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1.  AST: An Automated Sequence-Sampling Method for Improving the Taxonomic Diversity of Gene Phylogenetic Trees 
PLoS ONE  2014;9(6):e98844.
A challenge in phylogenetic inference of gene trees is how to properly sample a large pool of homologous sequences to derive a good representative subset of sequences. Such a need arises in various applications, e.g. when (1) accuracy-oriented phylogenetic reconstruction methods may not be able to deal with a large pool of sequences due to their high demand in computing resources; (2) applications analyzing a collection of gene trees may prefer to use trees with fewer operational taxonomic units (OTUs), for instance for the detection of horizontal gene transfer events by identifying phylogenetic conflicts; and (3) the pool of available sequences is biased towards extensively studied species. In the past, the creation of subsamples often relied on manual selection. Here we present an Automated sequence-Sampling method for improving the Taxonomic diversity of gene phylogenetic trees, AST, to obtain representative sequences that maximize the taxonomic diversity of the sampled sequences. To demonstrate the effectiveness of AST, we have tested it to solve four problems, namely, inference of the evolutionary histories of the small ribosomal subunit protein S5 of E. coli, 16 S ribosomal RNAs and glycosyl-transferase gene family 8, and a study of ancient horizontal gene transfers from bacteria to plants. Our results show that the resolution of our computational results is almost as good as that of manual inference by domain experts, hence making the tool generally useful to phylogenetic studies by non-phylogeny specialists. The program is available at http://csbl.bmb.uga.edu/~zhouchan/AST.php.
doi:10.1371/journal.pone.0098844
PMCID: PMC4044049  PMID: 24892935
2.  Quality of life in rectal cancer patients after radical surgery: a survey of Chinese patients 
Background
We aimed to investigate the impact of sociodemographic and clinical characteristics on health-related quality of life (HRQoL) in disease-free survivors after radical surgery for rectal cancer in a Chinese mainland population.
Methods
We performed a cross-sectional survey from August 2002 to February 2011 by use of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR38 questionnaires of 438 patients who underwent curative surgery for rectal cancer. Patients who were followed up for a minimum of 6 months, had no relevant major comorbidities and whose disease had not recurred were asked to complete both questionnaires. The impact of sociodemographic and clinical characteristics on HRQoL were compared by univariate and multivariate regression analyses.
Results
In total, 285 patients responded to the survey (response rate, 65.1%). Psychological-related HRQoL variables such as emotional function (P = 0.021) and future perspectives (P = 0.044) were poorer for younger patients than for older patients; and physiological-related HRQoL was reflected by physical function (P = 0.039), which was poorer for older patients than for younger patients. In terms of physiologic function and symptoms concerning HRQoL, such as pain (P = 0.002) and insomnia (P = 0.018), females had lower values than males. Low education and unemployment were associated with a worse HRQoL. HRQoL was worse for patients with stomas compared to those without, especially in psychosocial areas such as role function (P = 0.025), social function (P <0.001) and body image (P = 0.004). Financial HRQoL was worse for younger patients and patients with stoma.
Conclusions
HRQoL aspects and degrees to which they were impaired after curative surgery for rectal cancer were different when compared by many sociodemographic and clinical factors in Chinese mainland patients.
doi:10.1186/1477-7819-12-161
PMCID: PMC4059026  PMID: 24886668
Health-related quality of life; Rectal cancer; Surgery; Chinese
3.  Does mechanical disturbance affect the performance and species composition of submerged macrophyte communities? 
Scientific Reports  2014;4:4888.
Submerged macrophyte communities are frequently subjected to disturbance of various frequency and strength. However, there is still little experimental evidence on how mechanical disturbance affects the performance and species composition of such plant communities. In a greenhouse experiment, we constructed wetland communities consisting of five co-occurring clonal submerged macrophyte species (Hydrilla verticillata, Elodea canadensis, Ceratophyllum demersum, Chara fragilis, and Myriophyllum spicatum) and subjected these communities to three mechanical disturbance regimes (no, moderate and strong disturbance). Strong mechanical disturbance greatly decreased overall biomass, number of shoot nodes and total shoot length, and increased species diversity (evenness) of the total community. It also substantially decreased the growth of the most abundant species (H. verticillata), but did not affect growth of the other four species. Our data reveal that strong disturbance can have different effects on different submerged macrophyte species and thus alters the performance and species composition of submerged macrophyte communities.
doi:10.1038/srep04888
PMCID: PMC4013934  PMID: 24811826
4.  Peritoneal Protein Leakage, Systemic Inflammation, and Peritonitis Risk in Patients on Peritoneal Dialysis 
♦ Background: Whether peritoneal protein leakage predicts risk for peritonitis in patients on peritoneal dialysis (PD) is unknown. In this observational cohort study, we aimed to determine that association and, further, to explore if it might be explained by systemic inflammation.
♦ Methods: We prospectively followed 305 incident PD patients to first-episode peritonitis, censoring, or the end of the study. Demographics, comorbidity score, biochemistry, and peritoneal protein clearance (PrC) were collected at baseline. The predictors of first-episode peritonitis were analyzed prospectively.
♦ Results: During follow-up, 14 868 patient months and 251 episodes of peritonitis were observed. The baseline PrC was 73.2 mL/day (range: 53.2 - 102 mL/day). Patients with a high PrC were prone to be older and malnourished. They also had a higher comorbidity score and higher C-reactive protein values. In 132 first episodes of peritonitis, baseline PrC was shown to be a significant independent predictor after adjustment for age, sex, body mass index, diabetes, residual renal function, hemoglobin, and peritoneal transport rate. Systemic inflammatory markers such as serum albumin, C-reactive protein, and interleukin-6 could not explain the association of PrC and high risk for peritonitis.
♦ Conclusions: Baseline peritoneal protein leakage was able to independently predict risk for peritonitis, which is not explained by systemic inflammation. The underlying mechanisms should be explored in future.
doi:10.3747/pdi.2011.00326
PMCID: PMC3649896  PMID: 23284072
Peritonitis; protein leakage; inflammation
5.  National Surveillance of Methicillin-Resistant Staphylococcus aureus in China Highlights a Still-Evolving Epidemiology with 15 Novel Emerging Multilocus Sequence Types 
Journal of Clinical Microbiology  2013;51(11):3638-3644.
The global spread of methicillin-resistant Staphylococcus aureus (MRSA) is a serious problem, particularly in mainland China. In order to better understand the national molecular epidemiology and resistance profiles of hospital-associated MRSA (HA-MRSA) in China, a laboratory-based multicenter surveillance study was conducted. Sixty-nine hospitals in 45 large cities in 27 provinces were involved, and a total of 1,141 HA-MRSA isolates were collected during the 6-month study period in 2011. All MRSA isolates were characterized by multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) typing, spa typing, detection of the Panton-Valentine leukocidin (PVL) locus (lukS-PV and lukF-PV), and antibiogram analysis. ST239-III-t030, ST239-III-t037, and ST5-II-t002 were the predominant HA-MRSA clones (overall prevalence rates, 57.1%, 12.9%, and 8.1%, respectively), although the prevalence rates of these major clones varied markedly in different administrative regions. Of note, 6.6% of the HA-MRSA isolates were found to belong to ST59, which had typical community-associated MRSA (CA-MRSA) features, including carriage of SCCmec type IV or V and PVL and less antimicrobial resistance than other major HA-MRSA clones. Moreover, among 36 MLST sequence types (STs) identified, 15 STs, accounting for 3.5% of total isolates, were novel. A novel ST designated ST2590, which is a single-locus variant of ST5-II-t002, was identified in three hospitals in two large cities, with a total of 17 isolates. To further monitor trends in HA-MRSA prevalence, epidemic clonal shifts, clone emergence, and transmission between community and health care settings, longitudinal national MRSA surveillance is required.
doi:10.1128/JCM.01375-13
PMCID: PMC3889745  PMID: 23985906
6.  Treatment with Panax Ginseng Antagonizes the Estrogen Decline in Ovariectomized Mice 
Ginseng is a popular herb for alleviating menopausal symptoms; however, no conclusive scientific data has shown ginseng as being efficient in such therapies. The present study was designed to evaluate the estrogenic efficacy of ginseng on reproductive target tissues of ovariectomized (OVX) mice. The OVX mice were treated with ginseng at doses of 12.0, 18.0 and 24.0 g/kg per day for four weeks. Ginseng treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by the reversal of the atrophy of the uterus and vagina, upregulation of estrogen receptor (ER) α and ER β expression at the protein and mRNA level in the reproductive tissues, where ER α upregulation was stronger than that of ER β. Meanwhile, treatment with ginseng significantly increased adrenal gland weight and serum estradiol and clearly decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in circulation. Notably, the largest changes in these parameters were found at the highest dose of 24.0 g/kg. Moreover, ginseng at 18.0 g/kg resulted in the greatest decrease in weight gain caused by ovariectomy. The data suggest that ginseng estrogenic responses show tissue variation that reflects different affinities of ERs for ginseng components. This study demonstrates that ginseng activity is mediated through estrogenic components and provides further evidence for ginseng treatment of postmenopausal symptoms.
doi:10.3390/ijms15057827
PMCID: PMC4057706  PMID: 24806341
ginseng; estrogenic activity; uterus; vagina; ER α; ER β
7.  mhpT Encodes an Active Transporter Involved in 3-(3-Hydroxyphenyl)Propionate Catabolism by Escherichia coli K-12 
Applied and Environmental Microbiology  2013;79(20):6362-6368.
Escherichia coli K-12 utilizes 3-(3-hydroxyphenyl)propionate (3HPP) as a sole carbon and energy source. Among the genes in its catabolic cluster in the genome, mhpT was proposed to encode a hypothetical transporter. Since no transporter for 3HPP uptake has been identified, we investigated whether MhpT is responsible for 3HPP uptake. MhpT fused with green fluorescent protein was found to be located at the periphery of cells by confocal microscopy, consistent with localization to the cytoplasmic membrane. Gene knockout and complementation studies clearly indicated that mhpT is essential for 3HPP catabolism in E. coli K-12 W3110 at pH 8.2. Uptake assays with 14C-labeled substrates demonstrated that strain W3110 and strain W3110ΔmhpT containing recombinant MhpT specifically transported 3HPP but not benzoate, 3-hydroxybenzoate, or gentisate into cells. Energy dependence assays suggested that MhpT-mediated 3HPP transport was driven by the proton motive force. The change of Ala-272 of MhpT to a histidine, surprisingly, resulted in enhanced transport activity, and strain W3110ΔmhpT containing the MhpT A272H mutation had a slightly higher growth rate than the wild-type strain at pH 8.2. Hence, we demonstrated that MhpT is a specific 3HPP transporter and vital for E. coli K-12 W3110 growth on this substrate under basic conditions.
doi:10.1128/AEM.02110-13
PMCID: PMC3811207  PMID: 23934492
8.  Comparison of Predictive Value of Cardiometabolic Indices for Subclinical Atherosclerosis in Chinese Adults 
PLoS ONE  2014;9(4):e93538.
Objectives
Metabolic disturbances are well-known risk factors for atherosclerosis, but it remains unclear which cardiometabolic components are the predominant determinants. This study aimed to compare and identify the key determinants of carotid atherosclerosis in asymptomatic middle-aged and elderly Chinese.
Methods
A community-based cross-sectional study including 3,162 apparently healthy residents aged 37–75 years was performed from July 2008 to June 2010 in Guangzhou, China. Carotid artery intima-media thickness (IMT) was assessed by B-mode ultrasound, and increased IMT was defined as IMT>1.00 mm. Obesity indices, blood pressure, fasting blood lipids, glucose and uric acid levels were determined. Principal components factor analysis was used to extract common factors underlying 11 metabolic factors.
Results
Four common factors, defined as “adiposity,” “blood lipids,” “triglycerides/uric acid (TG/UA)” (in men) or “triglycerides/uric acid/glucose (TG/UA/Glu)” (in women), and “blood pressure,” were retained for both sexes. After adjustment for potential covariates, the “adiposity” factor showed the strongest positive association with increased IMT in men. Comparing the extreme quartiles, ORs (95% CI) of increased IMT were 4.64 (2.04–10.59) at the CCA and 2.37 (1.54–3.64) at the BIF), followed by “blood pressure”, the corresponding OR (95% CI) was 2.85 (1.37–5.90) at the CCA. Whereas, the four common factors showed comparable and weak relationship with increased IMTs, the ORs for quartile 4 vs. quartile 1 varied from 0.89 to 3.59 in women.
Conclusions
Among the metabolic factors, “adiposity” and “blood pressure” play predominant roles in the presence of carotid atherosclerosis in men, but no key factor is identified in women.
doi:10.1371/journal.pone.0093538
PMCID: PMC3972246  PMID: 24691185
9.  GBE50 Attenuates Inflammatory Response by Inhibiting the p38 MAPK and NF-κB Pathways in LPS-Stimulated Microglial Cells 
Overactivated microglia contribute to a variety of pathological conditions in the central nervous system. The major goal of the present study is to evaluate the potential suppressing effects of a new type of Ginko biloba extract, GBE50, on activated microglia which causes proinflammatory responses and to explore the underlying molecular mechanisms. Murine BV2 microglia cells, with or without pretreatmentof GBE50 at various concentrations, were activated by incubation with lipopolysaccharide (LPS). A series of biochemical and microscopic assays were performed to measure cell viability, cell morphology, release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and signal transduction via the p38 MAPK and nuclear factor-kappa B (NF-κB) p65 pathways. We found that GBE50 pretreatment suppressed LPS-induced morphological changes in BV2 cells. Moreover, GBE50 treatment significantly reduced the release of proinflammatory cytokines, TNF-α and IL-1β, and inhibited the associated signal transduction through the p38 MAPK and NF-κB p65 pathways. These results demonstrated the anti-inflammatory effect of GBE50 on LPS-activated BV2 microglia cells, and indicated that GBE50 reduced the LPS-induced proinflammatory TNF-α and IL-1β release by inhibiting signal transduction through the NF-κB p65 and p38 MAPK pathways. Our findings reveal, at least in part, the molecular basis underlying the anti-inflammatory effects of GBE50.
doi:10.1155/2014/368598
PMCID: PMC3982279  PMID: 24782908
10.  Directed differentiation of skin-derived precursors into fibroblast-like cells 
Skin-derived precursors (SKPs), which are located at skin’s dermis, display multi-lineage potential and can produce both neural and mesodermal progeny in vitro. SKPs are considered to take part in dermal reconstruction and may be an important source of fibroblast during wound repairing. To explore the possibility of differentiation of SKPs into fibroblasts, the 3rd passage SKPs were treated with 0, 20, 40, 100, or 500 ng/ml human recombinant connective tissue growth factor (CTGF) for 48 h or treated with 100 ng/ml CTGF for 0, 24, 48, 72, or 96 h. Subsequently, a series of methods were to be used to observe cells immunocytochemistry changes under fluorescence microscope, to validate the mRNA expression change of collagen I, collagen III, fibroblast-specific protein 1 (FSP-1) and alpha smooth muscle actin (α-SMA) by quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR), to analyze the expression of collagen I and collagen III protein by Enzyme-linked immunosorbent assay (ELISA), to semiquantitatively measure the expression of FSP-1 and α-SMA by western-blot. After differentiation, cells showed that positively staining for collagen I, collagen III, α-SMA, and FSP-1, which are markers for fibroblasts, but negative expression for neural precursors. The effects of CTGF on collagen I, collagen III, FSP-1 and α-SMA in SKPs were detected both on the transcriptional and posttranscriptional levels. These findings indicate that SKPs can be induced to differentiate into fibroblast-like cells with CTGF treatment that may be a key source of fibroblast in wound healing.
PMCID: PMC4014227  PMID: 24817943
Skin-derived precursor (SKP); differentiation; fibroblast-like cell; connective tissue growth factor (CTGF)
11.  Epidemiological and Clinical Characteristics and Risk Factors for Death of Patients with Avian Influenza A H7N9 Virus Infection from Jiangsu Province, Eastern China 
PLoS ONE  2014;9(3):e89581.
Background
A novel avian influenza A (H7N9) virus has caused great morbidity as well as mortality since its emergence in Eastern China in February 2013. However, the possible risk factors for death are not yet fully known.
Methods and Findings
Patients with H7N9 virus infection between March 1 and August 14, 2013 in Jiangsu province were enrolled. Data were collected with a standard form. Mean or percentage was used to describe the features, and Fisher's exact test or t-test test was used to compare the differences between fatal and nonfatal cases with H7N9 virus infection. A total of 28 patients with H7N9 virus infection were identified among whom, nine (32.1%) died. The median age of fatal cases was significant higher than nonfatal cases (P<0.05). Patients with older age were more strongly associated with increased odds of death (OR = 30.0; 95% CI, 2.85–315.62). Co-morbidity with chronic lung disease and hypertension were risk factors for mortality (OR = 14.40; 95% CI, 1.30–159.52, OR = 6.67; 95% CI, 1.09–40.43, respectively). Moreover, the presence of either bilateral lung inflammation or pulmonary consolidation on chest imaging on admission was related with fatal outcome (OR = 7.00; 95%CI, 1.10–44.61). Finally, dynamic monitoring showed that lymphopenia was more significant in fatal group than in nonfatal group from day 11 to week five (P<0.05). The decrease in oxygenation indexes were observed in most cases and more significantly in fatal cases after week three (P<0.05), and the value of nearly all fatal cases were below 200 mmHg during our evaluation period.
Conclusions
Among cases with H7N9 virus infection, increased age accompanied by co-morbidities was the risk of death. The severity of lung infection at admission, the persistence of lymphocytopenia, and the extended duration of lower oxygenation index all contributed to worsened outcomes of patients with H7N9 virus infection.
doi:10.1371/journal.pone.0089581
PMCID: PMC3942409  PMID: 24595034
12.  A systems biology-based investigation into the therapeutic effects of Gansui Banxia Tang on reversing the imbalanced network of hepatocellular carcinoma 
Scientific Reports  2014;4:4154.
Several complex molecular events are involved in tumorigenesis of hepatocellular carcinoma (HCC). The interactions of these molecules may constitute the HCC imbalanced network. Gansui Banxia Tang (GSBXT), as a classic Chinese herbal formula, is a popular complementary and alternative medicine modality for treating HCC. In order to investigate the therapeutic effects and the pharmacological mechanisms of GSBXT on reversing HCC imbalanced network, we in the current study developed a comprehensive systems approach of integrating disease-specific and drug-specific networks, and successfully revealed the relationships of the ingredients in GSBXT with their putative targets, and with HCC significant molecules and HCC related pathway systems for the first time. Meanwhile, further experimental validation also demonstrated the preventive effects of GSBXT on tumor growth in mice and its regulatory effects on potential targets.
doi:10.1038/srep04154
PMCID: PMC3932480  PMID: 24561634
13.  Second-hand smoke exposure in different types of venues: before and after the implementation of smoke-free legislation in Guangzhou, China 
BMJ Open  2014;4(2):e004273.
Objectives
Smoke-free legislation was implemented in Guangzhou on 1 September 2010. However, the smoke-free policy did not cover all indoor areas and smoking rooms can be set in some public places. This study aimed to assess changes in self-reported second-hand smoke (SHS) exposure in different types of venues and in homes, in order to evaluate the effectiveness of smoke-free legislation.
Methods/design
A repeated cross-sectional survey of representative participants was conducted in Guangzhou before and after the smoke-free legislation. Logistic regression models were used to examine the effectiveness of smoke-free legislation.
Main outcome measures
Self-reported exposure to SHS,antitobacco advertisements and tobacco advertisements.
Participants
A total of 4900 participants before the ban and 5135 participants after the ban were selected using a multistage stratified design.
Results
In full smoking ban places, overall self-reported SHS exposure has declined significantly from 58.8% to 50.3% (p<0.05) with greater drops in cultural venues, government offices and commercial venues. The smoke-free policy did not alter SHS exposure in smokers’ homes (39.6% in 2009 vs 40.0% in 2011; p=0.454). Although a slight decrease in SHS exposure was observed in smoking rooms in hotels, workplaces, restaurants, cafes/bars/nightclubs and amusement parks, SHS continued to be high in those areas. The implementation of smoke-free legislation was accompanied by an increase in antitobacco advertisements.
Conclusions
SHS exposure declines more significantly in full smoking ban places than in partial smoking ban places. The smoke-free policy in public places does not lead to more SHS exposure in homes. Therefore, it is recommended that Guangzhou should implement a 100% smoke-free policy in all public places and workplaces in the future.
doi:10.1136/bmjopen-2013-004273
PMCID: PMC3927996  PMID: 24534259
Epidemiology; Public Health
14.  Seroprevalence of Toxoplasma gondii Infection in Sows in Hunan Province, China 
The Scientific World Journal  2014;2014:347908.
Toxoplasma gondii infections are prevalent in animals and humans worldwide. Although the prevalence of T. gondii has been reported in many animals in China, little is known of T. gondii infection in sows. Antibodies to T. gondii in sows in Hunan province, subtropical China, were examined using indirect hemagglutination test (IHAT). Overall, 31.3% (373/1191) of the examined sows were seropositive for T. gondii. Among 11 representative regions of Hunan province, the seroprevalence ranged from 14.8% to 45.1%. In addition, the T. gondii seroprevalence was higher in summer (37.4%) and autumn (34.9%) than in spring (24.6%) and winter (23.9%). Regarding different antibody titers, the seroprevalence ranged from 1.8% (titer ≥ 1 : 1024) to 17.4% (titer = 1 : 64). The findings of the present investigation revealed the high seroprevalence of T. gondii in sows in Hunan province, China, which poses a potential risk for T. gondii infection in humans and animals in this province. Therefore, effective measures should be taken to prevent and control toxoplasmosis of pigs in this province. This is the first report of the comprehensive survey of T. gondii seroprevalence in sows in Hunan Province, subtropical China.
doi:10.1155/2014/347908
PMCID: PMC3932812  PMID: 24683331
15.  Deletion of microRNA miR-223 increases Langerhans cell cross-presentation 
Langerhans cells (LCs) are skin-residential dendritic cells that regulate skin immunity. MicroRNAs (miRNAs) are key regulators in the control of biological functions in a variety of cell types. Deletion of all miRNAs interrupts the homeostasis and function of epidermal LCs. However, the roles of individual miRNAs in regulating LC development and function are still completely unknown. MiRNA miR-233 is especially expressed in the myeloid compartment. Here, we reported that miR-223 is highly expressed in freshly isolated epidermal LCs, and tested whether miR-223 regulates LC development and function using miR-223 knockout (KO) mice. We found that the number, maturation, migration and phagocytic capacity of LCs were comparable between miR-223KO and wild-type mice. However, lack of miR-223 significantly increases LCs-mediated antigen-specific CD8+ T cell proliferation in vivo and in vitro, while LCs from KO and WT mice showed comparable stimulation for antigen-specific CD4+ T cells. Our data suggest that miR-223 negatively regulates LC cross-presentation, but may not be required for normal LC homeostasis and development.
doi:10.1016/j.biocel.2012.11.004
PMCID: PMC3757948  PMID: 23153510
Langerhans cells; microRNA; miR-223; cross-presentation
16.  FUNCTIONAL UNDERSTANDING OF THE DIVERSE EXON-INTRON STRUCTURES OF HUMAN GPCR GENES 
The GPCR genes have a variety of exon-intron structures even though their proteins are all structurally homologous. We have examined all human GPCR genes with at least two functional protein isoforms, totaling 199, aiming to gain an understanding of what may have contributed to the large diversity of the exon-intron structures of the GPCR genes. The 199 genes have a total of 808 known protein splicing isoforms with experimentally verified functions. Our analysis reveals that 1,301 (80.6%) adjacent exon-exon pairs out of the total of 1,613 in the 199 genes have either exactly one exon skipped or the intron in-between retained in at least one of the 808 protein splicing isoforms. This observation has a statistical significance p-value of 2.051762* e−09, assuming that the observed splicing isoforms are independent of the exon-intron structures. Our interpretation of this observation is that the exon boundaries of the GPCR genes are not randomly determined; instead they may be selected to facilitate specific alternative splicing for functional purposes.
doi:10.1142/S0219720013500194
PMCID: PMC3905620  PMID: 24467758
gene structure; alternative splicing; G protein-coupled receptor; GPCR; exon-intron structures
17.  Cluster Subcutaneous Allergen Specific Immunotherapy for the Treatment of Allergic Rhinitis: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(1):e86529.
Background
Although allergen specific immunotherapy (SIT) represents the only immune- modifying and curative option available for patients with allergic rhinitis (AR), the optimal schedule for specific subcutaneous immunotherapy (SCIT) is still unknown. The objective of this study is to systematically assess the efficacy and safety of cluster SCIT for patients with AR.
Methods
By searching PubMed, EMBASE and the Cochrane clinical trials database from 1980 through May 10th, 2013, we collected and analyzed the randomized controlled trials (RCTs) of cluster SCIT to assess its efficacy and safety.
Results
Eight trials involving 567 participants were included in this systematic review. Our meta-analysis showed that cluster SCIT have similar effect in reduction of both rhinitis symptoms and the requirement for anti-allergic medication compared with conventional SCIT, but when comparing cluster SCIT with placebo, no statistic significance were found in reduction of symptom scores or medication scores. Some caution is required in this interpretation as there was significant heterogeneity between studies. Data relating to Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in 3 included studies were analyzed, which consistently point to the efficacy of cluster SCIT in improving quality of life compared to placebo. To assess the safety of cluster SCIT, meta-analysis showed that no differences existed in the incidence of either local adverse reaction or systemic adverse reaction between the cluster group and control group.
Conclusion
Based on the current limited evidence, we still could not conclude affirmatively that cluster SCIT was a safe and efficacious option for the treatment of AR patients. Further large-scale, well-designed RCTs on this topic are still needed.
doi:10.1371/journal.pone.0086529
PMCID: PMC3904879  PMID: 24489740
18.  Biosynthetic Multitasking Facilitates Thalassospiramide Structural Diversity in Marine Bacteria 
Thalassospiramides A and B are immunosuppressant cyclic lipopeptides first reported from the marine α-proteobacterium Thalassospira sp. CNJ-328. We describe here the discovery and characterization of an extended family of 14 new analogues from four Tistrella and Thalassospira isolates. These potent calpain 1 protease inhibitors belong to six structure classes in which the length and composition of the acylpeptide side chain varies extensively. Genomic sequence analysis of the thalassospiramide-producing microbes revealed related, genus-specific biosynthetic loci encoding hybrid nonribosomal peptide synthetase/polyketide synthases consistent with thalassospiramide assembly. The bioinformatics analysis of the gene clusters suggests that structural diversity, which ranges from the 803.4 Da thalassospiramide C to the 1291.7 Da thalassospiramide F, results from a complex sequence of reactions involving amino acid substrate channeling and enzymatic multi-module skipping and iteration. Preliminary biochemical analysis of the N-terminal NRPS module from the Thalassospira TtcA megasynthase supports a biosynthetic model in which in cis amino acid activation competes with in trans activation to increase the range of amino acid substrates incorporated at the N-terminus.
doi:10.1021/ja3119674
PMCID: PMC3563429  PMID: 23270364
19.  Utility of C4d Immunostaining in the First Year after Pediatric and Young Adult Heart Transplantation 
Background
C4d assessment of endomyocardial biopsies (EMB) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether to assess all patients routinely and at what frequency/duration. We sought to evaluate the utility of routine C4d immunostaining in the first-year after pediatric and young adult HTx.
Methods
We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse, capillary staining (≥2+) was present. Rare/focal capillary staining or absence of staining was considered negative.
Results
Twenty-six of 406 first-year EMBs (6%) were C4d+ in 6 (12%) patients. Sixty-five percent of all C4d+ EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA) ≥4000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA ≥4000 MFI and/or a positive DSXM were C4d+ compared to only 1 of 41 without (50% vs. 2%; p=0.001).
Conclusions
In the first-year after HTx, C4d+ occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. While our data suggests that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA ≥4000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance.
doi:10.1016/j.healun.2012.10.009
PMCID: PMC3530146  PMID: 23260709
21.  Clinical Characteristics and Outcomes of “Silent” and “Non-Silent” Peritonitis in Patients on Peritoneal Dialysis 
♦ Objectives: We compared the clinical characteristics and outcomes of “silent” peritonitis (meaning episodes without fever and abdominal pain) and “non-silent” peritonitis in patients on peritoneal dialysis (PD).
♦ Methods: Our cohort study collected data about all peritonitis episodes occurring between January 2008 and April 2010. Disease severity score, demographics, and biochemistry and nutrition data were recorded at baseline. Effluent cell counts were examined at regular intervals, and the organisms cultured were examined. Treatment failure was defined as peritonitis-associated death or transfer to hemodialysis.
♦ Results: Of 248 episodes of peritonitis occurring in 161 PD patients, 20.9% led to treatment failure. Of the 248 episodes, 51 (20.6%) were not accompanied by fever and abdominal pain. Patients with these silent peritonitis episodes tended to be older (p = 0.003). The baseline values for body mass index, triglycerides, and daily energy intake were significantly lower before silent peritonitis episodes than before non-silent episodes (p = 0.01, 0.003, and 0.001 respectively). Although silent peritonitis episodes were more often culture-negative and less often caused by gram-negative organisms, and although they presented with low effluent white cell counts on days 1 and 3, the risk for treatment failure in those episodes was not lower (adjusted odds ratio: 1.33; 95% confidence interval: 0.75 to 2.36; p = 0.33).
♦ Conclusions: Silent peritonitis is not a rare phenomenon, especially in older patients on PD. Although these episodes were more often culture-negative, silent presentation was not associated with a better outcome.
doi:10.3747/pdi.2011.00236
PMCID: PMC3598251  PMID: 22855888
Peritonitis; outcomes
22.  Thermodynamic Analysis of Protein-Ligand Binding Interactions in Complex Biological Mixtures using the Stability of Proteins from Rates of Oxidation (SPROX) Method 
Nature protocols  2012;8(1):148-161.
The detection and quantitation of protein-ligand binding interactions is critical in a number of different areas of biochemical research from fundamental studies of biological processes to drug discovery efforts. Described here is a protocol that can be used to identify the protein targets of biologically relevant ligands (e.g. drugs like tamoxifen or cyclosporin A) in complex protein mixtures such as cell lysates. The protocol utilizes quantitative, bottom-up, shotgun proteomics technologies (iTRAQ) with a covalent labeling technique, termed Stability of Proteins from Rates of Oxidation (SPROX). In SPROX, the thermodynamic properties of proteins and protein-ligand complexes are assessed using the hydrogen peroxide-mediated oxidation of methionine residues as a function of the chemical denaturant (e.g. guanidine Hydrochloride or urea) concentration. The proteome-wide SPROX experiments described here enable the ligand binding properties of hundreds of proteins to be simultaneously assayed in the context of complex biological samples. The proteomic capabilities of the protocol render it amenable to detection of both the on- and off-target effects of ligand binding.
doi:10.1038/nprot.2012.146
PMCID: PMC3717606  PMID: 23257983
Protein-ligand; protein-drug; interaction; mass spectrometry; iTRAQ; shotgun proteomics; hydrogen peroxide; H2O2; methionine oxidation; denaturant; guanidine; urea; protein folding/unfolding
23.  PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation 
Clinics  2014;69(1):15-22.
OBJECTIVE:
This study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation.
METHODS:
A cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual-luciferase reporter assay system.
RESULTS:
Two novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts.
CONCLUSION:
The findings of this study associate PITX2c loss-of-function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia.
doi:10.6061/clinics/2014(01)03
PMCID: PMC3870307  PMID: 24473555
Atrial Fibrillation; Transcriptional Factor; PITX2c; Genetics; Reporter Gene
24.  An Improved MLVF Method and Its Comparison with Traditional MLVF, spa Typing, MLST/SCCmec and PFGE for the Typing of Methicillin-Resistant Staphylococcus aureus 
Methicillin-resistant Staphylococcus aureus (MRSA) has become an important nosocomial pathogen, causing considerable morbidity and mortality. During the last 20 years, a variety of genotyping methods have been introduced for screening the prevalence of MRSA. In this study, we developed and evaluated an improved approach capillary gel electrophoresis based multilocus variable-number tandem-repeat fingerprinting (CGE/MLVF) for rapid MRSA typing. A total of 42 well-characterized strains and 116 non-repetitive clinical MRSA isolates collected from six hospitals in northeast China between 2009 and 2010 were tested. The results obtained by CGE/MLVF against clinical isolates were compared with traditional MLVF, spa typing, Multilocus sequence typing/staphylococcal cassette chromosome mec (MLST/SCCmec) and pulse field gel electrophoresis (PFGE). The discriminatory power estimated by Simpson’s index of diversity was 0.855 (28 types), 0.855 (28 patterns), 0.623 (11 types), 0.517 (8 types) and 0.854 (28 patterns) for CGE/MLVF, traditional MLVF, spa typing, MLST/SCCmec and PFGE, respectively. All methods tested showed a satisfied concordance in clonal complex level calculated by adjusted Rand’s coefficient. CGE/MLVF showed better reproducibility and accuracy than traditional MLVF and PFGE methods. In addition, the CGE/MLVF has potential to produce portable results. In conclusion, CGE/MLVF is a rapid and easy to use MRSA typing method with lower cost, good reproducibility and high discriminatory power for monitoring the outbreak and clonal spread of MRSA isolates.
doi:10.3390/ijms15010725
PMCID: PMC3907834  PMID: 24406728
methicillin-resistant Staphylococcus aureus (MRSA); genotyping; multilocus variable-number tandem repeat fingerprinting (MLVF); capillary gel electrophoresis; pulse field gel electrophoresis (PFGE); Multilocus sequence typing (MLST); staphylococcal cassette chromosome mec (SCCmec)
25.  A phylogenetic model for understanding the effect of gene duplication on cancer progression 
Nucleic Acids Research  2013;42(5):2870-2878.
As biotechnology advances rapidly, a tremendous amount of cancer genetic data has become available, providing an unprecedented opportunity for understanding the genetic mechanisms of cancer. To understand the effects of duplications and deletions on cancer progression, two genomes (normal and tumor) were sequenced from each of five stomach cancer patients in different stages (I, II, III and IV). We developed a phylogenetic model for analyzing stomach cancer data. The model assumes that duplication and deletion occur in accordance with a continuous time Markov Chain along the branches of a phylogenetic tree attached with five extended branches leading to the tumor genomes. Moreover, coalescence times of the phylogenetic tree follow a coalescence process. The simulation study suggests that the maximum likelihood approach can accurately estimate parameters in the phylogenetic model. The phylogenetic model was applied to the stomach cancer data. We found that the expected number of changes (duplication and deletion) per gene for the tumor genomes is significantly higher than that for the normal genomes. The goodness-of-fit test suggests that the phylogenetic model with constant duplication and deletion rates can adequately fit the duplication data for the normal genomes. The analysis found nine duplicated genes that are significantly associated with stomach cancer.
doi:10.1093/nar/gkt1320
PMCID: PMC3950708  PMID: 24371277

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