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1.  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.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0116079
PMCID: PMC4300093  PMID: 25602284
2.  The 5-Year Onset and Regression of Diabetic Retinopathy in Chinese Type 2 Diabetes Patients 
PLoS ONE  2014;9(11):e113359.
Purpose
To determine the rate and risk factors of diabetic retinopathy (DR) onset and regression in Chinese type 2 diabetes mellitus patients.
Methods
This is a 5-year community-based prospective study. The demographic information, systemic examination results and ophthalmological test results of each participant were collected. The study outcomes were DR incidence, defined as the onset of DR in at least one eye, and DR regression, defined as full regression from existing DR to no retinopathy without invasive treatments. The associations between each potential risk factor and the outcomes were studied.
Results
In total, 778 participants were enrolled. There were 322 patients without DR at baseline, of which 151 participants developed DR during follow-up (DR incidence rate = 46.89%). Baseline hyperglycemia and high blood pressure were two independent risk factors associated with DR incidence. Among the 456 participants with existing DR at entry, 110 fully recovered after 5 years (DR regression rate = 24.12%). Low baseline glucose and low serum triglyceride were two independent factors associated with DR regression.
Conclusions
DR incidence occurred more frequently in patients with hyperglycemia and high blood pressure. DR regression occurred mostly in patients with lower glucose and lower serum triglyceride levels among Chinese type 2 diabetes patients.
doi:10.1371/journal.pone.0113359
PMCID: PMC4234658  PMID: 25402474
3.  The Incidence and Distribution of Surgical Site Infection in Mainland China: A Meta-Analysis of 84 Prospective Observational Studies 
Scientific Reports  2014;4:6783.
Surgical site infection (SSI) is one of the most common surgical complications in the world, particularly in developing countries. This study aimed to estimate the incidence and distribution of SSI in mainland China. Eighty-four prospective observational studies (82 surveillance studies, 1 nested case control study, and 1 cohort study) were selected for inclusion in this meta-analysis. The average incidence of SSI in mainland China was 4.5% (95% CI: 3.1–5.8) from 2001 to 2012 and has decreased significantly in recent years. The remote western regions had a higher incidence of 4.6% (95% CI: 4.0–5.3). The most common surgical procedure was abdominal surgery (8.3%, 95% CI: 6.5–10.0). SSI occurred frequently in the elderly (5.1%, 95% CI: 2.2–8.0), patients confined to hospital for over 2 weeks (5.7%, 95% CI: 0.9–10.0), superficial incision wounds (5.6%, 95% CI: 4.4–6.8), dirty wounds (8.7%, 95% CI: 6.9–10.6), operations lasting for over 2 hours (7.3%, 95% CI: 4.9–9.7), general anaesthesia operations (4.7%, 95% CI: 2.7–6.6), emergency surgeries (5.9%, 95% CI: 4.2–7.7), and non-intra-medication operations (7.4%, 95% CI: 1.0–13.7).
doi:10.1038/srep06783
PMCID: PMC4214160  PMID: 25356832
4.  Exercise Training Preserves Ischemic Preconditioning in Aged Rat Hearts by Restoring the Myocardial Polyamine Pool 
Background. Ischemic preconditioning (IPC) strongly protects against myocardial ischemia reperfusion (IR) injury. However, IPC protection is ineffective in aged hearts. Exercise training reduces the incidence of age-related cardiovascular disease and upregulates the ornithine decarboxylase (ODC)/polyamine pathway. The aim of this study was to investigate whether exercise can reestablish IPC protection in aged hearts and whether IPC protection is linked to restoration of the cardiac polyamine pool. Methods. Rats aging 3 or 18 months perform treadmill exercises with or without gradient respectively for 6 weeks. Isolated hearts and isolated cardiomyocytes were exposed to an IR and IPC protocol. Results. IPC induced an increase in myocardial polyamines by regulating ODC and spermidine/spermine acetyltransferase (SSAT) in young rat hearts, but IPC did not affect polyamine metabolism in aged hearts. Exercise training inhibited the loss of preconditioning protection and restored the polyamine pool by activating ODC and inhibiting SSAT in aged hearts. An ODC inhibitor, α-difluoromethylornithine, abolished the recovery of preconditioning protection mediated by exercise. Moreover, polyamines improved age-associated mitochondrial dysfunction in vitro. Conclusion. Exercise appears to restore preconditioning protection in aged rat hearts, possibly due to an increase in intracellular polyamines and an improvement in mitochondrial function in response to a preconditioning stimulus.
doi:10.1155/2014/457429
PMCID: PMC4227379  PMID: 25404991
5.  Don’t forget the posters! Quality and content variables associated with accepted abstracts at a national trauma meeting 
BACKGROUND
As a primary venue for presenting research results, abstracts selected for presentation at national meetings should be of the highest scientific merit and research quality. It is uncertain to what degree this is achieved as the methodological quality of abstracts submitted to national surgical meetings has not been previously described. The objective of this study was to evaluate abstracts presented at a leading trauma meeting for methodological quality.
METHODS
All abstracts accepted for the 2009 American Association for the Surgery of Trauma meeting were reviewed and scored for methodological quality based on 10 criteria (scores, 0–10; 10 being the highest). Criteria were based on nationally published methodology guidelines. Two independent reviewers who were blinded to institution, region, and author reviewed each abstract.
RESULTS
A total of 187 abstracts were accepted for presentation (67 oral and 120 posters). The most frequent clinical topics were shock/transfusion (23%), abdomen (12%), and nervous system (11%). Shock/transfusion abstracts were more common in the oral presentations (31% vs. 19%; p =0.06). Abstracts from the northeast and south regions were the most common in both oral (26% and 29%) and posters (25% and 24%). Basic science accounted for 12% of accepted studies, while 51% were clinical and 28% were health services/outcomes. Only 8% of abstracts presented randomized data and only 11% reported null findings. Overall abstract scores ranged from 3 to 10 (median, 7; mean, 7.4). Abstracts selected for poster presentation had an overall higher score than those selected for oral presentation (7.4 ±1.7 vs. 6.8 ±1.7; p =0.02).
CONCLUSION
Although oral presentations traditionally receive the most attention and interest, the methodological quality of abstracts accepted for poster presentation equals (and sometimes exceeds) that of oral abstracts. Attendees of these national meetings should reconsider their time spent in viewing and visiting these poster sessions as with the oral presentations. In light of our findings, we highly encourage that all members and guests attend the American Association for the Surgery of Trauma Poster Rounds at each year’s scientific assembly.
doi:10.1097/TA.0b013e3182479c9b
PMCID: PMC4198948  PMID: 22673278
Trauma; abstract; meeting; quality; methodology
6.  Neutrophil CD64 expression is a predictor of mortality for patients in the intensive care unit 
Background: Neutrophil CD64 has been shown to be a promising biomarker for bacterial infection and sepsis identification. However, the prognostic value of CD64 in predicting the likelihood of survival for patients in intensive care unit (ICU) is unclear. Methods: A total of 797 patients in the ICU of Xin-Hua Hospital, Shanghai, China were enrolled. We determined the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores from these patients and collected blood samples to measure the levels of neutrophil CD64, thyroid hormone and C-reactive protein (CRP). We assessed the association between APACHE II scores or these biomarkers and mortality of patients in the ICU. Receiver operating characteristic (ROC) curves were generated and the Area Under the Curve (AUC) for each indicator was determined. Results: The AUC for CD64 was 0.752 ± 0.026, which was higher than that of FT3 (0.696 ± 0.028) and CRP (0.672 ± 0.026). APACHE II scores had the highest AUC (0.872 ± 0.018). The level of neutrophil CD64 expression positively associated with CRP and APACHE II, and negatively correlated with FT3. Multiple regression analysis revealed that APACHE II scores (Standard β value = 0.183, P < 0.001), CD64 (Standard β value = 0.518, P < 0.001) or log (CRP) (Standard β value = 1.203, P < 0.001) independently predicted ICU mortality. Conclusion: CD64 had the greatest power for predicting ICU mortality other than APACHE II scores. This result indicates that CD64 may be used as a biomarker to in combination with the use of APACHE II scores to improve the accuracy of predicting mortality outcome for patients in the ICU.
PMCID: PMC4270525  PMID: 25550820
Neutrophil CD64; ICU; mortality; predictor
7.  A case of heart failure due to alcoholic cardiomyopathy combined with acute pulmonary embolism 
Journal of Thoracic Disease  2014;6(9):E176-E180.
It has not been reported that cases of alcoholic cardiomyopathy (ACM) combined with acute pulmonary embolism (PE). We hereby present a case of a 48-year-old male with ACM with significant enlargement of the heart and heart failure is described. Then, the patient was seized with acute PE which was confirmed by specific examination and his symptoms.
doi:10.3978/j.issn.2072-1439.2014.07.32
PMCID: PMC4178092  PMID: 25276392
Alcoholic cardiomyopathy (ACM); pulmonary embolism (PE); heart failure
8.  Primary clear cell adenocarcinoma of the colon presenting as a huge extracolic mass: A case report 
Oncology Letters  2014;8(4):1873-1875.
A primary clear cell adenocarcinoma of the colon is a rare oncologic entity. The current study presents a case of such a tumor in the transverse colon of a 26-year-old male, and describes the computed tomography features of the neoplasm. The tumor appeared as an extensive extracolic mass, which displaced the loop of the small bowel and pancreas, and invaded the spleen. A laparotomy was performed and a huge mass measuring 12 cm maximally was revealed, arising from the transverse colon close to the left colonic flexure, with invasion of the spleen. The tumor and the spleen were resected concurrently. Histopathological examination of the excised mass revealed features of clear cell adenocarcinoma. A primary clear cell adenocarcinoma of the colon is a rare tumor, with only 13 cases reported in the English literature at present. The present case is reported here due to its rarity.
doi:10.3892/ol.2014.2420
PMCID: PMC4156264  PMID: 25202428
clear cell adenocarcinoma; computed tomography; young age; colon
9.  Quantitative analysis of mammalian GIRK2 channel regulation by G proteins, the signaling lipid PIP2 and Na+ in a reconstituted system 
eLife  2014;3:e03671.
GIRK channels control spike frequency in atrial pacemaker cells and inhibitory potentials in neurons. By directly responding to G proteins, PIP2 and Na+, GIRK is under the control of multiple signaling pathways. In this study, the mammalian GIRK2 channel has been purified and reconstituted in planar lipid membranes and effects of Gα, Gβγ, PIP2 and Na+ analyzed. Gβγ and PIP2 must be present simultaneously to activate GIRK2. Na+ is not essential but modulates the effect of Gβγ and PIP2 over physiological concentrations. Gαi1(GTPγS) has no effect, whereas Gαi1(GDP) closes the channel through removal of Gβγ. In the presence of Gβγ, GIRK2 opens as a function of PIP2 mole fraction with Hill coefficient 2.5 and an affinity that poises GIRK2 to respond to natural variations of PIP2 concentration. The dual requirement for Gβγ and PIP2 can help to explain why GIRK2 is activated by Gi/o, but not Gq coupled GPCRs.
DOI: http://dx.doi.org/10.7554/eLife.03671.001
eLife digest
Though every cell in the body is surrounded by a membrane, there are a number of ways that molecules can pass through this membrane to either enter or leave the cell. Proteins from the GIRK family form channels in the membranes of mammalian cells, and when open these channels allow potassium ions to flow through the membrane to control the membrane's voltage.
GIRK channels are found in the heart and in the central nervous system, and can be activated in a variety of ways. Sodium ions and molecules called ‘signaling lipids’ can regulate the activation of GIRK channels. These channels can also be caused to open by G proteins: proteins that are found inside cells and that help to transmit signals from the outside of a cell to the inside. Three G proteins—called Gα, Gβ, and Gγ—work together in a complex that functions a bit like a switch. When switched on, the Gα subunit is separated from the other two subunits (called Gβγ); and both parts can then activate different signaling pathways inside the cell.
The Gβγ subunits and a signaling lipid have been known to regulate the opening of GIRK channels for a number of years, but these events have only been studied in the context of living cells. The specific role of each molecule, and whether the Gα subunit can also regulate the GIRK channels, remains unknown. Now Wang et al. have produced one type of mouse GIRK channel, called GIRK2, in yeast cells, purified this protein, and added it into an artificial membrane. This ‘reconstituted system’ allowed the regulation of a GIRK channel to be investigated under more controlled conditions than in previous experiments.
Wang et al. found that the Gβγ subunits and the signaling lipid both need to be present to activate the GIRK2 channel. Sodium ions were not essential, but promoted further opening when Gβγ and the signaling lipid were already present. When locked in its ‘on’ state, the Gα subunit had no effect on GIRK2, but adding Gα locked in the ‘off’ state closed these channels by removing the Gβγ proteins.
The findings of Wang et al. suggest that it should be possible to use a similar reconstituted system to investigate what allows different G proteins to activate specific signaling pathways.
DOI: http://dx.doi.org/10.7554/eLife.03671.002
doi:10.7554/eLife.03671
PMCID: PMC4135351  PMID: 25049222
G protein gated potassium channel; planar lipid bilayer; G proteins; PIP2; sodium activation; G protein coupled receptor; human; mouse
10.  Multiscale model of platelet translocation and collision 
The tethering of platelets on the injured vessel surface mediated by glycoprotein Ibα (GPIbα) - Von Willebrand factor (vWF) bonds, as well as the interaction between flowing platelets and adherent platelets, are two key events that take place immediately following blood vessel injury. This early-stage platelet deposition and accumulation triggers the initiation of hemostasis, a self-defensive mechanism to prevent the body from excessive blood loss. To understand and predict this complex process, one must integrate experimentally determined information on the mechanics and biochemical kinetics of participating receptors over very small time frames (1–1000 µs) and length scales (10–100 nm), to collective phenomena occurring over seconds and tens of microns. In the present study, a unique three dimensional multiscale computational model, platelet adhesive dynamics (PAD), was applied to elucidate the unique physics of (i) a non-spherical, disk-shaped platelet interacting and tethering onto the damaged vessel wall followed by (ii) collisional interactions between a flowing platelet with a downstream adherent platelet. By analyzing numerous simulations under different physiological conditions, we conclude that the platelet’s unique spheroid-shape provides heterogeneous, orientation-dependent translocation (rolling) behavior which enhances cell-wall interactions. We also conclude that platelet-platelet near field interactions are critical for cell-cell communication during the initiation of microthrombi. The PAD model described here helps to identify the physical factors that control the initial stages of platelet capture during this process.
doi:10.1016/j.jcp.2012.08.014
PMCID: PMC3706308  PMID: 23853387
Adhesion; Multiscale modeling; Platelet; Receptors; Shear flow; Von Willebrand factor
11.  miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1 
Background
microRNAs (miRNAs) are a class of small non-coding RNAs that play important roles in carcinogenesis. In the present study, we investigated the effect of miR-212 on pancreatic ductal adenocarcinoma (PDAC) and its target protein.
Methods
Quantitative real-time PCR(qRT-PCR) was performed to detect the expression of miR-212 in PDAC tissues and pancreatic cancer cell lines. miR-212 mimic, miR-212 inhibitor and negative control were transfected into pancreatic cancer cells and the effect of miR-212 up-regulation and down-regulation on the proliferation, migration and invasion of cells were investigated. Furthermore, the mRNA and protein levels of Patched-1(PTCH1) were measured. Meanwhile, luciferase assays were performed to validate PTCH1 as miR-212 target in PDAC.
Results
miR-212 was up-regulated in PDAC tissues and cells.Using both gain-of function and loss-of function experiments, a pro-oncogenic function of miR-212 was demonstrated in PDAC. Moreover, up-regulated of PTCH1 could attenuate the effect induced by miR-212.
Conclusion
These data suggest that miR-212 could facilitate PDAC progression and metastasis through targeting PTCH1, implicating a novel mechanism for the progression of PDAC.
doi:10.1186/1756-9966-33-54
PMCID: PMC4085644  PMID: 24961235
miR-212; Patched-1; Pancreatic cancer; Proliferation; Migration; Invasion
12.  PinX1-siRNA/mPEG-PEI-SPION combined with doxorubicin enhances the inhibition of glioma growth 
Resistance to chemotherapy and the side effects of anticancer drugs are the major obstacles for glioma treatment. The aim of the present study was to develop a novel approach for the treatment of gliomas that improved the therapeutic effect; the anticancer drug, doxorubicin (DOX), was combined with short interfering (si)RNA and monomethoxy polyethylene glycol polyethylenimine superparamagnetic iron oxide nanoparticle (mPEG-PEI-SPION), a magnetic resonance imaging (MRI)-visible nanoparticle. Specific siRNA molecules, delivered by mPEG-PEI-SPION, were employed to knockdown the PIN2-interacting protein 1 (PinX1) gene in C6 glioma cells. PinX1 is a nucleolar protein associated with telomere and telomerase. C6 cells were treated with DOX and/or PinX1-siRNA. The results of the transfection experiments revealed that siRNA/mPEG-PEI-SPION was transfected into C6 cells with high efficiency. PinX1-siRNA was unable to inhibit C6 cells, while in the PinX1-siRNA + DOX group, the same dose of DOX caused an increased loss of cell viability. Therefore, mPEG-PEI-SPION was shown to be viable for siRNA delivery into C6 cells and coadministration of DOX with PinX1-siRNA may be a potential therapeutic method for inhibiting gliomas.
doi:10.3892/etm.2014.1586
PMCID: PMC3991531  PMID: 24940406
monomethoxy polyethylene glycol polyethyleneimine superparamagnetic iron oxide nanoparticle; doxorubicin; PIN2-interacting protein 1; short interfering RNA; glioma
13.  Ginsenoside Metabolite Compound K Promotes Recovery of Dextran Sulfate Sodium-Induced Colitis and Inhibits Inflammatory Responses by Suppressing NF-κB Activation 
PLoS ONE  2014;9(2):e87810.
Phytogenic compounds with anti-oxidant and anti-inflammatory properties, such as ginsenoside metabolite compound K (CK) or berberine (BBR), are currently discussed as promising complementary agents in the prevention and treatment of cancer and inflammation. The latest study showed that ginsenoside Rb1 and its metabolites could inhibit TNBS-induced colitis injury. However, the functional mechanisms of anti-inflammation effects of ginsenoside, particularly its metabolite CK are still not clear. Here, using dextran sulfate sodium (DSS)-induced colitis in mice, clinical parameters, intestinal integrity, pro-inflammatory cytokines production, and signaling pathways in colonic tissues were determined. In mild and sever colitis mice, CK and BBR (as a positive agent) alleviated colitis histopathology injury, ameliorated myeloperoxidase (MPO) activity, reduced pro-inflammatory cytokines production, such as, IL-6, IL-1β, TNF-α, and increased anti-inflammatory cytokine IL-10 production in both mice colon tissues and blood. Nevertheless, the results revealed that CK and BBR inhibited NF-κB p65 nuclear translocation, downregulated p-IκBα and upregulated IκBα, indicating that CK, as well as BBR, suppressed the activation of the NF-κB pathway in the progression of colitis with immunofluorescence, immunohistochemical and western blotting analysis. Furthermore, CK inhibited pro-inflammatory cytokines production in LPS-activated macrophages via down-regulation of NF-κB signaling pathway. Taken together, our results not only reveal that CK promotes the recovery of the progression of colitis and inhibits the inflammatory responses by suppressing NF-κB activation, but also suggest that CK downregulates intestinal inflammation through regulating the activation of macrophages and pro-inflammatory cytokines production.
doi:10.1371/journal.pone.0087810
PMCID: PMC3913696  PMID: 24504372
14.  Physiological and Biochemical Characterization of a Novel Nicotine-Degrading Bacterium Pseudomonas geniculata N1 
PLoS ONE  2014;9(1):e84399.
Management of solid wastes with high nicotine content, such as those accumulated during tobacco manufacturing, poses a major challenge, which can be addressed by using bacteria such as Pseudomonas and Arthrobacter. In this study, a new species of Pseudomonas geniculata, namely strain N1, which is capable of efficiently degrading nicotine, was isolated and identified. The optimal growth conditions for strain N1 are a temperature of 30°C, and a pH 6.5, at a rotation rate of 120 rpm min−1 with 1 g l−1 nicotine as the sole source of carbon and nitrogen. Myosmine, cotinine, 6-hydroxynicotine, 6-hydroxy-N-methylmyosmine, and 6-hydroxy-pseudooxynicotine were detected as the five intermediates through gas chromatography-mass and liquid chromatography-mass analyses. The identified metabolites were different from those generated by Pseudomonas putida strains. The analysis also highlighted the bacterial metabolic diversity in relation to nicotine degradation by different Pseudomonas strains.
doi:10.1371/journal.pone.0084399
PMCID: PMC3885553  PMID: 24416227
16.  A framework for correcting brain retraction based on an eXtended Finite Element Method using a laser range scanner 
Background
Brain retraction causes great distortion that limits the accuracy of an image-guided neurosurgery system that uses preoperative images. Therefore, brain retraction correction is an important intraoperative clinical application.
Methods
We used a linear elastic biomechanical model, which deforms based on the eXtended Finite Element Method (XFEM) within a framework for brain retraction correction. In particular, a laser range scanner was introduced to obtain a surface point cloud of the exposed surgical field including retractors inserted into the brain. A brain retraction surface tracking algorithm converted these point clouds into boundary conditions applied to XFEM modeling that drive brain deformation. To test the framework, we performed a brain phantom experiment involving the retraction of tissue. Pairs of the modified Hausdorff distance between Canny edges extracted from model-updated images, pre-retraction, and post-retraction CT images were compared to evaluate the morphological alignment of our framework. Furthermore, the measured displacements of beads embedded in the brain phantom and the predicted ones were compared to evaluate numerical performance.
Results
The modified Hausdorff distance of 19 pairs of images decreased from 1.10 to 0.76 mm. The forecast error of 23 stainless steel beads in the phantom was between 0 and 1.73 mm (mean 1.19 mm). The correction accuracy varied between 52.8 and 100 % (mean 81.4 %).
Conclusions
The results demonstrate that the brain retraction compensation can be incorporated intraoperatively into the model-updating process in image-guided neurosurgery systems.
doi:10.1007/s11548-013-0958-8
PMCID: PMC4082653  PMID: 24293030
Brain retraction; Extended finite element method; Laser range scanner; Image-guided neurosurgery system
17.  Systematic Unraveling of the Unsolved Pathway of Nicotine Degradation in Pseudomonas 
PLoS Genetics  2013;9(10):e1003923.
Microorganisms such as Pseudomonas putida play important roles in the mineralization of organic wastes and toxic compounds. To comprehensively and accurately elucidate key processes of nicotine degradation in Pseudomonas putida, we measured differential protein abundance levels with MS-based spectral counting in P. putida S16 grown on nicotine or glycerol, a non-repressive carbon source. In silico analyses highlighted significant clustering of proteins involved in a functional pathway in nicotine degradation. The transcriptional regulation of differentially expressed genes was analyzed by using quantitative reverse transcription-PCR. We observed the following key results: (i) The proteomes, containing 1,292 observed proteins, provide a detailed view of enzymes involved in nicotine metabolism. These proteins could be assigned to the functional groups of transport, detoxification, and amino acid metabolism. There were significant differences in the cytosolic protein patterns of cells growing in a nicotine medium and those in a glycerol medium. (ii) The key step in the conversion of 3-succinoylpyridine to 6-hydroxy-3-succinoylpyridine was catalyzed by a multi-enzyme reaction consisting of a molybdopeterin binding oxidase (spmA), molybdopterin dehydrogenase (spmB), and a (2Fe-2S)-binding ferredoxin (spmC) with molybdenum molybdopterin cytosine dinucleotide as a cofactor. (iii) The gene of a novel nicotine oxidoreductase (nicA2) was cloned, and the recombinant protein was characterized. The proteins and functional pathway identified in the current study represent attractive targets for degradation of environmental toxic compounds.
Author Summary
Pseudomonas putida strains are among the microorganisms that have acquired the capability to use toxic and xenobiotic compounds, such as nicotine, for growth. Although nicotine degradation by Pseudomonas was first discovered more than 50 years ago, the underlying molecular mechanisms remain unclear. In the last few years, we have made significant efforts to identify the key genes for the hydroxylation of 3-succinoylpyridine (SP) through genomic library screening and purification of wild-type enzymes. However, these efforts did not result in identifying any genes related to SP hydroxylation. In this study, by using comparative genetic analysis, we report the identification of 3 key genes, spmA, spmB and spmC from P. putida S16. The heterotrimeric enzyme encoded by these genes requires molybdopterin-cytosine dinucleotide as a cofactor. The proteomes of strain S16 grown on nicotine or glycerol contain 1,292 observed proteins, and provide a detailed view of enzymes involved in nicotine degradation. Our comparative analysis of the proteomic profiles of nicotine grown versus glycerol grown bacterial cells reveals a wide range of cellular processes and functions related to nicotine catabolism.
doi:10.1371/journal.pgen.1003923
PMCID: PMC3812094  PMID: 24204321
18.  Integrated Analysis of Long Noncoding RNA and Coding RNA Expression in Esophageal Squamous Cell Carcinoma 
Tumorigenesis is a complex dynamic biological process that includes multiple steps of genetic and epigenetic alterations, aberrant expression of noncoding RNA, and changes in the expression profiles of coding genes. We call the collection of those perturbations in genome space the “cancer initiatome.” Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and they have key regulatory functions in chromatin remodeling and gene expression. Spatiotemporal variation in the expression of lncRNAs has been observed in development and disease states, including cancer. A few dysregulated lncRNAs have been studied in cancers, but the role of lncRNAs in the cancer initiatome remains largely unknown, especially in esophageal squamous cell carcinoma (ESCC). We conducted a genome-wide screen of the expression of lncRNAs and coding RNAs from ESCC and matched adjacent nonneoplastic normal tissues. We identified differentially expressed lncRNAs and coding RNAs in ESCC relative to their matched normal tissue counterparts and validated the result using polymerase chain reaction analysis. Furthermore, we identified differentially expressed lncRNAs that are co-located and co-expressed with differentially expressed coding RNAs in ESCC and the results point to a potential interaction between lncRNAs and neighboring coding genes that affect ether lipid metabolism, and the interaction may contribute to the development of ESCC. These data provide compelling evidence for a potential novel genomic biomarker of esophageal squamous cell cancer.
doi:10.1155/2013/480534
PMCID: PMC3814080  PMID: 24222893
19.  Simulation of Platelet, Thrombus and Erythrocyte Hydrodynamic Interactions in a 3D Arteriole with In Vivo Comparison 
PLoS ONE  2013;8(10):e76949.
Cylindrical blood vessels, ellipsoid platelets and biconcave-shaped deformable erythrocytes (RBCs) are important participants in hemostasis and thrombosis. However, due to the challenge of combining these components in simulation tools, few simulation studies have included all of them in realistic three-dimensional models. In the present study, we apply a recently developed simulation model to incorporate these components and analyze the flow in a thrombotic tubular arteriole, particularly the detailed hydrodynamic interactions between the thrombus shape, RBCs and platelets. It was found that at certain azimuth positions, the velocity drops in the proximity of both the upstream and downstream edge of the thrombus, which is accompanied by a rapid velocity increase in the narrowed region. The RBCs alter the flow profiles significantly from the typical low Reynolds (Re) number flow, and also enhance the deposition of free flowing platelets onto the thrombus. By evaluating the platelet-thrombus interaction and platelet-RBC interaction together, several mechanisms of platelet deposition augmentation are identified. With in vivo data comparison, our model illustrates the potential of future thrombosis studies that incorporate detailed receptor-ligand adhesion modules.
doi:10.1371/journal.pone.0076949
PMCID: PMC3788741  PMID: 24098571
20.  Increased TGF-β Contributes to Deterioration of Refrigerated Fresh Frozen Plasma's Effects in vitro on Endothelial Cells 
Shock (Augusta, Ga.)  2011;36(1):54-59.
Resuscitation with fresh frozen plasma (FFP) is associated with improved outcomes after hemorrhagic shock (HS). Many trauma centers are using thawed plasma which has been stored for up to 5 days at 4°C (refrigeration), yet the effect of refrigeration on FFP is relatively unknown. Previously our group showed that refrigeration of FFP changed its coagulation factors and diminished its beneficial effects on endothelial cell (EC) function and resuscitation in an animal model of HS.We hypothesize that growth factor composition of FFP is altered during refrigeration, leading to a diminished beneficial effect on EC. Transforming growth factor (TGF)-β is a potent inhibitor of EC migration and is released during refrigeration of platelets. We found increased TGF-β1 protein levels and greater activation of downstream mediators Smad2/3 during refrigeration of FFP. Both Day 0 FFP (used on the same day after being thawed) and Day 5 FFP (used after being thawed and refrigerated for 5 days) stimulated EC migration in vitro; however, the EC migration in Day 5 FFP was significantly reduced. Inhibition of TGF-β type I receptor blocked FFP-induced Smad3 signaling in EC cells and restored the effectiveness of Day 5 FFP on EC migration to a comparable level seen in Day 0 FFP. These data suggest that the increased TGF-β levels during FFP refrigeration contribute to the deterioration of refrigerated FFP's effects on EC migration. This study identifies a novel molecular mechanism contributing to the reduced efficacy of refrigerated FFP.
doi:10.1097/SHK.0b013e318214475e
PMCID: PMC3763495  PMID: 21330944
Hemorrhagic shock; resuscitation; Smad; TGF-β type I receptor
21.  Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney 
Endogenous mechanisms exist to limit inflammation. One such molecule is netrin. This study examined the impact of ischemia-reperfusion (I/R) on netrin expression and the role of netrin in preventing renal inflammation and injury. All three isoforms of netrin (1, 3, and 4) are expressed in normal kidney. I/R significantly downregulated netrin-1 and -4 mRNA expression, whereas expression of netrin-3 was moderately upregulated at 24 h of reperfusion. The netrin receptor UNC5B mRNA increased at 3 h and but decreased at later time points. Expression of a second netrin receptor, DCC, was not altered significantly. I/R was associated with dramatic changes in netrin-1 protein abundance and localization. Netrin-1 protein levels increased between 3 and 24 h after reperfusion. Immunolocalization showed an interstitial distribution of netrin-1 in sham-operated kidneys which colocalized with Von Willebrand Factor suggesting the presence of netrin-1 in peritubular capillaries. After I/R, interstitial netrin-1 expression decreased and netrin-1 appeared in tubular epithelial cells. By 72 h after reperfusion, netrin-1 reappeared in the interstitium while tubular epithelial staining decreased significantly. Downregulation of netrin-1 in the interstitium corresponded with increased MCP-1 and IL-6 expression and infiltration of leukocytes into the reperfused kidney. Administration of recombinant netrin-1 significantly improved kidney function (blood urea nitrogen: 161 ± 7 vs. 104 ± 24 mg/dl, creatinine: 1.3 ± 0.07 vs. 0.75 ± 0.16 mg/dl, P < 0.05 at 24 h) and reduced tubular damage and leukocyte infiltration in the outer medulla. These results suggest that downregulation of netrin-1 in vascular endothelial cells may promote endothelial cell activation and infiltration of leukocytes into the kidney thereby enhancing tubular injury.
doi:10.1152/ajprenal.00508.2007
PMCID: PMC3713074  PMID: 18216145
netrin-4; inflammation; endothelial cell; chemokine
22.  ICU Exposures for Long-Term Outcomes Research: Development and Description of Exposures for 150 ALI Patients 
Journal of critical care  2007;22(4):275-284.
Purpose
Long-term follow-up studies in critical care have described survivors’ outcomes, but provided less insight into the patient/disease characteristics and intensive care therapies (“exposures”) associated with these outcomes. Such insights are essential for improving patients’ long-term outcomes. This report describes the development of a strategy for comprehensively measuring relevant exposures for long-term outcomes research, and presents empirical results from its implementation.
Materials and Methods
A multi-step, iterative process was used to develop the exposures strategy. First, a comprehensive list of potential exposures was generated and subsequently reduced based on feasibility, redundancy, and relevance criteria. Next, data abstraction methods were designed and tested. Finally, the strategy was implemented in 150 acute lung injury patients with iterative refinement.
Results
The strategy resulted in development of >60 unique exposures requiring <45 minutes per patient-day for data collection. The vast majority of exposures had minimal missing data and adequate reliability. These data revealed that evidence-based practices including lower tidal volume ventilation, spontaneous breathing trials, sedation interruption, adequate nutrition, and blood glucose <6.1 mmol/L (110 mg/dl) occurred in only 23%-50% of assessments.
Conclusions
Using a multi-step, iterative process, a comprehensive and feasible exposure measurement strategy for long-term outcomes research was successfully developed and implemented.
doi:10.1016/j.jcrc.2007.02.001
PMCID: PMC3678945  PMID: 18086397
23.  Appoptosin is a Novel Proapoptotic Protein and Mediates Cell Death in Neurodegeneration 
Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer’s disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel proapoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders and cancers.
doi:10.1523/JNEUROSCI.3668-12.2012
PMCID: PMC3509748  PMID: 23115192
24.  Hfq-bridged ternary complex is important for translation activation of rpoS by DsrA 
Nucleic Acids Research  2013;41(11):5938-5948.
The rpoS mRNA, which encodes the master regulator σS of general stress response, requires Hfq-facilitated base pairing with DsrA small RNA for efficient translation at low temperatures. It has recently been proposed that one mechanism underlying Hfq action is to bridge a transient ternary complex by simultaneously binding to rpoS and DsrA. However, no structural evidence of Hfq simultaneously bound to different RNAs has been reported. We detected simultaneous binding of Hfq to rpoS and DsrA fragments. Crystal structures of AU6A•Hfq•A7 and Hfq•A7 complexes were resolved using 1.8- and 1.9-Å resolution, respectively. Ternary complex has been further verified in solution by NMR. In vivo, activation of rpoS translation requires intact Hfq, which is capable of bridging rpoS and DsrA simultaneously into ternary complex. This ternary complex possibly corresponds to a meta-stable transition state in Hfq-facilitated small RNA–mRNA annealing process.
doi:10.1093/nar/gkt276
PMCID: PMC3675490  PMID: 23605038
25.  Identification of Hepatotropic Viruses from Plasma Using Deep Sequencing: A Next Generation Diagnostic Tool 
PLoS ONE  2013;8(4):e60595.
We conducted an unbiased metagenomics survey using plasma from patients with chronic hepatitis B, chronic hepatitis C, autoimmune hepatitis (AIH), non-alcoholic steatohepatitis (NASH), and patients without liver disease (control). RNA and DNA libraries were sequenced from plasma filtrates enriched in viral particles to catalog virus populations. Hepatitis viruses were readily detected at high coverage in patients with chronic viral hepatitis B and C, but only a limited number of sequences resembling other viruses were found. The exception was a library from a patient diagnosed with hepatitis C virus (HCV) infection that contained multiple sequences matching GB virus C (GBV-C). Abundant GBV-C reads were also found in plasma from patients with AIH, whereas Torque teno virus (TTV) was found at high frequency in samples from patients with AIH and NASH. After taxonomic classification of sequences by BLASTn, a substantial fraction in each library, ranging from 35% to 76%, remained unclassified. These unknown sequences were assembled into scaffolds along with virus, phage and endogenous retrovirus sequences and then analyzed by BLASTx against the non-redundant protein database. Nearly the full genome of a heretofore-unknown circovirus was assembled and many scaffolds that encoded proteins with similarity to plant, insect and mammalian viruses. The presence of this novel circovirus was confirmed by PCR. BLASTx also identified many polypeptides resembling nucleo-cytoplasmic large DNA viruses (NCLDV) proteins. We re-evaluated these alignments with a profile hidden Markov method, HHblits, and observed inconsistencies in the target proteins reported by the different algorithms. This suggests that sequence alignments are insufficient to identify NCLDV proteins, especially when these alignments are only to small portions of the target protein. Nevertheless, we have now established a reliable protocol for the identification of viruses in plasma that can also be adapted to other patient samples such as urine, bile, saliva and other body fluids.
doi:10.1371/journal.pone.0060595
PMCID: PMC3629200  PMID: 23613733

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