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In genome-wide association studies (GWAS), a wide variety of analysis tools have been designed, leading to various formats of GWAS data. How to convert a dataset in non-PLINK format into PLINK format to use its powerful analysis performance, or to convert a dataset in PLINK format into the format of other analysis tools, is a problem that needs to be faced and solved. To address this issue, we developed a tool called coPLINK, a complementary tool to PLINK, to cooperate with PLINK to implement the conversions of GWAS data formats and to provide some additional functions, such as data files comparison. The tool can implement mutual conversions not only between an existing data format and PLINK PED/BED, but also between a user-defined data format and PLINK PED. The usage and performance of the tool are similar to PLINK. The characteristics of the conversions of existing data formats and user-defined formats make it be a good assistant to PLINK or other tools and, have good potential for GWAS studies or other works.

1,3-Propanediol (1,3-PDO) is an important compound that is mainly used in industry for polymer production. Fermentation of 1,3-PDO from glycerol by Klebsiella pneumoniae is accompanied by formation of 2,3-butanediol (2,3-BDO) as one of the main byproduct. The first step in the formation of 2,3-BDO from pyruvate is catalyzed by acetolactate synthase (ALS), an enzyme that competes with 1,3-PDO oxidoreductase for the cofactor NADH. This study aimed to analyze the impact of engineering the 2,3-BDO formation pathway via inactivation of ALS on 1,3-PDO fermentation by K. pneumoniae HSL4. An ALS mutant was generated using Red recombinase assisted gene replacement. The ALS specific activities of K. pneumoniae ΔALS were notably lower than that of the wild-type strain. Fed-batch fermentation of the mutant strain resulted in a 1,3-PDO concentration, productivity and conversion of 72.04 g L-1, 2.25 g L-1 h-1, and 0.41 g g-1, increase by 4.71%, 4.65% and 1.99% compared with the parent strain. Moreover, inactivation of ALS decreased meso-2,3-BDO formation to trace amounts, significantly increased 2S,3S-BDO and lactate production, and a pronounced redistribution of intracellular metabolic flux was apparent.

The hypothesis of data probability density distributions has many effects on the design of a new statistical method. Based on the analysis of a group of real gene expression profiles, this study reveal that the primary density distributions of the real profiles are normal/log-normal and t distributions, accounting for 80% and 19% respectively. According to these distributions, we generated a series of simulation data to make a more comprehensive assessment for a novel statistical method, maximal information coefficient (MIC). The results show that MIC is not only in the top tier in the overall performance of identifying differentially expressed genes, but also exhibits a better adaptability and an excellent noise immunity in comparison with the existing methods.

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity. The rats were fed either a high fat (HFD) or normal rat chow diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP), aortic superoxide (O2-) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR). Nicotine further increased SBP, O2- and impaired eNOS and EDR in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2-4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet-induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.

OBJECTIVE:To establish a point-scoring diagnostic system for Sjögren's syndrome (SS) based on quantified SPECT imaging of salivary gland, and evaluate its feasibility and performance compared with 2002 AECG criteria and 2012 ACR criteria. METHODS:213 patients with suspected SS enrolled in this study. The related clinical data of all patients were collected. All patients were evaluated and grouped on a clinical basis and posttreatment follow-up by rheumatology specialists as the unified standard (SS group with 149 cases and nSS group with 64 cases). From SPECT imaging of salivary gland, Tmax, UImax, Ts and EFs were derived for bilateral parotid and submandibular glands, and compared between the groups. A point-scoring diagnostic system for SS was established based on the quantified SPECT imaging of salivary gland. We estimated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the new diagnostic system, compared with 2002 AECG criteria and 2012 ACR criteria. RESULTS:When 7.0 was used as the cut-off point, the sensitivity, specificity, PPV, NPV and accuracy for the new point-scoring system in diagnosing SS were 89.93% (134/149), 93.75% (60/64), 97.10% (134/138), 80.00% (60/75) and 91.08% (194/213), respectively. The new point-scoring diagnostic system based on quantified SPECT imaging of salivary gland keeps the specificity comparatively to 2002 AECG criteria and 2012 ACR criteria, but improves the sensitivity significantly (P

To investigate the activation of three unfolded protein response (UPR) pathways in the lenses of age-related, high myopia-related and congenital cataracts.Lens specimens were collected from patients during small incision cataract surgery. Lenses from young cadaver eyes were collected as normal controls. Real-time PCR and Western blotting were performed to detect the expression of GRP78, p-eIF2α, spliced XBP1, ATF6, ATF4 and p-IRE1α in the lenses of normal human subjects and patients with age-related, myopia-related or congenital cataracts.In the lenses of the age-related and high myopia-related cataract groups, the protein levels of ATF6, p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78, ATF6 and ATF4 were greatly increased. Additionally, in the congenital cataract group, the protein levels of p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78 and ATF4 were greatly increased. However, the protein and gene expression levels of ATF6 were not up-regulated in the congenital cataract group compared with the normal control group.The UPR is activated via different pathways in the lenses of age-related, high myopia-related and congenital cataracts. UPR activation via distinct pathways might play important roles in cataractogenesis mechanisms in different types of cataracts.

To investigate the expression of αA- and αB-crystallin and the unfolded protein response in the lens epithelium of patients with high myopia-related cataracts.The central portion of the human anterior lens capsule together with the adhering epithelial cells, approximately 5 mm in diameter, were harvested and processed within two hours after cataract surgery from high myopia-related (spherical equivalent ≥-10.00 diopters) and age-related cataract patients or from high myopia but non-cataractous patients (tissue were collected from ocular trauma patients with high myopia and lens trauma). Anterior lens samples from fresh cadaver normal human eyes were used as normal control (collected within 6 hours from death). Real-time PCR was performed to detect the mRNA levels of α-crystallins as well as unfolded protein response (UPR)-related GRP78, spliced-XBP1, ATF4 and ATF6. Western blot analysis was used to determine the protein level of α-crystallin, GRP78, p-IRE1α, p-eIF2α and ATF6.In the lens epithelium of the high myopia-related cataract group and the age related cataract group, the mRNA and soluble protein expression of αA- and αB-crystallin were both decreased; additionally, the protein levels of ATF6, p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78, ATF6 and ATF4 were greatly increased relative to the normal control.These results suggest the significant loss of soluble α-crystallin and the activation of the UPR in the lens epithelium of patients with high myopia-related cataract, which may be associated with the cataractogenesis of high myopia-related cataract.

OBJECTIVES: The purpose of this study was to assess image quality and radiation dose of lower extremity CT angiography (CTA) with 70 kVp, high pitch acquisition and sinogram-affirmed iterative reconstruction (SAFIRE). METHODS: Lower extremity CTAs were performed on 44 patients: 22 patients were examined using protocol A (120 kVp, pitch of 0.85 and 120 ml of contrast agent on a first-generation dual-source CT) (120 kVp group) and 22 patients were evaluated with protocol B (70 kVp, pitch of 2.2 and 80 ml of contrast agent on a second-generation dual-source CT) (70 kVp group). Images from the 120 kVp group were reconstructed with filtered back projection (FBP) and images from the 70 kVp group with SAFIRE. The attenuation, image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Two radiologists subjectively assessed image quality of lower extremity arteries, plantar arterial enhancement and venous contamination of all patients. Radiation dose was compared between the two groups. RESULTS: Higher mean intravascular attenuation was obtained in the 70 kVp group (70 vs. 120 kVp group, 555.4 ± 83.4 HU vs. 300.9 ± 81.4 HU, P0.05). The venous contamination score was 1.5 ± 0.8 for 120 kVp group while no venous contamination was found in 70 kVp group. The inter-observer agreement was moderate to good for both groups (0.515∼1, P

BACKGROUND: Conducted in Wuhan China, this study examined follow-up and health markers in HIV patients receiving care in two treatment settings. Participants, all men who have sex with men, were followed for 18-24 months. METHOD: Patients in a "one-stop" service (ACC; N = 89) vs those in standard care clinics (CDC; N = 243) were compared on HIV treatment and retention in care outcomes. RESULTS: Among patients with CD4 cell count ≦350 cells/µL, the proportion receiving cART did not differ across clinic groups. The ACC was favored across five other indicators: proportion receiving tests for CD4 cell count at the six-month interval (98.2% vs. 79.4%, 95% CI 13.3-24.3, p = 0.000), proportion with HIV suppression for patients receiving cART for 6 months (86.5% vs. 57.1%, 95% CI 14.1-44.7, p = 0.000), proportion with CD4 cell recovery for patients receiving cART for 12 months (55.8% vs. 22.2%, 95% CI 18.5-48.6, p = 0.000), median time from HIV confirmation to first test for CD4 cell count (7 days, 95% CI 4-8 vs. 10 days, 95% CI 9-12, log-rank p = 0.000) and median time from first CD4 cell count ≦350 cells/µL to cART initiation (26 days, 95% CI 16-37 vs. 41.5 days, 95% CI 35-46, log-rank p = 0.031). Clinic groups did not differ on any biomedical indicator at baseline, and no baseline biomedical or demographic variables remained significant in the multivariate analysis. Nonetheless, post-hoc analyses suggest the possibility of self-selection bias. CONCLUSIONS: Study findings lend preliminary support to a one-stop patient-centered care model that may be useful across various HIV care settings.

OBJECTIVE: Haemostatic biomarkers associated with poor outcome in acute ischemic stroke (AIS). The objective of the study was to evaluate the predictive value of plasma D-dimer (D-D) on functional outcome at 90-day follow-up from stroke onset. METHODS: We conducted a prospective, observational cohort study in the emergency department and enrolled 220 patients with AIS. Plasma D-D concentrations, determined by a particle-enhanced, immunoturbidimetric assay, were measured. Each patient's medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted. RESULTS: There was a positive correlation between levels of D-D and the NIHSS (r = 0.361, p

Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered hematopoiesis including T-cell leukemia. Newer vectors have been designed to decrease the incidence of these adverse events but require appropriate pre-clinical assays to demonstrate safety. We have used two distinct mouse serial transplant assays to evaluate the safety of a self-inactivating lentiviral vector intended for use in X-linked severe combined immunodeficiency (XSCID) gene therapy trials. These experiments entailed 28 months of total follow-up and included 386 mice. There were no cases in which the XSCID lentiviral vector clearly caused hematopoietic malignancies, although a single case of B cell malignancy was observed that contained the lentiviral vector as a likely passenger event. In contrast, a SFFV-DsRed γ-retroviral vector resulted in clonal transformation events in multiple secondary recipients. Non-specific pathology not related to vector insertions was noted including T cell leukemias arising from irradiated recipient cells. Overall, this comprehensive study of mouse transplant safety assays demonstrate the relative safety of the XSCID lentiviral vector but also highlight the limitations of these assays.

PurposeTo present rare benign orbital tumors with bone destruction in children who could not be diagnosed pre-surgically and may simulate malignant ones.MethodsA retrospective review of cases. Clinical, operative and pathological records in all children with a diagnosis of benign orbital tumors who showed remarkable bone destruction at a tertiary Ophthalmic Center in China between Jan 1, 2000 and Dec 31, 2009 were reviewed. All patients had definitive histopathologic diagnosis.ResultsEight patients with benign orbital tumors showed obvious bone destruction, including six cases of eosinophilic granuloma, one case of leiomyoma and one case of primary orbital intraosseous hemangioma. Among them, three patients were females and five patients were males. Tumors were unilateral in all cases, with both the right and left side affected equally. Age ranged from 3 to 7 years (mean 4.1 years). Symptom duration ranged from 1 to 5 weeks (mean 4.8 weeks). Eyelid swelling and palpable mass were the most common complaint. There was no evidence for multifocal involvement in cases with eosinophilic granuloma. Among six patients with eosinophilic granuloma, two were treated with low dose radiation (10 Gy), three received systemic corticosteroid and one was periodically observed only after incisional biopsy or subtotal curettage. There was no postoperative therapeutic intervention in the two patients with leiomyoma and intraosseous hemangioma. All eight patients regained normal vision without local recurrence after a mean follow-up time of 32.8 months.ConclusionBenign orbital tumors such as isolated eosinophilic granuloma, leiomyoma and primary orbital intraosseous hemangioma may show remarkable bone destruction.

OBJECTIVE: MicroRNAs (miRNAs) expression is altered in cancer cells, and miRNAs could serve as diagnostic and prognostic biomarker for cancer patients. This study was designed to analyze circulating miRNAs expression in the malignant pleural effusion (MPE) and their association with patient survival in non-small cell lung cancer (NSCLC). METHODS: Pleural effusion from 184 patients with NSCLC and MPE were collected. MiRNA microarray and bioinformatics interpretation were used to evaluate miRNA expression profiles in 10 NSCLC patients with different survival prognosis. Associations were validated in 184 patients (randomly classified into training and validation set with equal number in each group) using quantitative RT-PCR. Risk scores were formulated based on the expression signature of miRNAs. Clinical data, such as patient survival, were collected for correlation analysis. RESULTS: Thirty-three miRNAs were found to be altered more than two-fold by microarray in malignant effusions between longer-survival and shorter-survival groups, and levels of five miRNAs (miRNA-93, miRNA-100, miRNA-134, miRNA-151 and miRNA-345) were significantly associated with overall survival. High expression of miR-100 and low expression of miRNA-93, miRNA-134, miRNA-151 and miRNA-345 were associated with poor survival in both the training and validation cohort. Patients with high risk scores had overall poor survival compared to the patients with low risk scores. Risk score was an independent predictor of patient survival. CONCLUSIONS: Expression patterns of miRNAs are systematically altered in MPE of patient with NSCLC. The five miRNA signature from the effusion may serve as a predictor for the overall survival of patients with lung cancers.

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60×10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.

Plant phenology models, especially leafing models, play critical roles in evaluating the impact of climate change on the primary production of temperate plants. Existing models based on temperature alone could not accurately simulate plant leafing in arid and semi-arid regions. The objective of the present study was to test the suitability of the existing temperature-based leafing models in arid and semi-arid regions, and to develop a temperature-precipitation based leafing model (TP), based on the long-term (i.e., 12-27 years) ground leafing observation data and meteorological data in Northeast China. The better simulation of leafing for all the plant species in Northeast China was given by TP with the fixed starting date (TPn) than with the parameterized starting date (TPm), which gave the smallest average root mean square error (RMSE) of 4.21 days. Tree leafing models were validated with independent data, and the coefficient of determination (R(2)) was greater than 0.60 in 75% of the estimates by TP and the spring warming model (SW) with the fixed starting date. The average RMSE of herb leafing simulated by TPn was 5.03 days, much lower than other models (>9.51 days), while the average R(2) of TPn and TPm were 0.68 and 0.57, respectively, much higher than the other models (