Association of DTNBP1 With Schizophrenia: Findings From Two Independent Samples of Han Chinese Population

Objectives: Schizophrenia (SZ) is a complex psychiatric disorder that has a strong genetic basis. Dystrobrevin-binding protein 1 (DTNBP1) is one of the genes thought to be pivotal in regulating the glutamatergic system. Studies have suggested that variations in DTNBP1 confer susceptibility to SZ and clinical symptoms. Here, we performed a two-stage independent verification study to identify polymorphisms of the DTNBP1 gene that might be associated with SZ in the Han Chinese population. Methods: In stage 1, 14 single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 healthy controls (HCs) using the Illumina GoldenGate assays on a BeadStation 500G Genotyping System. In stage 2, ten SNPs were genotyped in an independent sample of 1,031 SZ patients and 621 HCs using the Illumina 660k Genotyping System. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. Results: There was a significant association related to allele frequency, and a trend association in relation to genotype between SZ patients and HCs at rs4712253 (p = 0.03 and 0.05, respectively). These associations were not evident following Bonferroni correction (p \u3e 0.05 for both). Haplotype association analysis revealed that only two haplotypes (GAG and GAA; rs16876575-rs9464793-rs4712253) were significantly different between SZ patients and HCs (chi(2) = 4.24, 6.37, p = 0.04 and 0.01, respectively). In addition, in SZ patients there was a significant association in the rs4964793 genotype for positive symptoms, and in the rs1011313 genotype for excitement/hostility symptoms (p = 0.01 and 0.002, respectively). We found a significant association in the baseline symbol digital modalities test (SDMT), forward-digital span (DS), backward-DS, and semantic fluency between SZ patients and HCs (p \u3c 0.05 for all). Finally, the SNP rs1011313 genotypes were associated with SDMT in SZ patients (p = 0.04). Conclusion: This study provides further evidence that SNP rs4712253 of DTNBP1 has a nominal association with SZ in the Han Chinese population. Such a genotype variation may play a role in psychopathology and cognitive function

Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H.

BackgroundOnly Clostridium botulinum strain IBCA10-7060 produces the recently described novel botulinum neurotoxin type H (BoNT/H). BoNT/H (N-terminal two-thirds most homologous to BoNT/F and C-terminal one-third most homologous to BoNT/A) requires antitoxin to toxin ratios ≥1190:1 for neutralization by existing antitoxins. Hence, more potent and safer antitoxins against BoNT/H are needed.MethodsWe therefore evaluated our existing monoclonal antibodies (mAbs) to BoNT/A and BoNT/F for BoNT/H binding, created yeast-displayed mutants to select for higher-affinity-binding mAbs by using flow cytometry, and evaluated the mAbs' ability to neutralize BoNT/H in the standard mouse bioassay.ResultsAnti-BoNT/A HCC-binding mAbs RAZ1 and CR2 bound BoNT/H with high affinity. However, only 1 of 6 BoNT/F mAbs (4E17.2A) bound BoNT/H but with an affinity >800-fold lower (equilibrium dissociation binding constant [KD] = 7.56 × 10(-8)M) than its BoNT/F affinity (KD= 9.1 × 10(-11)M), indicating that the N-terminal two-thirds of BoNT/H is immunologically unique. The affinity of 4E17.2A for BoNT/H was increased >500-fold to KD= 1.48 × 10(-10)M (mAb 4E17.2D). A combination of mAbs RAZ1, CR2, and 4E17.2D completely protected mice challenged with 280 mouse median lethal doses of BoNT/H at a mAb dose as low as 5 µg of total antibody.ConclusionsThis 3-mAb combination potently neutralized BoNT/H and represents a potential human antitoxin that could be developed for the prevention and treatment of type H botulism

Neoproterozoic subduction along the Ailaoshan zone, South China : geochronological and geochemical evidence from amphibolite

This study was supported by China Natural Science Foundation (41190073 and 41372198), National Basic Research Program of China (2014CB440901) and Natural Environment Research Council (grant NE/J021822/1).Lenses of amphibolites occur along the Ailaoshan suture zone at the southwestern margin of the Yangtze Block, South China. Petrological, geochemical and zircon U-Pb geochronological data indicate that they are divisible into two coeval groups. Group 1, represented by the Jinping amphibolite, has mg-number of 71-76 and (La/Yb)cn ratios of 7.2-7.7, and displays a geochemical affinity to island arc volcanic rocks. Group 2 amphibolites occur at Yuanyang and are characterized by high Nb contents (14.3-18.4 ppm), resembling Nb-enriched basalts. The epsilon(Nd)(t) values for Group 1 range from -3.45 to -2.04 and for Group 2 from +4.08 to +4.39. A representative sample for Group 1 yields a U-Pb zircon age of 803 7 Ma, whereas two samples for Group 2 give U-Pb zircon ages of 813 +/- 11 Ma and 814 +/- 12 Ma. Petrogenetic analysis suggests that Group 1 originated from an orthopyroxene-rich source and Group 2 from a mantle wedge modified by slab-derived melt. In combination with other geological observations, these amphibolites are inferred to constitute part of an early Neoproterozoic (similar to 815-800 Ma) arc-back-arc basin system. The Neoproterozoic amphibolites and related rocks along the Ailaoshan zone may be the southward extension of the Neoproterozoic supra-subduction zone that developed along the western margin of the Yangtze Block. (C) 2014 Elsevier B.V. All rights reserved.PostprintPeer reviewe

The Bet-Hedging Strategies for Seedling Emergence of Calligonum mongolicum to Adapt to the Extreme Desert Environments in Northwestern China

Calligonum mongolicum is a dominant native perennial shrub on sand dunes in arid deserts of northwestern China, and is therefore widely used in sand dune stabilization in these regions. However, it remains largely unknown how seedling emergence of C. mongolicum has adapted to unpredictable sand movement and extreme drought. Here we examined effects of seed burial depth, light intensity, and seed age on seedling emergence, and considered seed germination and seedling emergence strategies for the shrub’s adaption to the desert environment. In our pot experiment, the optimum seeding depth for emergence of C. mongolicum was 2 cm, indicating that for germination and seedling emergence only moderate sand burial is required. Light intensity at the surface soil (0 cm) was important for seedling emergence, while there was no significant difference between 50 and 20% light flux density, at burial depths of 1 and 2 cm, indicating that C. mongolicum seeds had adapted to sand burial, while not exposure from sand erosion. We also found C. mongolicum seedlings emerged in spring and in late summer to early autumn. Meanwhile, seedling emergence percentage for 3-year-old seeds was similar to that of 1-year-old seeds, which meant that C. mongolicum seeds were well preserved under normal sand dune conditions, thus were capable of developing a persistent, but shallow soil seed-bank. These results indicated that germination and seedling emergence take a bet-hedging strategies to adapt to variable desert environments. Our study confirmed that C. mongolicum desert shrubs combine strategies in its adaption to arid and variable sand environments

CASE STUDY ON THE LARGE DIAMETER PIPE JACKING FOR UTILITY TUNNEL

Pipe jacking have been widely used in utility tunnel constructions as an environment-friendly method in China. This study is focus on the critical technologies used in the pipe jacking for the utility tunnel in Huanggang Mingzhu road. The inner and outer diameter of this utility tunnel are 4m and 4.8m respectively, which is the largest circular pipe jacking project in China at present. This utility tunnel is designed under the urban main road with a heavy traffic, so the control accuracy of pipe jacking construction is required to be high. According to the characteristics of the project and actual construction technical measures, the key construction technologies including pipe jacking equipment, launching of small spacing, slurry circulating, the drag reduction technology, and the control of surface settlement are discussed in this paper. Meanwhile, the jacking force and ground settlement during pipe jacking construction are monitored. The results show that the selected pipe jacking machine has good adaptability to the geological conditions of the project. The actual jacking force is much smaller than the theoretical value, and the two intermediate jacking stations are not activated. In addition, the road surface deformation is -8–5mm during the whole process of pipe jacking construction, which has no impact on surface traffic

Development of an ELISA microarray assay for the sensitive and simultaneous detection of ten biodefense toxins

Plant and microbial toxins are considered bioterrorism threat agents because of their extreme toxicity and/or ease of availability. Additionally, some of these toxins are increasingly responsible for accidental food poisonings. The current study utilized an ELISA-based protein antibody microarray for the multiplexed detection of ten biothreat toxins, botulinum neurotoxins (BoNT) A, B, C, D, E, F, ricin, shiga toxins 1 and 2 (Stx), and staphylococcus enterotoxin B (SEB), in buffer and complex biological matrices. The multiplexed assay displayed a sensitivity of 1.3 pg mL(-1) (BoNT/A, BoNT/B, SEB, Stx-1 and Stx-2), 3.3 pg mL(-1) (BoNT/C, BoNT/E, BoNT/F) and 8.2 pg mL(-1) (BoNT/D, ricin). All assays demonstrated high accuracy (75-120 percent recovery) and reproducibility (most coefficients of variation <20%). Quantification curves for the ten toxins were also evaluated in clinical samples (serum, plasma, nasal fluid, saliva, stool, and urine) and environmental samples (apple juice, milk and baby food) with overall minimal matrix effects. The multiplex assays were highly specific, with little cross-reactivity observed between the selected toxin antibodies. The results demonstrate a multiplex microarray that improves current immunoassay sensitivity for biological warfare agents in buffer, clinical, and environmental samples

Insulin Resistance and Oxidative Stress: In Relation to Cognitive Function and Psychopathology in Drug-Naive, First-Episode Drug-Free Schizophrenia

Objective: The present study aimed to examine whether insulin resistance and oxidative stress are associated with cognitive impairment in first-episode drug-free schizophrenia (SZ) patients. Methods: Ninety first-episode SZ patients and 70 healthy controls were enrolled. Fasting insulin (FINS) and markers of oxidative stress [oxidized glutathione (GSSG), superoxide dismutase (SOD), nitric oxide (NO) and uric acid (UA) levels] were measured in serum before pharmacological treatment was initiated. Psychiatric symptoms and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB), respectively. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) was also studied. Results: HOMA-IR and serum levels of GSSG and NO were significantly higher in SZ patients than in healthy controls (P \u3c 0.001), while the serum levels of SOD were significantly lower than in healthy controls (P \u3c 0.001). HOMA-IR, GSSG and NO levels were significantly correlated to the total cognitive function scores of the patient group (r = -0.345,-0.369,-0.444, respectively, P \u3c 0.05). But these factors were not co-related to the cognitive functions in the healthy control group. And, levels of SOD, UA were not associated with the total cognitive function scores in both the patient and the healthy control groups. NO was positively correlated with general pathological and the total score in the PANSS, and was negatively correlated with six cognitive domains (r = -0.316 to -0.553, P \u3c 0.05). Conclusions: The levels of insulin resistance and oxidative stress are elevated, and correlated with the severity of cognitive impairment in drug-naive, first-episode SZ patients. Treatment approaches targeting on reducing insulin resistance and oxidative stress may improve cognitive function in SZ patients

Decreased Functional Connectivity of Insular Cortex in Drug Naive First Episode Schizophrenia: In Relation to Symptom Severity

BACKGROUND: This study was to examine the insular cortical functional connectivity in drug naive patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms. METHODS: Thirty-seven drug naive patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: There were significant reductions in the right insular cortical connectivity with the Heschl\u27s gyrus, anterior cingulate cortex (ACC), and caudate (p\u27s \u3c 0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl\u27s gyrus was further confirmed in the VBM analysis (FDR corrected p \u3c 0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl\u27s connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019). CONCLUSION: Reduced insula-Heschl\u27s functional connectivity is present in drug naive patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms