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1.  Nano-mole Scale Sequential Signal Assignment by 1H-Detected Protein Solid-state NMR using Ultra-Fast Magic-Angle Spinning and HIGHLIGHT Spectral Editing 
We present a 3D 1H-detected solid-state NMR (SSNMR) approach for main-chain signal assignments of 10–100 nmol of fully protonated proteins using ultra-fast magic-angle spinning (MAS) at ~80 kHz with a novel spectral-editing method, which permits drastic spectral simplification. The approach offers ~110 fold time saving over a traditional 3D 13C-detected SSNMR approach.
PMCID: PMC4589527  PMID: 26317132
2.  A HuR/TGF-β1 feedback circuit regulates airway remodeling in airway smooth muscle cells 
Respiratory Research  2016;17:117.
Asthma is a worldwide health burden with an alarming prevalence. For years, asthma-associated airway injury remains elusive. Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine that has been shown to be involved in the synthesis of the matrix molecules associated with airway remodeling. Human antigen R (HuR), the member of the Hu RNA-binding protein family, can bind to a subset of short-lived mRNAs in their 3′ untranslated regions (UTR). However, the functional roles and relevant signaling pathways of HuR in airway remodeling have not been well illustrated. Thus, we aim to explore the relationship between HuR and TGF-β1 in platelet derived growth factor(PDGF)-induced airway smooth muscle (ASM) cells and asthmatic animal.
Cultured human ASM cells were stimulated by PDGF for 0, 6, 12 and 24 h. Western blotting, RT-PCR and immunofluoresence were used to detect the expression of HuR, TGF-β1, α-smooth muscle actins (α-SMA) and collagen type I (Col-I). Then knockdown of HuR, flow cytomerty was used to detect the morphological change and western blotting for functionally change of ASM cells. Furthermore, the interference of TGF-β1 and exogenous TGF-β1 were implemented to testify the influence on HuR. A murine OVA-driven allergic model based on sensitization and challenge was developed. The inflammatory response was measured by bronchoalveolar lavage fluid (BALF), airway damage was analyzed by hematoxylin and eosin staining, airway remodeling was assessed by sirius red staining and periodic acid-schiff staining, the expression level of HuR, TGF-β1 and α-SMA were measured by RT-PCR, western blotting and immunohistochemistry.
Here, we found that PDGF elevated HuR expression both at mRNA and protein level in cultured ASM cells at a time-dependent manner, which was simultaneously accompanied by the enhanced expression of TGF-β1, α-SMA and Col-I. Further study revealed that the knockdown of HuR significantly increased the apoptosis of ASM cells and dampened TGF-β1, Col-I and α-SMA expression. However, interfering TGF-β1 with siRNA or extra addition of TGF-β1, HuR could restore its production as well as Col-I. Compared with normal mice stimulating with PBS, OVA-induced mice owned high amount of inflammatory cells, such as eosinophils, lymphocytes and neutrophils except macrophages. HE staining showed accumulation of inflammatory cells surrounding bronchiole and sirius red staining distinguished collagen type I and III deposition around the bronchiole. Higher abundance of HuR, TGF-β1 and α-SMA were verified in OVA-induced mice than PBS-induced mice by RT-PCR, western blotting and immunohistochemistry.
A HuR/TGF-β1 feedback circuit was established to regulate airway remodeling in vivo and in vitro and targeting this feedback has considerable potential for the intervention of asthma.
PMCID: PMC5034516  PMID: 27658983
Asthma; Human antigen R; Transforming growth factor; α-smooth muscle actins; Collagen 1a; Airway remodeling; Post-transcription regulation
3.  Killing of Staphylococcus aureus via Magnetic Hyperthermia Mediated by Magnetotactic Bacteria 
Staphylococcus aureus is a common hospital and household pathogen. Given the emergence of antibiotic-resistant derivatives of this pathogen resulting from the use of antibiotics as general treatment, development of alternative therapeutic strategies is urgently needed. Here, we assess the feasibility of killing S. aureus cells in vitro and in vivo through magnetic hyperthermia mediated by magnetotactic bacteria that possess magnetic nanocrystals and demonstrate magnetically steered swimming. The S. aureus suspension was added to magnetotactic MO-1 bacteria either directly or after coating with anti-MO-1 polyclonal antibodies. The suspensions were then subjected to an alternating magnetic field (AMF) for 1 h. S. aureus viability was subsequently assessed through conventional plate counting and flow cytometry. We found that approximately 30% of the S. aureus cells mixed with uncoated MO-1 cells were killed after AMF treatment. Moreover, attachment between the magnetotactic bacteria and S. aureus increased the killing efficiency of hyperthermia to more than 50%. Using mouse models, we demonstrated that magnetic hyperthermia mediated by antibody-coated magnetotactic MO-1 bacteria significantly improved wound healing. These results collectively demonstrated the effective eradication of S. aureus both in vitro and in vivo, indicating the potential of magnetotactic bacterium-mediated magnetic hyperthermia as a treatment for S. aureus-induced skin or wound infections.
PMCID: PMC4807527  PMID: 26873320
4.  Predicting Diagnostic Gene Biomarkers for Non-Small-Cell Lung Cancer 
BioMed Research International  2016;2016:3952494.
Lung cancer is the primary reason for death due to cancer worldwide, and non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer. Most patients die from complications of NSCLC due to poor diagnosis. In this paper, we aimed to predict gene biomarkers that may be of use for diagnosis of NSCLC by integrating differential gene expression analysis with functional association network analysis. We first constructed an NSCLC-specific functional association network by combining gene expression correlation with functional association. Then, we applied a network partition algorithm to divide the network into gene modules and identify the most NSCLC-specific gene modules based on their differential expression pattern in between normal and NSCLC samples. Finally, from these modules, we identified genes that exhibited the most impact on the expression of their functionally associated genes in between normal and NSCLC samples and predicted them as NSCLC biomarkers. Literature review of the top predicted gene biomarkers suggested that most of them were already considered critical for development of NSCLC.
PMCID: PMC4989060  PMID: 27579312
5.  Citrate Accumulation-Related Gene Expression and/or Enzyme Activity Analysis Combined With Metabolomics Provide a Novel Insight for an Orange Mutant 
Scientific Reports  2016;6:29343.
‘Hong Anliu’ (HAL, Citrus sinensis cv. Hong Anliu) is a bud mutant of ‘Anliu’ (AL), characterized by a comprehensive metabolite alteration, such as lower accumulation of citrate, high accumulation of lycopene and soluble sugars in fruit juice sacs. Due to carboxylic acid metabolism connects other metabolite biosynthesis and/or catabolism networks, we therefore focused analyzing citrate accumulation-related gene expression profiles and/or enzyme activities, along with metabolic fingerprinting between ‘HAL’ and ‘AL’. Compared with ‘AL’, the transcript levels of citrate biosynthesis- and utilization-related genes and/or the activities of their respective enzymes such as citrate synthase, cytosol aconitase and ATP-citrate lyase were significantly higher in ‘HAL’. Nevertheless, the mitochondrial aconitase activity, the gene transcript levels of proton pumps, including vacuolar H+-ATPase, vacuolar H+-PPase, and the juice sac-predominant p-type proton pump gene (CsPH8) were significantly lower in ‘HAL’. These results implied that ‘HAL’ has higher abilities for citrate biosynthesis and utilization, but lower ability for the citrate uptake into vacuole compared with ‘AL’. Combined with the metabolites-analyzing results, a model was then established and suggested that the reduction in proton pump activity is the key factor for the low citrate accumulation and the comprehensive metabolite alterations as well in ‘HAL’.
PMCID: PMC4935991  PMID: 27385485
6.  Vascular-targeted TNFα and IFNγ inhibits orthotopic colorectal tumor growth 
Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. Unfortunately, several clinical studies of relevant cancer therapy did not observe significant response in maximum tolerated dose whether given alone or in combination. We have identified a tumor vasculature homing peptide (TCP-1 peptide) which targets only the vasculature of colorectal tumors but not normal blood vessels in animals and humans. In the current study, the antitumor effect of TCP-1/TNFα and TCP-1/IFNγ alone or in combination was studied in orthotopic colorectal tumor model.
TCP-1/TNFα and TCP-1/IFNγ recombinant proteins were prepared and i.v. injected to study the in vivo anticancer effect in orthotopic colorectal tumor model. Tumor apoptosis was determined by TUNEL staining and cleaved caspase-3 immunofluorescent staining. Tumor infiltrating lymphocytes were analyzed by immunofluorescent staining and flow cytometry. Western-blot was performed to examine the expression of proteins. Cell apoptosis was measured by Annexin V/PI flow cytometry.
Targeted delivery of TNFα or IFNγ by TCP-1 peptide exhibited better antitumor activity than unconjugated format by inducing more tumor apoptosis and also enhancing antitumor immunity shown by increased infiltration of T lymphocytes inside the tumor. More importantly, combination therapy of TCP-1/TNFα and TCP-1/IFNγ synergistically suppressed tumor growth and alleviated systematic toxicity associated with untargeted therapy. This combination therapy induced massive apoptosis/secondary necrosis in the tumor.
Taken together, our data demonstrate TCP-1 is an efficient drug carrier for targeted therapy of colorectal cancer (CRC). TCP-1/TNFα combined with TCP-1/IFNγ is a promising combination therapy for CRC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-0944-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4919862  PMID: 27342639
Vascular targeting; TNFα; IFNγ; Colorectal cancer; Drug delivery
7.  Use of a Force-Torque Sensor for Self-Calibration of a 6-DOF Medical Robot 
The aim of this paper is to improve the position accuracy of a six degree of freedom medical robot. The improvement in accuracy is achieved without the use of any external measurement device. Instead, this work presents a novel calibration approach based on using an embedded force-torque sensor to identify the robot’s kinematic parameters and thereby enhance the positioning accuracy. A simulation study demonstrated that our calibration approach is effective, whether or not any measurement noise is present: the position error is improved, inside the robot target workspace, from 12 mm to 0.320 mm, for the maximum values, and from 9 mm to 0.2771 mm, for the mean errors.
PMCID: PMC4934224  PMID: 27258278
robot calibration; robot accuracy; observability; medical robot; robot kinematic; robotic metrology
8.  Tracheobronchopathia Osteochondroplastica 
Medicine  2016;95(19):e3396.
Tracheobronchopathia osteochondroplastica (TO) is a relatively rare and benign disease of unknown etiology that is characterized by the accumulation of diffuse cartilaginous and osseous nodules protruding into the anterolateral walls of the trachea and bronchus. However, TO is easy to ignore or misdiagnose due to its nonspecific clinical manifestation. A chest computed tomography (CT) scan with a fiber bronchoscope and pathological biopsy shows the clinical features supporting the ultimate diagnosis.
Here, we report 2 misdiagnosed cases of TO and review the literature to further define the diagnosis for clinicians. The first case was a 34-year-old male admitted to the hospital because of recurrent cough and intermittent fever for 10 years. CT scans showed irregular stenosis of the main bronchus and bronchofibroscope showed multiple nodules producing into the lumen. He was initially misdiagnosed of bronchial tuberculosis and received antitubercular agents for nearly half year. Symptoms got no relief and another bronchofibroscope with biopsy tests in our hospital exactly diagnosed of TO. Symptoms were significantly relieved after receiving budesonide associated with antibiotics, etc. Another case was a 46-year-old woman presenting with a history of repeated hoarseness for 8 years and a 2-month exacerbation. She underwent an electronic laryngoscopy 3 times and was diagnosed of laryngitis. Symptoms got no relief after antiinflammatory. CT scan indicated variable degrees of stenosis and calcification of the distal trachea and main bronchi and bronchofibroscope showed dozens of white nodules extruding into the lumen. Histopathologic findings revealed the ultimate diagnosis of TO and antiinflammatories, spasm relievers, and inhaled corticosteroids, showed apparent effects.
Poor specificity of TO is observed in clinical manifestation and laboratory inspection. However, a CT scan associated with a bronchoscopy and histopathologic examination greatly contributes to a definitive diagnosis. No specific treatments are recommended, except treatments to alleviate symptoms. Thus, it is of great importance to consider TO when facing unsolved respiratory or external respiratory symptoms to improve the quality of life.
PMCID: PMC4902481  PMID: 27175639
9.  Moderate hypothermic circulatory arrest in total arch repair for acute type A aortic dissection: clinical safety and efficacy 
Journal of Thoracic Disease  2016;8(5):925-933.
Continued debates exist regarding the optimal temperature during hypothermic circulatory arrest (HCA) in aortic arch repair for patients with type A aortic dissection (TAAD). This study seeks to examine whether the use of moderate HCA in emergency aortic arch surgery provides comparable operative outcomes to deep HCA for patients with acute TAAD.
We prospectively enrolled 74 consecutive patients (mean age 47.7±9.8 years, 54 males) with acute TAAD, who underwent emergency total arch replacement and frozen elephant trunk implantation under HCA (18–28 °C) with unilateral selective antegrade cerebral perfusion (uSACP). Patients were divided into two groups based on the nasopharyngeal temperature at the initiation of HCA: deep HCA (DHCA, <20 °C) in 35 (47.3%) and moderate HCA (MHCA, 20–28 °C) in 39 (52.7%). Operative outcomes including mortality, morbidity and visceral organ functions were compared between the two groups.
The mean times of cardiopulmonary bypass (CPB) and aortic cross-clamp were 211±54 and 238±62 minutes (P=0.053) and 118±27 and 142±45 minutes (P=0.005) in the MHCA and DHCA groups, respectively. Operative mortality did not differ between two groups (10.2% in MHCA vs. 14.3% in DHCA groups, P=0.862). Nor did the incidence of morbidities differ between the two groups (P>0.05). The temporal trend in the changes of postoperative levels of creatinine, aspartate aminotransferase, total bilirubin and lactate did not differ between two groups (P>0.05). Multivariate analysis found that the temperature during HCA (MHCA vs. DHCA) did not affect operative mortality, morbidities and neurologic complications. Instead, CPB time (in minutes) was the risk factor for operative mortality (odds ratio, 1.032; 95% confidence interval, 1.004–1.061; P=0.023).
Conclusions: Moderate HCA is associated with equivalent operative mortality and morbidity and visceral organ functions compared to deep HCA in patients with acute TAAD undergoing total arch replacement under uSACP. This study implies the clinical safety and efficacy of moderate HCA in emergency aortic arch repair for such patients, which provides equivalent cerebral and visceral organ protection while decreasing CPB and cross-clamp times without increasing the risk of operative mortality and morbidity.
PMCID: PMC4842827  PMID: 27162668
Aortic dissection; hypothermia; heart arrest; outcome; mortality
10.  Development of a restriction length polymorphism combined with direct PCR technique to differentiate goose and Muscovy duck parvoviruses 
A restriction fragment length polymorphism combined with direct PCR technique to differentiate goose and Muscovy duck parvoviruses (GPV and MDPV) was developed based on comparison of the NS gene of GPV and MDPV. Both GPV and MDPV genomic DNA can be amplified with 641 bp using the specific PCR primers. The PCR fragments can be cut into 463 bp and 178 bp only in the case of MDPV-derived PCR products, whereas the GPV-derived PCR products cannot. The method established in this study can be used to differentiate GPV and MDPV with high specificity and precision, by using a direct PCR kit and QuickCut enzyme, as quickly as conventional PCR.
PMCID: PMC4905843  PMID: 26854108
direct PCR; goose parvovirus; muscovy duck parvovirus; restriction fragment length polymorphism
11.  Acute myocardial infarction following erlotinib treatment for NSCLC: A case report 
Oncology Letters  2016;11(6):4240-4244.
Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is an oral targeted anticancer drug that is used to treat non-small cell lung cancer (NSCLC). Previous studies have confirmed that erlotinib is safe and is well-tolerated by patients. The most common adverse reactions observed following erlotinib treatment include a rash and mild diarrhea. In the current study, the first case of acute myocardial infarction following one month of treatment with erlotinib in a 63-year-old male NSCLC patient is presented. The present study highlights the importance of clinicians remaining cautious following erlotinib administration. In elderly NSCLC patients and those with a history of coronary heart disease, cardiac function must be carefully monitored following erlotinib treatment so that serious adverse reactions, such as myocardial infarction, may be identified early and treated quickly.
PMCID: PMC4888202  PMID: 27313772
lung cancer; targeted therapy; erlotinib; adverse reactions; myocardial infarction
12.  Metadherin regulates epithelial–mesenchymal transition in carcinoma 
OncoTargets and therapy  2016;9:2429-2436.
Metadherin (MTDH) was first identified in primary human fetal astrocytes exposed to HIV-1 in 2002 and then recognized as an important oncogene mediating tumorigenesis, progression, invasiveness, and metastasis of carcinomas. Epithelial–mesenchymal transition (EMT) is a vital process in embryonic development, organ repair, and cancer progression. MTDH and EMT have also been proved to be related to the prognosis of patients with cancers. Recent studies reveal a relationship between MTDH overexpression and EMT in some malignancies. This review highlights the overexpression of MTDH and EMT in cancers and their correlations in clinical studies. Positive correlations have been established between MTDH and mesenchymal biomarkers, and negative correlations between MTDH and epithelial biomarkers have also been established. Furthermore, experiments reveal EMT regulated by MTDH, and some signal pathways have been established. Some anticancer drugs targeting MTDH and EMT are introduced in this review. Some perspectives concerning EMT regulation by MTDH are also presented in this review.
PMCID: PMC4844438  PMID: 27143938
signal pathway; chemoprevention; oncogene; biomarker; progression; therapeutic target
13.  Opposite and Coordinated Rotation of Amphitrichous Flagella Governs Oriented Swimming and Reversals in a Magnetotactic Spirillum 
Journal of Bacteriology  2015;197(20):3275-3282.
Current knowledge regarding the mechanism that governs flagellar motor rotation in response to environmental stimuli stems mainly from the study of monotrichous and peritrichous bacteria. Little is known about how two polar flagella, one at each cell pole of the so-called amphitrichous bacterium, are coordinated to steer the swimming. Here we fluorescently labeled the flagella of Magnetospirillum magneticum AMB-1 cells and took advantage of the magnetically controllable swimming of this bacterium to investigate flagellar rotation in moving cells. We identified three motility behaviors (runs, tumbles, and reversals) and two characteristic fluorescence patterns likely corresponding to flagella rotating in opposite directions. Each AMB-1 locomotion mode was systematically associated with particular flagellar patterns at the poles which led us to conclude that, while cell runs are allowed by the asymmetrical rotation of flagellar motors, their symmetrical rotation triggers cell tumbling. Our observations point toward a precise coordination of the two flagellar motors which can be temporarily unsynchronized during tumbling.
IMPORTANCE Motility is essential for bacteria to search for optimal niches and survive. Many bacteria use one or several flagella to explore their environment. The mechanism by which bipolarly flagellated cells coordinate flagellar rotation is poorly understood. We took advantage of the genetic amenability and magnetically controlled swimming of the spirillum-shaped magnetotactic bacterium Magnetospirillum magneticum AMB-1 to correlate cell motion with flagellar rotation. We found that asymmetric rotation of the flagella (counterclockwise at the lagging pole and clockwise at the leading pole) enables cell runs whereas symmetric rotation triggers cell tumbling. Taking into consideration similar observations in spirochetes, bacteria possessing bipolar ribbons of periplasmic flagella, we propose a conserved motility paradigm for spirillum-shaped bipolarly flagellated bacteria.
PMCID: PMC4573727  PMID: 26240070
14.  Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein 
Oncotarget  2016;7(8):8850-8865.
Nogo-B receptor (NgBR), a type I single transmembrane domain receptor is the specific receptor for Nogo-B. Our previous work demonstrated that NgBR is highly expressed in breast cancer cells, where it promotes epithelial mesenchymal transition (EMT), an important step in metastasis. Here, we show that both in vitro and in vivo increased expression of NgBR contributes to the increased chemoresistance of Bel7402/5FU cells, a stable 5-FU (5-Fluorouracil) resistant cell line related Bel7402 cells. NgBR knockdown abrogates S-phase arrest in Bel7402/5FU cells, which correlates with a reduction in G1/S phase checkpoint proteins p53 and p21. In addition, NgBR suppresses p53 protein levels through activation of the PI3K/Akt/MDM2 pathway, which promotes p53 degradation via the ubiquitin proteasome pathway and thus increases the resistance of human hepatocellular cancer cells to 5-FU. Furthermore, we found that NgBR expression is associated with a poor prognosis of human hepatocellular carcinoma (HCC) patients. These results suggest that targeting NgBR in combination with chemotherapeutic drugs, such as 5-FU, could improve the efficacy of current anticancer treatments.
PMCID: PMC4891009  PMID: 26840457
NgBR; chemoresistance; HCC
15.  Growing Teratoma Syndrome Secondary to Ovarian Giant Immature Teratoma in an Adolescent Girl 
Medicine  2016;95(7):e2647.
Growing teratoma syndrome (GTS) is a rare clinical entity first described by Logothetis et al in 1982. Although it is unusual for GTS to be located in the ovary, this report is of a case of an adolescent girl who underwent a complete surgical resection of the mass. Histopathology confirmed only an immature teratoma had originated from the ovary and so she received adjuvant chemotherapy with blemycin, etopside, and cisplatin over 4 cycles. Results from an abdominal enhanced CT (computed tomography) 9 years later revealed a giant mass had compressed adjacent tissues and organs. Laparotomy was performed and a postoperative histopathology showed the presence of a mature teratoma, and so the diagnosis of ovarian GTS was made. One hundred one cases of ovarian GTS from English literature published between 1977 and 2015 were collected and respectively analyzed in large samples for the first time.
The median age of diagnosis with primary immature teratoma was 22 years (range 4–48 years, n = 56). GTS originating from the right ovary accounted for 57% (27/47, n = 47) whereas the left contained 43% (20/47, n = 47). Median primary tumor size was 18.7 cm (range 6–45 cm, n = 28) and median subsequent tumor size was 8.6 cm (range 1–25 cm, n = 25). From the primary treatment to the diagnosis of ovarian GTS, median tumor growth speed was 0.94 cm/month (range 0.3–4.3 cm/month, n = 21). Median time interval was 26.6 months (range 1–264 months, n = 41). According to these findings, 5 patients did have a pregnancy during the time interval between primary disease and GTS, making our patient the first case of having a pregnancy following the diagnosis of ovarian GTS. Because of its high recurrence and insensitiveness to chemotherapy, complete surgical resection is the preferred treatment and fertility-sparing surgery should be considered for women of child-bearing age.
Anyhow GTS of the ovary has an excellent prognosis. Patients with GTS had no evidence of recurrence or were found to be disease free during a 40.3-month (range 1–216 months, n = 48) median follow-up. Moreover, regular follow-ups with imaging and serum tumor markers are important and must not be neglected.
PMCID: PMC4998604  PMID: 26886604
16.  Duplication and Deletion of CFC1 Associated with Heterotaxy Syndrome 
DNA and Cell Biology  2015;34(2):101-106.
Heterotaxy syndrome, which causes significant morbidity and mortality, is a class of congenital disorders, in which normal left–right asymmetry cannot be properly established. To explore the role of copy number variants (CNVs) in the occurrence of heterotaxy syndrome, we recruited 93 heterotaxy patients and studied 12 of them by the Affymetrix Genome-Wide Human SNP 6.0 Array. The results were confirmed in the remaining 81 patients and 500 healthy children by quantitative real-time polymerase chain reaction (qPCR). The analysis of the SNP6.0 array showed a duplication of chromosome 2q21.1, which was verified by qPCR. The result of qPCR in the other 81 patients showed that 8/81 patients had the CNVs of 2q21.1 and the only overlapping gene in these patients is CFC1. However, in the 500 healthy children, only one carried the duplication of CFC1 (p=3.5×10−7). The duplication and deletion of CFC1 may play key roles in the occurrence of heterotaxy syndrome. Moreover, the transposed great arteries, double outlet right ventricle, single atrium, and single ventricle may share a common genetic etiology with the heterotaxy syndrome.
PMCID: PMC4308825  PMID: 25423076
17.  Rapid Identification and Characterization of Francisella by Molecular Biology and Other Techniques 
Francisella tularensis is the causative pathogen of tularemia and a Tier 1 bioterror agent on the CDC list. Considering the fact that some subpopulation of the F. tularensis strains is more virulent, more significantly associated with mortality, and therefore poses more threat to humans, rapid identification and characterization of this subpopulation strains is of invaluable importance. This review summarizes the up-to-date developments of assays for mainly detecting and characterizing F. tularensis and a touch of caveats of some of the assays.
PMCID: PMC4899538  PMID: 27335619
Francisella tularensis; molecular characterization; subpopulation typing; virulence
18.  Asymmetric stem-cell division ensures sustained keratinocyte hyperproliferation in psoriatic skin lesions 
Excessive expansion of the transit-amplifying (TA) cell compartment is a distinct morphological characteristic of psoriatic epidermal hyperplasia. In order to examine the activation of basal stem cells and how they replenish such an enlarged compartment of TA cells in psoriatic epidermis, we utilized a BrdU labeling method to monitor mitotic stem cells in a mouse model of psoriasiform dermatitis, which was induced by imiquimod. Our results showed that perpendicular and parallel cell division characteristics of dividing stem cells existed in the inflamed epidermis. When we analyzed template-DNA strand segregation in trypsin-dissociated human psoriatic keratinocytes using BrdU pulse-chase labeling, we found that the percentage of asymmetric segregation of BrdU was significantly increased in the cell pairs of psoriatic epidermal cells compared with normal epidermal cells. Furthermore, we also examined the effects of both interleukin (IL)-17A and IL-22 cytokines on the differentiation status of cultured human keratinocytes. The results indicated that both cytokines had synergistic effects on passage-one epidermal cell sheets derived from skin explants and also on cultured keratinocytes, were involved in the maintenance of the undifferentiated stem cell phenotype, and these results suggest an efficient mechanism for preventing the premature loss of basal stem-cell pools in the pro-inflammatory cytokine-enriched milieu of the psoriatic epidermis. Our findings suggest that inhibition of hyperactive stem cells represents a potential therapeutic target to combat recalcitrant epidermal hyperplasia in psoriasis.
PMCID: PMC4716788  PMID: 26707630
keratinocyte; mitosis; interleukin; stem cell; psoriasis
19.  Genomic insights into the uncultured genus ‘Candidatus Magnetobacterium' in the phylum Nitrospirae 
The ISME Journal  2014;8(12):2463-2477.
Magnetotactic bacteria (MTB) of the genus ‘Candidatus Magnetobacterium' in phylum Nitrospirae are of great interest because of the formation of hundreds of bullet-shaped magnetite magnetosomes in multiple bundles of chains per cell. These bacteria are worldwide distributed in aquatic environments and have important roles in the biogeochemical cycles of iron and sulfur. However, except for a few short genomic fragments, no genome data are available for this ecologically important genus, and little is known about their metabolic capacity owing to the lack of pure cultures. Here we report the first draft genome sequence of 3.42 Mb from an uncultivated strain tentatively named ‘Ca. Magnetobacterium casensis' isolated from Lake Miyun, China. The genome sequence indicates an autotrophic lifestyle using the Wood–Ljungdahl pathway for CO2 fixation, which has not been described in any previously known MTB or Nitrospirae organisms. Pathways involved in the denitrification, sulfur oxidation and sulfate reduction have been predicted, indicating its considerable capacity for adaptation to variable geochemical conditions and roles in local biogeochemical cycles. Moreover, we have identified a complete magnetosome gene island containing mam, mad and a set of novel genes (named as man genes) putatively responsible for the formation of bullet-shaped magnetite magnetosomes and the arrangement of multiple magnetosome chains. This first comprehensive genomic analysis sheds light on the physiology, ecology and biomineralization of the poorly understood ‘Ca. Magnetobacterium' genus.
PMCID: PMC4260714  PMID: 24914800
20.  Aβ(1–42) Fibril Structure Illuminates Self-recognition and Replication of Amyloid in Alzheimer’s 
Increasing evidence suggests that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1–42)), rather than the more abundant Aβ(1–40), provokes the Alzheimer’s cascade. To date, structural details of misfolded Aβ(1–42) have remained elusive. Here we present the atomic model of Aβ(1–42) amyloid fibril based on solid-state NMR (SSNMR) data. It displays triple parallel-β-sheet segments that are different from reported structures of Aβ(1–40) fibrils. Remarkably, Aβ(1–40) is not compatible with the triple-β motif, as seeding with Aβ(1–42) fibrils does not promote conversion of monomeric Aβ(1–40) into fibrils via cross-replication. SSNMR experiments suggest that the Ala42 carboxyl terminus, absent in Aβ(1–40), forms a salt-bridge with Lys28 as a self-recognition molecular switch that excludes Aβ(1–40). The results provide insight into Aβ(1–42)-selective self-replicating amyloid propagation machinery in early-stage Alzheimer’s disease.
PMCID: PMC4476499  PMID: 25938662
21.  Risk factors for distal stent graft-induced new entry following endovascular repair of type B aortic dissection 
Journal of Thoracic Disease  2015;7(11):1907-1916.
Distal stent graft-induced new entry (DSINE) has been increasingly observed following thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD). We seek to identify the risk factors for DSINE following TEVAR in patients with TBAD.
Between January 2009 and January 2013, we performed TEVAR for 579 patients with TBAD. The clinical data were retrospectively analyzed with univariate and multivariate analyses to identify the risk factors for DSINE.
Two patients (0.3%) died after the initial TEVAR. Morbidity included spinal cord injury in 2 (0.3%), stroke in 3 (0.5%) and endoleak in 12 (2.1%) patients. Clinical and radiological follow-up was complete in 100% (577/577) averaging 47±16 months. Late death occurred in 6 patients. DSINE occurred in 39 patients (6.7%) at mean 22±17 months after the initial TEVAR, which was managed with re-TEVAR in 25 and medically in 14. At 33±18 months after DSINE, 11 of patients managed medically (11/14) and all patients managed with re-TEVAR (25/25) survived (P=0.048). Freedom from DSINE was 92.7% at 5 years (95% CI: 90.0-94.7%). Using tapered stent grafts with a proximal end 4-8 mm larger than the distal end, TEVAR performed in the acute phase (≤14 days from onset) was associated with a significantly lower incidence of DSINE than TEVAR performed in the chronic phase (4.3%, 7/185 vs. 13.9%, 15/108; P=0.003). Risk factors for DSINE were stent grafts less than 145 mm in length [odds ratio (OR) 2.268; 95% CI: 1.121-4.587; P=0.023] and TEVAR performed in the chronic phase (OR 1.935; 95% CI: 1.004-3.731; P=0.049).
Our results show that TEVAR performed during the acute phase and using stent grafts longer than 145 mm could decrease the incidence of DSINE in patients with TBAD. Tapered stent grafts with a proximal end 4-8 mm larger than the distal end may be helpful in preventing DSINE after TEVAR performed in the acute phase than TEVAR performed in the chronic phase, due to the difference in mobility of the dissected flap. Expedite repeat TEVAR is recommended to improve the clinical prognosis for patients with DSINE.
PMCID: PMC4669288  PMID: 26716029
Aortic dissection; type B; endovascular; stent graft; new entry
22.  Integrated Analyses of Gene Expression Profiles Digs out Common Markers for Rheumatic Diseases 
PLoS ONE  2015;10(9):e0137522.
Rheumatic diseases have some common symptoms. Extensive gene expression studies, accumulated thus far, have successfully identified signature molecules for each rheumatic disease, individually. However, whether there exist shared factors across rheumatic diseases has yet to be tested.
We collected and utilized 6 public microarray datasets covering 4 types of representative rheumatic diseases including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and osteoarthritis. Then we detected overlaps of differentially expressed genes across datasets and performed a meta-analysis aiming at identifying common differentially expressed genes that discriminate between pathological cases and normal controls. To further gain insights into the functions of the identified common differentially expressed genes, we conducted gene ontology enrichment analysis and protein-protein interaction analysis.
We identified a total of eight differentially expressed genes (TNFSF10, CX3CR1, LY96, TLR5, TXN, TIA1, PRKCH, PRF1), each associated with at least 3 of the 4 studied rheumatic diseases. Meta-analysis warranted the significance of the eight genes and highlighted the general significance of four genes (CX3CR1, LY96, TLR5, and PRF1). Protein-protein interaction and gene ontology enrichment analyses indicated that the eight genes interact with each other to exert functions related to immune response and immune regulation.
The findings support that there exist common factors underlying rheumatic diseases. For rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and osteoarthritis diseases, those common factors include TNFSF10, CX3CR1, LY96, TLR5, TXN, TIA1, PRKCH, and PRF1. In-depth studies on these common factors may provide keys to understanding the pathogenesis and developing intervention strategies for rheumatic diseases.
PMCID: PMC4564267  PMID: 26352601
23.  Clinical evaluation of short 6-mm implants alone, short 8-mm implants combined with osteotome sinus floor elevation and standard 10-mm implants combined with osteotome sinus floor elevation in posterior maxillae: study protocol for a randomized controlled trial 
Trials  2015;16:324.
Nowadays, short dental implants are being increasingly applied in extremely resorbed posterior regions. The recent studies have indicated that short implants present a similar success rate to conventional implants. It is assumed that short implants can avoid additional surgical morbidity and are less technically demanding. However, high-quality evidence (≥Ib: evidence from at least one randomized controlled trial) on comparing the clinical outcome of short implants and longer implants combined with osteotome sinus floor elevation (OSFE) technique is limited.
The proposed study is designed as a prospective single-center, three-arm parallel group, randomized controlled trial. We plan to enroll 150 patients in need of dental implant treatment in the posterior maxilla. The inclusion criteria include: age ≧18 years, partial edentulism in the posterior maxilla for at least 3 months from tooth loss, residual bone height ranging from 6 to 8 mm, sufficient bone width (≥6 mm) in the edentulous region. The patients will be divided into three groups according to a table of random numbers: group 1: short implants (6 mm) alone; group 2: short implants (8 mm) combined with osteotome sinus floor elevation (OSFE); group 3: standard implants (10 mm) combined with OSFE. The assignment will be concealed from the clinical operators until the beginning of implant surgery. The outcome examiners and patients will be kept blinded to the assignment. Implant survival rates, implant success rates, complications, resonance frequency analysis (RFA) measurements, marginal bone level, treatment time and patient-reported outcome (visual analogue scale for intraoperative discomfort and postoperative pain) will be recorded. Clinical re-evaluations will be performed at 12, 24, 36 and 60 months after crown placement.
The results of the trial will support better decision-making for dental implant treatment in atrophic maxillary ridges. If favorable, the use of short implants may avoid adjunct procedures used for implant insertion, thus reducing operative time, complexity and postoperative discomfort.
Trial registration identifier: NCT02350075 (registered on 17 February 2015).
PMCID: PMC4518682  PMID: 26223254
Dental implants; Short implants; Osteotome sinus floor elevation; Clinical evaluation
24.  Identification of Gene Biomarkers for Distinguishing Small-Cell Lung Cancer from Non-Small-Cell Lung Cancer Using a Network-Based Approach 
BioMed Research International  2015;2015:685303.
Lung cancer consists of two main subtypes: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) that are classified according to their physiological phenotypes. In this study, we have developed a network-based approach to identify molecular biomarkers that can distinguish SCLC from NSCLC. By identifying positive and negative coexpression gene pairs in normal lung tissues, SCLC, or NSCLC samples and using functional association information from the STRING network, we first construct a lung cancer-specific gene association network. From the network, we obtain gene modules in which genes are highly functionally associated with each other and are either positively or negatively coexpressed in the three conditions. Then, we identify gene modules that not only are differentially expressed between cancer and normal samples, but also show distinctive expression patterns between SCLC and NSCLC. Finally, we select genes inside those modules with discriminating coexpression patterns between the two lung cancer subtypes and predict them as candidate biomarkers that are of diagnostic use.
PMCID: PMC4531169  PMID: 26290870
25.  Angle Sensing in Magnetotaxis of Magnetospirillum magneticum AMB-1 
The mechanism of how magnetotactic bacteria navigate along magnetic field has been a puzzle. Two main models disagree on whether the magnetotactic behavior results from passive alignment to the magnetic field or active sensing of the magnetic force. Here, we quantitatively studied the swimming patterns of Magnetospirillum magneticum AMB-1 cells to understand the origin of their magnetotaxis behaviors. Single-cell tracking and swimming pattern analysis showed that the cells follow a mixed run/reverse/tumble pattern. The average run time decreased with the angle between the cell’s moving velocity and the external magnetic field. For mutant cells without the methyl-accepting chemotaxis protein (MCP) Amb0994, such dependence disappeared and bacteria failed to align to magnetic field lines. This dysfunction was recovered by complementary amb0994 on plasmid. At high magnetic field (>5mT), all strains with intact magnetosome chains (including the Δamb0994-0995 strain) showed alignment with the external magnetic field. These results suggested that the mechanism for magnetotaxis is magnetic field dependent. Due to the magnetic dipole moment of the cell, the external magnetic field exerts a torque on the cell. In high magnetic fields, this torque is large enough to overcome the random re-orientation of the cell, and the cells align passively with the external magnetic field, much like a compass. In smaller (and biologically more relevant) external fields, the external force alone is not strong enough to align the cell mechanically. However, magnetotactic behaviors persist due to an active sensing mechanism in which the cell senses the torque by Amb0994 and actively regulate the flagella bias accordingly to align its orientation with the external magnetic field. Our results reconciled the two putative models for magnetotaxis and revealed a key molecular component in the underlying magneto-sensing pathway.
PMCID: PMC4134682  PMID: 24877161

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