are vaccinated worldwide each year to stimulate their adaptive immune systems to produce protective antibodies and T-cell response against pathogens. Since glycosylation of the Fc region of immunoglobulin G (IgG) can be influenced by the host's immune status, it was inferred that glycosylation profile of IgG might be altered as a result of the immune response. Therefore, subclass-specific glycosylation profiles of serum IgGs from 26 healthy adults before and after vaccination with a trivalent subunit influenza virus vaccine were comprehensively analyzed to explore glycomic signatures for vaccination. The results showed that no significant changes in the glycosylation of total IgGs took place before and after vaccination, but distinct glycosylation profiles in responders (fourfold or more increase of HI titer after vaccination) and nonresponders (less than fourfold increase of HI titer) were observed. This difference between the responders and nonresponders occurred even in the resting state. On the basis of variable importance parameters, glycosylation markers that distinguish responders from nonresponders were identified. These markers can be used as molecular signatures to predict antibody titers after vaccination. This is the first study of serum IgG glycosylation profiles in healthy adults receiving a trivalent inactivated influenza vaccine.
PMCID: PMC4303884  PMID: 25612906
9.  Regulation of Active DNA Demethylation by an α-Crystallin Domain Protein in Arabidopsis 
Molecular cell  2014;55(3):361-371.
DNA methylation patterns are dynamically controlled by DNA methylation and active DNA demethylation, but the mechanisms of regulation of active DNA demethylation are not well understood. Through forward genetic screens for Arabidopsis mutants showing DNA hypermethylation at specific loci and increased silencing of reporter genes, we identified IDM2 (increased DNA methylation 2) as a regulator of DNA demethylation and gene silencing. IDM2 dysfunction causes DNA hypermethylation and silencing of reporter genes and some endogenous genes. These effects of idm2 mutations are similar to those of mutations in IDM1, a regulator of active DNA demethylation. IDM2 encodes an α-crystallin domain protein in the nucleus. IDM2 and IDM1 interact physically and partially colocalize at discrete subnuclear foci. IDM2 is required for the full activity of H3K18 acetylation but not H3K23 acetylation of IDM1 in planta. Our results suggest that IDM2 functions in active DNA demethylation and in antisilencing by regulating IDM1.
PMCID: PMC4302764  PMID: 25002145
10.  The Correlations between Health-Related Quality of Life Changes and Pain and Anxiety in Orthodontic Patients in the Initial Stage of Treatment 
BioMed Research International  2015;2015:725913.
This study aimed to assess generic health-related quality of life (HRQoL), pain intensity, and anxiety levels and the relationship between the three aspects in healthy young Chinese orthodontic patients in the early stage of orthodontic treatment. We enrolled 252 eligible participants (10–29 years old) to complete validated Chinese versions of questionnaires, including the State-Trait Anxiety Inventory (S-AI), the visual analogue scale (VAS), and the Short-Form 36-Item Health Survey (SF-36) at baseline and on days 1, 2, 3, 7, 14, and 30 after initial archwire placement (SF-36 only at baseline and day 30). The response rate was 96% (243 of 252). SF-36 had moderate reliability (Cronbach's alpha coefficient exceeding 0.7, good fit on day 30). Statistical significant changes were observed in physical function (P < 0.01), body pain (P = 0.01), and general health (P < 0.01) domains. Spearman correlation coefficients for SF-36 with S-AI were −0.131~−0.515 (P < 0.05); SF-36 with VAS were −0.141~−0.273 (P < 0.05), indicating significant but moderate negative correlations between HRQoL and pain/anxiety. Overall, the application of SF-36 in assessing HRQoL is reluctantly suitable for young Chinese orthodontic patients in the early stage of orthodontic treatment. Early treatment-related pain and anxiety are important factors in HRQoL.
PMCID: PMC4317575
11.  Proportions of Staphylococcus aureus and Methicillin-Resistant Staphylococcus aureus in Patients with Surgical Site Infections in Mainland China: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(1):e0116079.
Sufficient details have not been specified for the epidemiological characteristics of Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) among surgical site infections (SSIs) in mainland China. This systematic review aimed to estimate proportions of S. aureus and MRSA in SSIs through available published studies.
PubMed, Embase and four Chinese electronic databases were searched to identify relevant primary studies published between 2007 and 2012. Meta-analysis was conducted on the basis of logit-transformed metric for proportions of S. aureus and MRSA, followed by pre-defined subgroup meta-analysis. Random-effects meta-regression was also conducted to explore the impact of possible factors on S. aureus proportions.
106 studies were included, of which 38 studies involved MRSA. S. aureus accounted for 19.1% (95%CI 17.2-21.0%; I2 = 84.1%) of all isolates in SSIs, which was roughly parallel to 18.5% in the United States (US) (P-value = 0.57) but significantly exceeded those calculated through the surveillance system in China (P-value<0.001). In subgroup analysis, S. aureus in patients with thoracic surgery (41.1%, 95%CI 26.3-57.7%; I2 = 74.4%) was more common than in those with gynecologic surgery (20.1%, 95%CI 15.6-25.6%; I2 = 33.0%) or abdominal surgery (13.8%, 95%CI 10.3-18.4%; I2 = 70.0%). Similar results were found in meta-regression. MRSA accounted for 41.3% (95%CI 36.5-46.3%; I2 = 64.6%) of S. aureus, significantly lower than that in the US (P-value = 0.001). MRSA was sensitive to vancomycin (522/522) and linezolid (93/94), while 79.9% (95%CI 67.4-88.4%; I2 = 0%) and 92.0% (95%CI 80.2-97.0%; I2 = 0%) of MRSA was resistant to clindamycin and erythromycin respectively.
The overall proportion of S. aureus among SSIs in China was similar to that in the US but seemed higher than those reported through the Chinese national surveillance system. Proportions of S. aureus SSIs may vary with different surgery types. Commonly seen in SSIs, MRSA tended to be highly sensitive to vancomycin and linezolid but mostly resistant to clindamycin and erythromycin.
PMCID: PMC4300093  PMID: 25602284
12.  miR-136 Modulates TGF-β1-Induced Proliferation Arrest by Targeting PPP2R2A in Keratinocytes 
BioMed Research International  2015;2015:453518.
Keratinocytes proliferation is critical for the capacity to heal wounds and accumulating evidences have proved that dysregulation of microRNAs is involved in proliferation of keratinocytes. However, the molecular mechanisms remain to be completely elucidated. Here, we show that miR-136 was significantly decreased by TGF-β1 treatment in HaCaT cells and normal human epidermal keratinocytes (NHEK), and it was a Smad3-dependent manner. By cell proliferation assay and cell cycle analysis, we found that reintroduction of miR-136 by transfection, as well as PPP2R2A silencing, counteracted TGF-β-induced proliferation arrest in HaCaT cells. Further, PPP2R2A was verified as a direct target of miR-136 by dual-luciferase reporter assays and Western blotting. These data suggest that miR-136 may play an important role during TGF-β1-induced proliferation arrest by targeting PPP2R2A in keratinocytes, which might represent a potential target for improving skin wound healing.
PMCID: PMC4310454  PMID: 25654102
13.  Visual fatigue caused by watching 3DTV: an fMRI study 
BioMedical Engineering OnLine  2015;14(Suppl 1):S12.
The objective of this study is to observe the visual fatigue caused by watching 3DTV using the method of functional magnetic resonance imaging (fMRI). The data of fMRI during three kinds of visual stimulation tasks were obtained from twenty subjects. At first, blood-oxygen-level dependent (BOLD) signal changes during stimuli of checkerboard task were compared before and after one-hour watching 3D/2DTV, and subjective evaluation was conducted based on the questionnaire simultaneously. Then 3D and 2D images were used to stimulate healthy individuals to measure brain activities that correlated with stereoscopic vision. Finally, the relationship between front or back depth of field images and visual fatigue was investigated. The results reveal that the 3D group shows more significant differences of brain activities in BA8, BA17, BA18 and BA19 than the 2D group during the checkerboard stimulation. BA5, BA6, BA7 and BA8 were testified to have close relationship with stereoscopic perception via the 2D/3D images stimulation. Furthermore, the front depth of field image was proven to impose a more serious impact on visual fatigue than the back one. These conclusions are useful for healthy and reasonable 3DTV watching as well as properly designing of 3D scenes.
PMCID: PMC4306101  PMID: 25603496
Visual fatigue; fMRI; 3DTV; Stereoscopic images
14.  Cell death pathway induced by resveratrol-bovine serum albumin nanoparticles in a human ovarian cell line 
Oncology Letters  2015;9(3):1359-1363.
Resveratrol-bovine serum albumin nanoparticles (RES-BSANP) exhibit chemotherapeutic properties, which trigger apoptosis. The aim of the present study was to investigate the caspase-independent cell death pathway induced by RES-BSANP in human ovarian cancer SKOV3 cells and to analyze its mechanism. Morphological changes were observed by apoptotic body/cell nucleus DNA staining using inverted and fluorescence microscopy. The cell death pathway was determined by phosphatidylserine translocation. Western blot analysis was conducted to detect the activation of apoptosis-inducing factor (AIF), cytochrome c (Cyto c) and B-cell lymphoma 2-associated X protein (Bax). Apoptotic body and nuclear condensation and fragmentation were observed simultaneously following treatment with RES-BSANP. RES-BSANP induced apoptosis in a dose-dependent manner in the human ovarian cancer SKOV3 cells. The translocation of AIF from the mitochondria to the cytoplasm occurred earlier than that of Cyto c. In addition, Bax binding to the mitochondria was required for the release of AIF and Cyto c from the mitochondria. The AIF apoptosis pathway may present an alternative caspase-dependent apoptosis pathway in human ovarian cell death induced by RES-BSANP. Elucidation of this pathway may be critical for the treatment of cancer using high doses of RES-BSANP.
PMCID: PMC4315083  PMID: 25663913
resveratrol-bovine serum albumin nanoparticles; apoptosis; programmed cell death; caspase-independent
15.  Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo 
To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo.
Experimental Design
Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was used to examine the antitumor activity in vivo.
Our data indicate that sorafenib and MPT0E028 synergistically reduced cell viability in liver cancer cells, and also markedly induced apoptotic cell death in these cells, as evidenced by the cleavage of caspase-3, PARP, and DNA fragmentation. MPT0E028 altered the global modifications of histone and nonhistone proteins regardless of the presence of sorafenib. However, sorafenib blocked MPT0E028-induced Erk activation and its downstream signaling cascades, such as Stat3 phosphorylation (Ser727) and Mcl-1 upregulation. Ectopic expression of constitutively active Mek successively reversed the apoptosis triggered by the combined treatment. Pharmacologic inhibition of Mek by PD98059 potentiated MPT0E028-induced apoptosis, suggesting that the synergistic interaction between MPT0E028 and sorafenib occurs at least partly through inhibition of Erk signaling. The data demonstrated that transcriptional activation of fibroblast growth factor receptor 3 (FGFR3) contributes to MPT0E028-mediated Erk phosphorylation. Finally, MPT0E028 plus sorafenib significantly improved the tumor growth delay (TGD) in a Hep3B xenograft model.
These findings suggest that MPT0E028 in combination with sorafenib has significant anti-hepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.
PMCID: PMC4284945  PMID: 24520095
16.  Prognostic significance of G2/M arrest signaling pathway proteins in advanced non-small cell lung cancer patients 
Oncology Letters  2015;9(3):1266-1272.
The aim of the present study was to retrospectively assess the correlation between the expression levels of proteins involved in G2/M arrest signaling pathways in non-small cell lung cancer (NSCLC) tissue, as determined by immunohistochemical (IHC) methods, and the overall survival of patients with advanced stage NSCLC. IHC analysis of advanced NSCLC specimens was used to determine the expression levels of proteins involved in G2/M arrest signaling pathways, including ataxia telangiectasia mutated (ATM) kinase, ataxia telangiectasia and Rad3-related (ATR) kinase, checkpoint kinase (Chk) 1, Chk2, cell division cycle 25C (Cdc25C), total cyclin-dependent kinase 1 (Cdk1) and active Cdk1 signaling pathways, the latter of which refers to dephospho-Cdk1 (Tyr15) and phospho-Cdk1 (Thr161). Patients were enrolled continuously and followed up for ≥2 years. Univariate analysis demonstrated that the protein expression levels of dephospho-Cdk1 (P=0.015) and phospho-Cdk1 (P=0.012) exhibited prognostic significance, while the expression of the other proteins was not significantly associated with patient survival (ATM, P=0.843; ATR, P=0.245; Chk1, P=0.341; Chk2, P=0.559; Cdc25C, P=0.649; total Cdk1, P=0.093). Furthermore, the patients with tumors exhibiting low expression levels of active Cdk1 survived significantly longer than those with tumors exhibiting high active Cdk1 expression levels (P<0.05). In addition, Cox regression analysis demonstrated that the expression of active Cdk1 [odds ratio (OR), 0.624; 95% confidence ratio (CI), 0.400–0.973; P=0.038] and the pathological tumor-node-metastasis stage (OR, 0.515; 95% CI, 0.297–0.894; P=0.018) were significant independent prognostic factors for NSCLC. Therefore, the results of the present study indicated that active Cdk1 protein is an independent prognostic factor for advanced NSCLC and may validate Cdk1 as a therapeutic target for advanced NSCLC patients.
PMCID: PMC4315004  PMID: 25663895
G2/M arrest; advanced non-small cell lung cancer; prognostic biomarkers; molecular pathology
18.  Molecular complexes that direct rhodopsin transport to primary cilia 
Progress in retinal and eye research  2013;38:10.1016/j.preteyeres.2013.08.004.
Rhodopsin is a key molecular constituent of photoreceptor cells, yet understanding of how it regulates photoreceptor membrane trafficking and biogenesis of light-sensing organelles, the rod outer segments (ROS) is only beginning to emerge. Recently identified sequence of well-orchestrated molecular interactions of rhodopsin with the functional networks of Arf and Rab GTPases at multiple stages of intracellular targeting fits well into the complex framework of the biogenesis and maintenance of primary cilia, of which the ROS is one example. This review will discuss the latest progress in dissecting the molecular complexes that coordinate rhodopsin incorporation into ciliary-targeted carriers with the recruitment and activation of membrane tethering complexes and regulators of fusion with the periciliary plasma membrane. In addition to revealing the fundamental principals of ciliary membrane renewal, recent advances also provide molecular insight into the ways by which disruptions of the exquisitely orchestrated interactions lead to cilia dysfunction and result in human retinal dystrophies and syndromic diseases that affect multiple organs, including the eyes.
PMCID: PMC3883129  PMID: 24135424
Rhodopsin; Trafficking; Cilium; Arfs; Rabs
19.  Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair 
Cancer research  2013;74(1):387-397.
A growing body of genomic data on human cancers poses the critical question of how genomic variations translate to cancer phenotypes. We employed standardized shotgun proteomics and targeted protein quantitation platforms to analyze a panel of 10 colon cancer cell lines differing by mutations in DNA mismatch repair (MMR) genes. In addition, we performed transcriptome sequencing (RNA-seq) to enable detection of protein sequence variants from the proteomic data. Biological replicate cultures yielded highly consistent proteomic inventories with a cumulative total of 6,513 protein groups with a protein FDR of 3.17% across all cell lines. Networks of co-expressed proteins with differential expression based on MMR status revealed impact on protein folding, turnover and transport, on cellular metabolism and on DNA and RNA synthesis and repair. Analysis of variant amino acid sequences suggested higher stability of proteins affected by naturally occurring germline polymorphisms than of proteins affected by somatic protein sequence changes. The data provide evidence for multi-system adaptation to MMR deficiency with a stress response that targets misfolded proteins for degradation through the ubiquitin-dependent proteasome pathway. Enrichment analysis suggested epithelial-to-mesenchymal transition (EMT) in RKO cells, as evidenced by increased mobility and invasion properties compared to SW480. The observed proteomic profiles demonstrate previously unknown consequences of altered DNA repair and provide an expanded basis for mechanistic interpretation of MMR phenotypes.
PMCID: PMC3896054  PMID: 24247723
21.  Helicobacter pylori Seropositivities and Risk of Pancreatic Carcinoma 
Pathophysiologic actions of Helicobacter pylori colonization on gastric acidity have been hypothesized to modulate the effect of pancreatic carcinogens, through CagA-negative organism strain type, hyperchlorhydria and increased risk of pancreatic cancer, or CagA-positive strain, hypochlorhydria and decreased risk of pancreatic cancer. We aimed to determine H. pylori strain-specific associations with pancreatic cancer in a population where colonization by CagA-positive strains is common.
We carried out a large population-based case-control study of pancreatic carcinoma in Shanghai, China. Venipuncture specimens were obtained from a representative sample of 761 case patients and 794 randomly selected control subjects matched by category of age and gender. Antibody seropositivity for H. pylori and its virulence protein CagA were determined by commercial enzyme-linked immunosorbent IgG assays.
Compared to individuals seronegative for both H. pylori and CagA, decreased pancreas-cancer risk was seen for CagA seropositivity (adjusted odds ratio [OR], 0.68; 95% confidence interval (CI), 0.54–0.84), while some increased risk was suggested for CagA-negative H. pylori seropositivity (OR, 1.28; 95% CI, 0.76–2.13). No risk interactions were observed between CagA seropositivity and gender, cigarette smoking, or age-21 body mass index.
Similar to what has been seen in animal models, our results provide suggestive evidence in humans for the involvement of gastric acidity, through its bidirectional modification according to colonization by Helicobacter pylori CagA strain type, in the risk of pancreatic carcinoma.
Helicobacter pylori colonization may have diverse effects on cancer risk, depending on the organism strain type as well as on the particular cancer site.
PMCID: PMC3947155  PMID: 24234587
Cytotoxin-associated gene A; Case-control Studies; H. pylori; Pancreatic Cancer
22.  MyD88 Signaling Regulates Both Host Defense and Immunopathogenesis during Pneumocystis Infection 
The immune response protects against Pneumocystis infection, but is also a key component of PcP-related immunopathogenesis. Signaling through MyD88 is critical for activation of immune pathways downstream of TLRs and IL-1 receptor. To determine whether MyD88 regulates normal host defense against Pneumocystis, non-immunosuppressed wild-type (WT) and MyD88 deficient mice were infected. MyD88−/− mice had higher early Pneumocystis burdens than WT mice, but mounted an effective adaptive immune response and cleared Pneumocystis similar to WT. However, MyD88−/− mice displayed a more intense and prolonged pulmonary immune response than WT mice. To determine the role of MyD88 in the development of PcP-related immunopathogenesis, WT and MyD88−/− mice were rendered susceptible to PcP by depletion of CD4+ T cells. At 4 weeks post-infection, CD4-depleted WT and MyD88−/− mice harbored similar organism burdens, but MyD88−/− mice were protected from the PcP-related respiratory impairment observed in WT mice. Improved pulmonary physiology in MyD88−/− mice correlated with lower lung CCL2 levels, and reduced cell recruitment. However, by 5 weeks post-infection the overall health of MyD88−/− mice began to deteriorate rapidly relative to WT, with accelerated weight loss, impaired lung function, and exacerbated alveolar inflammation. This physiological decline of MyD88−/− mice was associated with increased TNF-α and IFN-γ in the lung, and by the inability to control Pneumocystis burden. Thus, MyD88 is not required for resistance to Pneumocystis infection, but limits the adaptive immune response in immunocompetent mice. In the setting of active PcP, MyD88 signaling contributes to both immunopathogenesis and control of fungal burden.
PMCID: PMC4140532  PMID: 24293628
We examined parameters of sexual partnerships, including respondents’ participation in concurrency, belief that their partner had concurrent partnerships (partners’ concurrency), and partnership intervals, among the 2,099 women in HIV Prevention Trials Network 064, a study of women at high risk for HIV infection, in ten US communities.
We analyzed baseline survey responses about partnership dates to determine prevalence of participants’ and partners’ concurrency, intervals between partnerships, knowledge of whether recent partner(s) had undergone HIV testing, and intercourse frequency during the preceding 6 months.
Prevalence of participants’ and partners’ concurrency was 40% and 36% respectively; 24% of respondents had both concurrent partnerships and non-monogamous partners. Among women with >1 partner and no concurrent partnerships themselves, the median gap between partners was one month. Multiple episodes of unprotected vaginal intercourse with >2 of their most recent partners was reported by 60% of women who had both concurrent partnerships and non-monogamous partners, 50% with only concurrent partners and no partners’ concurrency, and 33% with only partners’ concurrency versus 14% of women with neither type of concurrency (p<.0001). Women who had any involvement with concurrency were also more likely than women with no concurrency involvement to report lack of awareness of whether recent partners had undergone HIV testing (participants’ concurrency 41%, partners’ concurrency 40%, both participants’ and partners’ concurrency 48%, neither 17%; p<.0001).
These network patterns and short gaps between partnerships may create substantial opportunities for HIV transmission in this sample of women at high risk for HIV infection.
PMCID: PMC4172374  PMID: 24056163
24.  Early Onset and Severe Clinical Course Associated with the m.5540G>A Mutation in MT-TW 
We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic-myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case.
PMCID: PMC4185924  PMID: 25302159
Mitochondrial DNA; MT-TW gene; sensorineural hearing loss; ataxia; pigmentary retinopathy
25.  Percutaneous Intramyocardial Delivery of Mesenchymal Stem Cells Induces Superior Improvement in Regional Left Ventricular Function Compared with Bone Marrow Mononuclear Cells in Porcine Myocardial Infarcted Heart 
Theranostics  2015;5(2):196-205.
Aim: To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow-derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. Methods and Results: Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60min.Two weeks post AMI, BMMNC (n = 7, 245 ± 98×106), MSC (n = 8, 56 ± 17×106), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 ± 0.06 vs. 1.87 ± 0.10, WT 33.4 ± 2.3% vs.24.8 ± 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). Conclusion: This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI.
PMCID: PMC4279004  PMID: 25553108
Angiogenesis; Imaging; Myocardial infarction; Remodeling; Stem cells.

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