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1.  Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): A model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans 
Virology Journal  2012;9:170.
Background
Hepatitis B virus (HBV) infection continues to be an escalating global health problem. Feasible and effective animal models for HBV infection are the prerequisite for developing novel therapies for this disease. The tree shrew (Tupaia) is a small animal species evolutionary closely related to humans, and thus is permissive to certain human viral pathogens. Whether tree shrews could be chronically infected with HBV in vivo has been controversial for decades. Most published research has been reported on adult tree shrews, and only small numbers of HBV infected newborn tree shrews had been observed over short time periods. We investigated susceptibility of newborn tree shrews to experimental HBV infection as well as viral clearance over a protracted time period.
Results
Forty-six newborn tree shrews were inoculated with the sera from HBV-infected patients or tree shrews. Serum and liver samples of the inoculated animals were periodically collected and analyzed using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Southern blot, and immunohistochemistry. Six tree shrews were confirmed and four were suspected as chronically HBV-infected for more than 48 (up to 228) weeks after inoculation, including three that had been inoculated with serum from a confirmed HBV-infected tree shrew.
Conclusions
Outbred neonatal tree shrews can be long-term chronically infected with HBV at a frequency comparable to humans. The model resembles human disease where also a smaller proportion of infected individuals develop chronic HBV related disease. This model might enable genetic and immunologic investigations which would allow determination of underlying molecular causes favoring susceptibility for chronic HBV infection and disease establishment vs. viral clearance.
doi:10.1186/1743-422X-9-170
PMCID: PMC3511180  PMID: 22913805
Tree shrew (Tupaia); Hepatitis B virus; Chronic infection
2.  Biomaterial Strategies for Stem Cell Maintenance During In Vitro Expansion 
Stem cells, having the potential for self-renewal and multilineage differentiation, are the building blocks for tissue/organ regeneration. Stem cells can be isolated from various sources but are, in general, available in too small numbers to be used directly for clinical purpose without intermediate expansion procedures in vitro. Although this in vitro expansion of undifferentiated stem cells is necessary, stem cells typically diminish their ability to self-renew and proliferate during passaging. Consequently, maintaining the stemness of stem cells has been recognized as a major challenge in stem cell-based research. This review focuses on the latest developments in maintaining the self-renewal ability of stem cells during in vitro expansion by biomaterial strategies. Further, this review highlights what should be the focus for future studies using stem cells for regenerative applications.
doi:10.1089/ten.teb.2013.0349
PMCID: PMC4123465  PMID: 24168361
3.  Analysis of the GGGGCC Repeat Expansions of the C9orf72 Gene in SCA3/MJD Patients from China 
PLoS ONE  2015;10(6):e0130336.
Neurodegenerative disorders are a heterogeneous group of chronic progressive diseases and have pathological mechanisms in common. A certain causative gene identified for a particular disease may be found to play roles in more than one neurodegenerative disorder. We analyzed the GGGGCC repeat expansions of C9orf72 gene in patients with SCA3/MJD from mainland China to determine whether the C9orf72 gene plays a role in the pathogenesis of SCA3/MJD. In our study, there were no pathogenic repeats (>30 repeats) detected in either the patients or controls. SCA3/MJD patients with intermediate/intermediate or short/intermediate genotype (short: <7 repeats; intermediate: 7-30 repeats) of the GGGGCC repeats had an earlier onset compared with those with short/short genotype. The presence of the intermediate allele of the GGGGCC repeats in the patients decreased the age at onset by nearly 3 years. Our study firstly demonstrate that the development of SCA3/MJD may involve some physiological functions of the C9orf72 gene and provide new evidence to the hypothesis that a specific mutation identified in one of the neurodegenerative disorders may be a modulator in this class of diseases.
doi:10.1371/journal.pone.0130336
PMCID: PMC4470924  PMID: 26083476
4.  Preparation and evaluation of enrofloxacin microspheres and tissue distribution in rats 
Journal of Veterinary Science  2015;16(2):157-164.
New enrofloxacin microspheres were formulated, and their physical properties, lung-targeting ability, and tissue distribution in rats were examined. The microspheres had a regular and round shape. The mean diameter was 10.06 µm, and the diameter of 89.93% of all microspheres ranged from 7.0 µm to 30.0 µm. Tissue distribution of the microspheres was evaluated along with a conventional enrofloxacin preparation after a single intravenous injection (7.5 mg of enrofloxacin/kg bw). The results showed that the elimination half-life (t1/2β) of enrofloxacin from lung was prolonged from 7.94 h for the conventional enrofloxacin to 13.28 h for the microspheres. Area under the lung concentration versus time curve from 0 h to ∞ (AUC0-∞) was increased from 11.66 h·µg/g to 508.00 h·µg/g. The peak concentration (Cmax) in lung was increased from 5.95 µg/g to 93.36 µg/g. Three lung-targeting parameters were further assessed and showed that the microspheres had remarkable lung-targeting capabilities.
doi:10.4142/jvs.2015.16.2.157
PMCID: PMC4483498  PMID: 25643802
enrofloxacin; lung-targeting; microsphere; preparation; tissue distribution
5.  New breast cancer prognostic factors identified by computer-aided image analysis of HE stained histopathology images 
Scientific Reports  2015;5:10690.
Computer-aided image analysis (CAI) can help objectively quantify morphologic features of hematoxylin-eosin (HE) histopathology images and provide potentially useful prognostic information on breast cancer. We performed a CAI workflow on 1,150 HE images from 230 patients with invasive ductal carcinoma (IDC) of the breast. We used a pixel-wise support vector machine classifier for tumor nests (TNs)-stroma segmentation, and a marker-controlled watershed algorithm for nuclei segmentation. 730 morphologic parameters were extracted after segmentation, and 12 parameters identified by Kaplan-Meier analysis were significantly associated with 8-year disease free survival (P < 0.05 for all). Moreover, four image features including TNs feature (HR 1.327, 95%CI [1.001 - 1.759], P = 0.049), TNs cell nuclei feature (HR 0.729, 95%CI [0.537 - 0.989], P = 0.042), TNs cell density (HR 1.625, 95%CI [1.177 - 2.244], P = 0.003), and stromal cell structure feature (HR 1.596, 95%CI [1.142 - 2.229], P = 0.006) were identified by multivariate Cox proportional hazards model to be new independent prognostic factors. The results indicated that CAI can assist the pathologist in extracting prognostic information from HE histopathology images for IDC. The TNs feature, TNs cell nuclei feature, TNs cell density, and stromal cell structure feature could be new prognostic factors.
doi:10.1038/srep10690
PMCID: PMC4448264  PMID: 26022540
6.  Efficacy and Safety of Tangshen Formula on Patients with Type 2 Diabetic Kidney Disease: A Multicenter Double-Blinded Randomized Placebo-Controlled Trial 
PLoS ONE  2015;10(5):e0126027.
Background
Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD.
Methods
The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events.
Findings
After 24 weeks of treatment, no statistically significant difference in UAER (TSF −19.53 μg/min compared with placebo −7.01 μg/min, with a mean difference of −12.52 μg/min; 95%CI, −68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF−0.21 g compared with placebo 0.36 g, with a mean difference of −0.57g; 95%CI, −1.05 to −0.09, P = 0.024). Estimated glomerular filtration rate (eGFR) was improved in both patients with microalbuminuria and macroalbuminuria, with a mean difference of 15.51 ml/min/1.73 m2 (95%CI, 3.71 to 27.31), 9.01 ml/min/1.73 m2 (95%CI, −0.10 to 18.13), respectively. Other secondary outcomes showed no statistically significant difference between groups or in the incidence of adverse events.
Conclusions
Based on conventional treatments, TSF appears to provide additional benefits compared with placebo in decreasing proteinuria and improving eGFR in DKD patients with macroalbuminuria. Nevertheless, further study is needed to evaluate TSF treating patients with microalbuminuria.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TRC-10000843
doi:10.1371/journal.pone.0126027
PMCID: PMC4418676  PMID: 25938778
7.  GPR30 Mediates Estrogen Rapid Signaling and Neuroprotection 
G-protein-coupled estrogen receptor-30 (GPR30), also known as G-protein estrogen receptor-1 (GPER1), is a putative extranuclear estrogen receptor whose precise functions in the brain are poorly understood. Studies using exogenous administration of the GPR30 agonist, G1 suggests that GPR30 may have a neuroprotective role in cerebral ischemia. However, the physiological role of GPR30 in mediating estrogen (E2)-induced neuroprotection in cerebral ischemia remains unclear. Also unclear is whether GPR30 has a role in mediating rapid signaling by E2 after cerebral ischemia, which is thought to underlie its neuroprotective actions. To address these deficits in our knowledge, the current study examined the effect of antisense oligonucleotide (AS) knockdown of GPR30 in the hippocampal CA1 region upon E2-BSA-induced neuroprotection and rapid kinase signaling in a rat model of global cerebral ischemia (GCI). Immunohistochemistry demonstrated that GPR30 is strongly expressed in the hippocampal CA1 region and dentate gyrus, with less expression in the CA3 region. E2-BSA exerted robust neuroprotection of hippocampal CA1 neurons against GCI, an effect abrogated by AS knockdown of GPR30. Missense control oligonucleotides had no effect upon E2-BSA-induced neuroprotection, indicating specificity of the effect. The GPR30 agonist, G1 also exerted significant neuroprotection against GCI. E2-BSA and G1 also rapidly enhanced activation of the prosurvival kinases, Akt and ERK, while decreasing proapototic JNK activation. Importantly, AS knockdown of GPR30 markedly attenuated these rapid kinase signaling effects of E2-BSA. As a whole, the studies provide evidence of an important role of GPR30 in mediating the rapid signaling and neuroprotective actions of E2 in the hippocampus.
doi:10.1016/j.mce.2014.01.024
PMCID: PMC4019970  PMID: 24594140
Estrogen; Estradiol; GPR30; GPER1; hippocampus; neuroprotection; extranuclear; ischemia
8.  BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner 
Oncotarget  2015;6(10):7608-7618.
BRCA1 plays a key role in the regulation of p53-dependent target gene transcription activation. Meanwhile, the p53 inducible gene 3 (PIG3) is a downstream target of p53 and is involved in p53-initiated apoptosis. However, little is known about whether BRCA1 can regulate PIG3-mediated apoptosis. Using a tissue microarray containing 149 breast cancer patient samples, we found that BRCA1 and PIG3 expression status were significantly positively correlated (r = 0.678, P < 0.001) and identified a significant positive correlation between high expression of BRCA1 and/or PIG3 and overall survival (OS). Moreover, we reveal that overexpression of BRCA1 significantly increased expression of PIG3 in cells with intact p53, whereas no increase in PIG3 was observed in p53-null MDA-MB-157 cells and p53-depleted HCT116p53−/− cells. Meanwhile, ectopic expression of BRCA1 could not lead to an increase expression level of prohibitin (PHB), which we have previously identified to induce PIG3-mediated apoptosis. Finally, ChIP analysis revealed that PHB can bind to the PIG3 promoter and activate PIG3 transcription independent of p53, although p53 presence did enhance this process. Taken together, our findings suggest that BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner, and that PIG3 expression is associated with a better OS in breast cancer patients.
PMCID: PMC4480703  PMID: 25797244
PIG3; BRCA1; p53; prohibitin; breast cancer
9.  Individualized medicine and the microbiome in reproductive tract 
Humans have evolved along with the millions of microorganisms that populate their bodies. These microbes (1014) outnumber human cells by 10 to 1 and account for 3 × 106 genes, more than ten times the 25,000 human genes. This microbial metagenome acts as our “other genome” and like our own genes, is unique to the individual. Recent international efforts such as the Human Microbiome Project (HMP) and the MetaHIT Project have helped catalog these microbial genomes using culture-independent, high-throughput, next-generation sequencing. This manuscript will describe recent efforts to define microbial diversity in the female reproductive tract because of the impact that microbial function has on reproductive efficiency. In this review, we will discuss current evidence that microbial communities are critical for maintaining reproductive health and how perturbations of microbial community structures can impact reproductive health from the aspect of infection, reproductive cyclicity, pregnancy, and disease states. Investigations of the human microbiome are propelling interventional strategies from treating medical populations to treating individual patients. In particular, we highlight how understanding and defining microbial community structures in different disease and physiological states have lead to the discovery of biomarkers and, more importantly, the development and implementation of microbial intervention strategies (probiotics) into modern day medicine. Finally this review will conclude with a literature summary of the effectiveness of microbial intervention strategies that have been implemented in animal and human models of disease and the potential for integrating these microbial intervention strategies into standard clinical practice.
doi:10.3389/fphys.2015.00097
PMCID: PMC4381647  PMID: 25883569
individualized medicine; microbiome; reproductive tract infections; Pregnancy; biomarkers
10.  Forces exerted during microneurosurgery: a cadaver study 
Background
A prerequisite for the successful design and use of robots in neurosurgery is knowledge of the forces exerted by surgeons during neurosurgical procedures. The aim of the present cadaver study was to measure the surgical instrument forces exerted during microneurosurgery.
Methods
An experimental apparatus was set up consisting of a platform for human cadaver brains, a Leica microscope to provide illumination and magnification, and a Quanser 6 Degrees-Of-Freedom Telepresence System for tissue manipulation and force measurements.
Results
The measured forces varied significantly depending on the region of the brain (P = 0.016) and the maneuver performed (P < 0.0001). Moreover, blunt arachnoid dissection was associated with greater force exertion than sharp dissection (0.22 N vs. 0.03 N; P = 0.001).
Conclusions
The forces necessary to manipulate brain tissue were surprisingly low and varied depending on the anatomical structure being manipulated, and the maneuver performed. Knowledge of such forces could well increase the safety of microsurgery. © 2014 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons, Ltd.
doi:10.1002/rcs.1568
PMCID: PMC4377085  PMID: 24431265
neurosurgery; microsurgery; robotics; force
11.  Effects of Cold Atmospheric Plasma (CAP) on ß-Defensins, Inflammatory Cytokines, and Apoptosis-Related Molecules in Keratinocytes In Vitro and In Vivo 
PLoS ONE  2015;10(3):e0120041.
Cold atmospheric plasma (CAP) has been gaining increasing interest as a new approach for the treatment of skin diseases or wounds. Although this approach has demonstrated promising antibacterial activity, its exact mechanism of action remains unclear. This study explored in vitro and in vivo whether CAP influences gene expression and molecular mechanisms in keratinocytes. Our results revealed that a 2 min CAP treatment using the MicroPlaSter ß in analogy to the performed clinical studies for wound treatment induces expression of IL-8, TGF-ß1, and TGF-ß2. In vitro and in vivo assays indicated that keratinocyte proliferation, migration, and apoptotic mechanisms were not affected by the CAP treatment under the applied conditions. Further, we observed that antimicrobial peptides of the ß-defensin family are upregulated after CAP treatment. In summary, our results suggest that a 2 min application of CAP induces gene expression of key regulators important for inflammation and wound healing without causing proliferation, migration or cell death in keratinocytes. The induction of ß-defensins in keratinocytes describes an absolutely new plasma strategy. Activation of antimicrobial peptides supports the well-known antibacterial effect of CAP treatment, whereas the mechanism of ß-defensin activation by CAP is not investigated so far.
doi:10.1371/journal.pone.0120041
PMCID: PMC4359157  PMID: 25768736
12.  Biologically inspired band-edge laser action from semiconductor with dipole-forbidden band-gap transition 
Scientific Reports  2015;5:8965.
A new approach is proposed to light up band-edge stimulated emission arising from a semiconductor with dipole-forbidden band-gap transition. To illustrate our working principle, here we demonstrate the feasibility on the composite of SnO2 nanowires (NWs) and chicken albumen. SnO2 NWs, which merely emit visible defect emission, are observed to generate a strong ultraviolet fluorescence centered at 387 nm assisted by chicken albumen at room temperature. In addition, a stunning laser action is further discovered in the albumen/SnO2 NWs composite system. The underlying mechanism is interpreted in terms of the fluorescence resonance energy transfer (FRET) from the chicken albumen protein to SnO2 NWs. More importantly, the giant oscillator strength of shallow defect states, which is served orders of magnitude larger than that of the free exciton, plays a decisive role. Our approach therefore shows that bio-materials exhibit a great potential in applications for novel light emitters, which may open up a new avenue for the development of bio-inspired optoelectronic devices.
doi:10.1038/srep08965
PMCID: PMC4355669  PMID: 25758749
13.  Validation of NINDS-CSN neuropsychological battery for vascular cognitive impairment in Chinese stroke patients 
BMC Neurology  2015;15:20.
Background
The NINDS-Canadian Stroke Network (NINDS-CSN) recommended a neuropsychological battery of three protocols to diagnose vascular cognitive impairment (VCI), however, due to culture and language differences, the battery cannot be directly used in China. Validation of the battery in mandarin Chinese is lacking. Our study investigated the reliability and validity of the adapted Chinese versions of the battery in stroke patients with high probability of VCI.
Methods
Fifty mild stroke patients (median of National Institute of Health Stroke Scale [NIHSS] score, 2) and 50 stroke-free normal controls were recruited. All subjects’ demographics, clinical history, and stroke severity were recorded. The NINDS-CSN neuropsychological protocols were adapted into the Chinese versions. External validity, defined as the ability of the protocol summary scores to differentiate stroke patients from controls, was determined using the area under the curve (AUC) of the receiver operating characteristics curve. We also evaluated internal consistency and intra-rater reliability.
Results
Stroke patients performed significantly poorer than controls on all three protocols (F statistics between 24.9 and 31.4, P < 0.001). External validity evaluated by AUCs was 0.88 (95% confidence interval [CI], 0.81-0.95), 0.88 (95% CI, 0.81-0.94), and 0.86 (95% CI, 0.79-0.94) for the 60-min, 30-min and 5-min protocols, respectively. Cronbach’s alpha of the cognitive tests was 0.87 for all subjects. Intra-rater reliability was acceptable with intraclass correlation coefficients 0.90, 0.83 and 0.75 for the 60-min, 30-min and 5-min protocols, respectively.
Conclusions
The adapted Chinese versions of three NINDS-CSN neuropsychological protocols were valid and reliable for assessing VCI in Chinese patients with mild stroke.
doi:10.1186/s12883-015-0270-z
PMCID: PMC4350916  PMID: 25886571
Vascular cognitive impairment; Stroke; Neuropsychology; Validation study; China
14.  ALDH2 is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural Chinese sample 
Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 600 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum p = 4.73×10-8) and two AD-related phenotypes: flushing response (minimum p = 4.75×10-26) and maximum drinks in a 24-hour period (minimum p = 1.54×10-16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9% and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females – despite familial enrichment for AD – for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally-mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.
doi:10.1002/ajmg.b.32213
PMCID: PMC4149216  PMID: 24277619
Alcohol Dependence; Maximum Drinks; Flushing Response; Genome-Wide Association; Aldehyde Dehydrogenase
15.  Transcriptome Analysis of Methyl Jasmonate-Elicited Panax ginseng Adventitious Roots to Discover Putative Ginsenoside Biosynthesis and Transport Genes 
The Panax ginseng C.A. Meyer belonging to the Araliaceae has long been used as an herbal medicine. Although public databases are presently available for this family, no methyl jasmonate (MeJA) elicited transcriptomic information was previously reported on this species, with the exception of a few expressed sequence tags (ESTs) using the traditional Sanger method. Here, approximately 53 million clean reads of adventitious root transcriptome were separately filtered via Illumina HiSeq™2000 from two samples treated with MeJA (Pg-MeJA) and equal volumes of solvent, ethanol (Pg-Con). Jointly, a total of 71,095 all-unigenes from both samples were assembled and annotated, and based on sequence similarity search with known proteins, a total of 56,668 unigenes was obtained. Out of these annotated unigenes, 54,920 were assigned to the NCBI non-redundant protein (Nr) database, 35,448 to the Swiss-prot database, 43,051 to gene ontology (GO), and 19,986 to clusters of orthologous groups (COG). Searching in the Kyoto encyclopedia of genes and genomes (KEGG) pathway database indicated that 32,200 unigenes were mapped to 128 KEGG pathways. Moreover, we obtained several genes showing a wide range of expression levels. We also identified a total of 749 ginsenoside biosynthetic enzyme genes and 12 promising pleiotropic drug resistance (PDR) genes related to ginsenoside transport.
doi:10.3390/ijms16023035
PMCID: PMC4346879  PMID: 25642758
Panax ginseng; adventitious root; methyl jasmonate; Illumina/Solexa; transcriptome; ginsenoside biosynthesis; PDR (pleiotropic drug resistance) transporters; MVA (mevalonic acid) pathway
16.  Magnetic microbubble-mediated ultrasound-MRI registration based on robust optical flow model 
BioMedical Engineering OnLine  2015;14(Suppl 1):S14.
Background
As a dual-modality contrast agent, magnetic microbubbles (MMBs) can not only improve contrast of ultrasound (US) image, but can also serve as a contrast agent of magnetic resonance image (MRI). With the help of MMBs, a new registration method between US image and MRI is presented.
Methods
In this method, MMBs were used in both ultrasound and magnetic resonance imaging process to enhance the most important information of interest. In order to reduce the influence of the speckle noise to registration, semi-automatic segmentations of US image and MRI were carried out by using active contour model. After that, a robust optical flow model between US image segmentation (floating image) and MRI segmentation (reference image) was built, and the vector flow field was estimated by using the Coarse-to-fine Gaussian pyramid and graduated non-convexity (GNC) schemes.
Results
Qualitative and quantitative analyses of multiple group comparison experiments showed that registration results using all methods tested in this paper without MMBs were unsatisfactory. On the contrary, the proposed method combined with MMBs led to the best registration results.
Conclusion
The proposed algorithm combined with MMBs contends with larger deformation and performs well not only for local deformation but also for global deformation. The comparison experiments also demonstrated that ultrasound-MRI registration using the above-mentioned method might be a promising method for obtaining more accurate image information.
doi:10.1186/1475-925X-14-S1-S14
PMCID: PMC4306103  PMID: 25602434
17.  In Vivo Bone Regeneration Using Tubular Perfusion System Bioreactor Cultured Nanofibrous Scaffolds 
Tissue Engineering. Part A  2013;20(1-2):139-146.
The use of bioreactors for the in vitro culture of constructs for bone tissue engineering has become prevalent as these systems may improve the growth and differentiation of a cultured cell population. Here we utilize a tubular perfusion system (TPS) bioreactor for the in vitro culture of human mesenchymal stem cells (hMSCs) and implant the cultured constructs into rat femoral condyle defects. Using nanofibrous electrospun poly(lactic-co-glycolic acid)/poly(ɛ-caprolactone) scaffolds, hMSCs were cultured for 10 days in vitro in the TPS bioreactor with cellular and acellular scaffolds cultured statically for 10 days as a control. After 3 and 6 weeks of in vivo culture, explants were removed and subjected to histomorphometric analysis. Results indicated more rapid bone regeneration in defects implanted with bioreactor cultured scaffolds with a new bone area of 1.23±0.35 mm2 at 21 days compared to 0.99±0.43 mm2 and 0.50±0.29 mm2 in defects implanted with statically cultured scaffolds and acellular scaffolds, respectively. At the 21 day timepoint, statistical differences (p<0.05) were only observed between defects implanted with cell containing scaffolds and the acellular control. After 42 days, however, defects implanted with TPS cultured scaffolds had the greatest new bone area with 1.72±0.40 mm2. Defects implanted with statically cultured and acellular scaffolds had a new bone area of 1.26±0.43 mm2 and 1.19±0.33 mm2, respectively. The increase in bone growth observed in defects implanted with TPS cultured scaffolds was statistically significant (p<0.05) when compared to both the static and acellular groups at this timepoint. This study demonstrates the efficacy of the TPS bioreactor to improve bone tissue regeneration and highlights the benefits of utilizing perfusion bioreactor systems to culture MSCs for bone tissue engineering.
doi:10.1089/ten.tea.2013.0168
PMCID: PMC3875202  PMID: 23865551
18.  Concise Review: Cell-Based Strategies in Bone Tissue Engineering and Regenerative Medicine 
Cellular strategies play an important role in bone tissue engineering and regenerative medicine (BTE/RM). Variability in cell culture procedures (e.g., cell types, cell isolation and expansion, cell seeding methods, and preculture conditions before in vivo implantation) may influence experimental outcome. The present review provides an overview of the critical procedures during in vitro and in vivo phases for cell-based strategies (both monoculture and coculture) in BTE/RM.
Cellular strategies play an important role in bone tissue engineering and regenerative medicine (BTE/RM). Variability in cell culture procedures (e.g., cell types, cell isolation and expansion, cell seeding methods, and preculture conditions before in vivo implantation) may influence experimental outcome. Meanwhile, outcomes from initial clinical trials are far behind those of animal studies, which is suggested to be related to insufficient nutrient and oxygen supply inside the BTE/RM constructs as some complex clinical implementations require bone regeneration in too large a quantity. Coculture strategies, in which angiogenic cells are introduced into osteogenic cell cultures, might provide a solution for improving vascularization and hence increasing bone formation for cell-based constructs. So far, preclinical studies have demonstrated that cell-based tissue-engineered constructs generally induce more bone formation compared with acellular constructs. Further, cocultures have been shown to enhance vascularization and bone formation compared with monocultures. However, translational efficacy from animal studies to clinical use requires improvement, and the role implanted cells play in clinical bone regeneration needs to be further elucidated. In view of this, the present review provides an overview of the critical procedures during in vitro and in vivo phases for cell-based strategies (both monoculture and coculture) in BTE/RM to achieve more standardized culture conditions for future studies, and hence enhance bone formation.
doi:10.5966/sctm.2013-0126
PMCID: PMC3902295  PMID: 24300556
Mesenchymal stem cells; Endothelial cells; Bone marrow stromal cells; Adipose stem cells; Vascularization; Tissue regeneration
19.  Caries experience and its association with weight status among 8-year-old children in Qingdao, China 
Objectives:
Childhood obesity/underweight status and caries are both important public health problems. This study aims to investigate the caries status and its association with body weight in 8-year-old children in Qingdao, China.
Materials and Methods:
We initiated a cross-sectional investigation on 744 children aged 8 years during the Oral Health Survey in 2012. Dental caries assessments were carried out and weight status was recorded accordingly. The resulting caries status including caries prevalence, dmft (deciduous dentition), and (dmft + DMFT) (mixed dentition), as well as BMI indices were analyzed for comparison and correlation.
Results:
The prevalence of dental caries among the 744 children aged 8 years participating in this survey was 86.3%. The caries status represented by dmft (deciduous dentition) and (dmft + DMFT) (mixed dentition) values was 4.31 and 4.85, respectively, and the restoration rate was extremely low, which was no more than 3.0%. Significant difference was found in dmft/(dmft + DMFT) values between different BMI groups, and underweight individuals were found to have the highest dmft/(dmft + DMFT) value. An inverse relationship between body BMI and dmft/(dmft + DMFT) index was identified based on Pearson's correlation.
Conclusions:
A severe state of caries disease was revealed in 8-year-old children in the Chinese city of Qingdao, for whom urgent dental intervention and treatment were needed. Furthermore, underweight individuals were found with the most severe caries experience, indicating caries may affect the development and growth of the afflicted children. Thus, more emphasis should be placed on improving their dental health, with caries prevention being given the priority.
doi:10.4103/2231-0762.151978
PMCID: PMC4355851  PMID: 25767768
Caries; cross-sectional survey; epidemic survey; obesity; weight
20.  Need for achievement moderates the effect of motive-relevant challenge on salivary cortisol changes 
Motivation and Emotion  2014;39(3):321-334.
The hypothalamic–pituitary–adrenal (HPA) axis plays a key role in the physiological response to stress, preparing the organism for appropriate action. While some research has examined universally relevant threats, other research has suggested that individual differences may moderate the relationship between stress and cortisol release, such that some individuals exhibit modified reactivity to personally relevant stressors or challenges. In the present study we investigated whether one individual difference—the implicit need for achievement—moderates the effect of motive-relevant challenge on salivary cortisol. Participants’ salivary cortisol and felt affect were measured before and after engagement in an achievement task. In the positive- and no-feedback conditions, individuals high in implicit achievement motivation demonstrated increased cortisol response to the task, whereas in the negative feedback condition, individuals high in implicit achievement motivation demonstrated a dampened cortisol response. Furthermore, changes in cortisol were accompanied by changes in felt affect in the same direction, specifically hedonic tone. These results suggest that the HPA axis also responds to non-social-evaluative challenge in a personality-contingent manner.
doi:10.1007/s11031-014-9465-7
PMCID: PMC4412424  PMID: 25960584
Need for achievement; Implicit motives; Cortisol; Stress; HPA axis; Picture story exercise
21.  Aggressive Medical Care in Young Chinese Patients with Ischemic Stroke of Undetermined Etiology: A Retrospective Study 
Interventional Neurology  2014;3(1):56-66.
Objectives
This study aimed to investigate the clinical and angiographic characteristics of ischemic stroke of undetermined etiology in young Chinese adults and to observe the effects of medication on their long-term outcomes.
Methods
A total of 179 consecutive young patients with ischemic stroke of undetermined etiology were retrospectively analyzed for clinical and angiographic characteristics, laboratory tests, the choice of drug treatment, and follow-up outcomes. Any predictive power for recurrent stroke and new lesions or aggravated stenosis was analyzed.
Results
170 patients were clinically followed up for a median of 25 months (range, 4-92), and 65 patients with 114 lesions had angiographic follow-up for a median of 7 months. A total of 53 patients were enrolled in a routine medical management (RMM) group, and 117 were treated with corticosteroids plus RMM (aggressive medical management, AMM). Kaplan-Meier survival analysis revealed that differences in the 2-year cumulative stroke-free rate and in the 18-month cumulative worsening and/or new lesion-free rate between the RMM and AMM groups were significant (p < 0.05). Multivariate and Cox regression analyses revealed that the choice of drug therapy and erythrocyte sedimentation rate were associated with recurrent stroke, that AMM was independently associated with a decreased risk of worsening lesion, and that worsening lesion was the only independent predictor of recurrent stroke.
Conclusion
Compared with RMM, AMM is more efficacious in the prevention of secondary ischemic stroke and progressive arterial lesions among young adults with ischemic stroke of undetermined etiology.
doi:10.1159/000369481
PMCID: PMC4436531  PMID: 25999993
Medical care; Undetermined etiology; Young stroke patients
22.  Brain iron redistribution in mesial temporal lobe epilepsy: a susceptibility-weighted magnetic resonance imaging study 
BMC Neuroscience  2014;15:117.
Background
The roles of iron in epilepsy and its pathophysiological significance are poorly understood, especially whether iron levels are abnormal in subcortcal structures. This study aims to demonstrate whole-brain iron alterations and its clinical relevancies in mesial temporal lobe epilepsy (mTLE) in vivo, using susceptibility-weighted magnetic resonance imaging (SWI).
Methods
We studied 62 patients with mTLE and 62 healthy controls. Brain iron concentration was quantified using SWI phase values. Voxel-wise analysis was carried out to compare iron levels between mTLE and controls, and to assess the relationship between altered iron concentration and clinical parameters in mTLE.
Results
Patients with mTLE showed decreases of iron levels in the subcortical structures such as substantia nigra, red nucleus, and basal ganglia. Conversely, iron levels were decreased in the cortex. Subcortical iron levels were negatively correlated to those in the cortex. Moreover, cortical and basal ganglia iron levels were related to clinical variables including epilepsy duration, age at seizures onset, and histories of precipitating factors.
Conclusions
Our SWI findings suggest a redistribution of iron between subcortical and cortical structures in mTLE. The degree of redistribution is affected by both progression of epilepsy and precipitating factors. Investigation on brain iron redistribution offers new insights into the pathogenesis of mTLE, and may be a potential biomarker for monitoring the clinical progression of epilepsy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12868-014-0117-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12868-014-0117-3
PMCID: PMC4243317  PMID: 25413842
Brain iron; Mesial temporal lobe epilepsy; Susceptibility-weighted magnetic resonance imaging
23.  Biologically inspired flexible quasi-single-mode random laser: An integration of Pieris canidia butterfly wing and semiconductors 
Scientific Reports  2014;4:6736.
Quasi-periodic structures of natural biomaterial membranes have great potentials to serve as resonance cavities to generate ecological friendly optoelectronic devices with low cost. To achieve the first attempt for the illustration of the underlying principle, the Pieris canidia butterfly wing was embedded with ZnO nanoparticles. Quite interestingly, it is found that the bio-inspired quasi-single-mode random laser can be achieved by the assistance of the skeleton of the membrane, in which ZnO nanoparticles act as emitting gain media. Such unique characteristics can be interpreted well by the Fabry-Perot resonance existing in the window-like quasi-periodic structure of butterfly wing. Due to the inherently promising flexibility of butterfly wing membrane, the laser action can still be maintained during the bending process. Our demonstrated approach not only indicates that the natural biological structures can provide effective scattering feedbacks but also pave a new avenue towards designing bio-controlled photonic devices.
doi:10.1038/srep06736
PMCID: PMC4206842  PMID: 25338507
24.  Purification and in vitro antioxidant activities of tellurium-containing phycobiliproteins from tellurium-enriched Spirulina platensis 
Tellurium-containing phycocyanin (Te-PC) and allophycocyanin (Te-APC), two organic tellurium (Te) species, were purified from tellurium-enriched Spirulina platensis by a fast protein liquid chromatographic method. It was found that the incorporation of Te into the peptides enhanced the antioxidant activities of both phycobiliproteins. With fractionation by ammonium sulfate precipitation and hydroxylapatite chromatography, Te-PC and Te-APC could be effectively separated with high purity, and Te concentrations were 611.1 and 625.3 μg g−1 protein in Te-PC and Te-APC, respectively. The subunits in the proteins were identified by using MALDI-TOF-TOF mass spectrometry. Te incorporation enhanced the antioxidant activities of both phycobiliproteins, as examined by 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid assay. Moreover, Te-PC and Te-APC showed dose-dependent protection on erythrocytes against the water-soluble free radical initiator 2,2′-azo(2-asmidinopropane)dihydrochloride-induced hemolysis. In the hepatoprotective model, apoptotic cell death and nuclear condensation induced by tert-butyl hydroperoxide in HepG2 cells was significantly attenuated by Te-PC and Te-APC. Taken together, these results suggest that Te-PC and Te-APC are promising Te-containing proteins with application potential for treatment of diseases related to oxidative stress.
doi:10.2147/DDDT.S62530
PMCID: PMC4199980  PMID: 25336922
tellurium; phycocyanin; allophycocyanin; purification; antioxidant activity
25.  The PathoChip, a functional gene array for assessing pathogenic properties of diverse microbial communities 
The ISME Journal  2013;7(10):1974-1984.
Pathogens present in the environment pose a serious threat to human, plant and animal health as evidenced by recent outbreaks. As many pathogens can survive and proliferate in the environment, it is important to understand their population dynamics and pathogenic potential in the environment. To assess pathogenic potential in diverse habitats, we developed a functional gene array, the PathoChip, constructed with key virulence genes related to major virulence factors, such as adherence, colonization, motility, invasion, toxin, immune evasion and iron uptake. A total of 3715 best probes were selected from 13 virulence factors, covering 7417 coding sequences from 1397 microbial species (2336 strains). The specificity of the PathoChip was computationally verified, and approximately 98% of the probes provided specificity at or below the species level, proving its excellent capability for the detection of target sequences with high discrimination power. We applied this array to community samples from soil, seawater and human saliva to assess the occurrence of virulence genes in natural environments. Both the abundance and diversity of virulence genes increased in stressed conditions compared with their corresponding controls, indicating a possible increase in abundance of pathogenic bacteria under environmental perturbations such as warming or oil spills. Statistical analyses showed that microbial communities harboring virulence genes were responsive to environmental perturbations, which drove changes in abundance and distribution of virulence genes. The PathoChip provides a useful tool to identify virulence genes in microbial populations, examine the dynamics of virulence genes in response to environmental perturbations and determine the pathogenic potential of microbial communities.
doi:10.1038/ismej.2013.88
PMCID: PMC3965316  PMID: 23765101
virulence genes; functional gene array; climate warming; oil-contamination; caries

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