Nitrite oxidation in the upper water column and oxygen minimum zone of the eastern tropical North Pacific Ocean

Nitrogen (N) is an essential nutrient in the sea and its distribution is controlled by microorganisms. Within the N cycle, nitrite (NO₂⁻) has a central role because its intermediate redox state allows both oxidation and reduction, and so it may be used by several coupled and/or competing microbial processes. In the upper water column and oxygen minimum zone (OMZ) of the eastern tropical North Pacific Ocean (ETNP), we investigated aerobic NO₂⁻ oxidation, and its relationship to ammonia (NH₃) oxidation, using rate measurements, quantification of NO₂⁻-oxidizing bacteria via quantitative PCR (QPCR), and pyrosequencing. ¹⁵NO₂⁻ oxidation rates typically exhibited two subsurface maxima at six stations sampled: one located below the euphotic zone and beneath NH₃ oxidation rate maxima, and another within the OMZ. ¹⁵NO₂⁻ oxidation rates were highest where dissolved oxygen concentrations were <5 μM, where NO₂⁻ accumulated, and when nitrate (NO₃⁻) reductase genes were expressed; they are likely sustained by NO₃⁻ reduction at these depths. QPCR and pyrosequencing data were strongly correlated (r²=0.79), and indicated that Nitrospina bacteria numbered up to 9.25% of bacterial communities. Different Nitrospina groups were distributed across different depth ranges, suggesting significant ecological diversity within Nitrospina as a whole. Across the data set, ¹⁵NO₂⁻ oxidation rates were decoupled from ¹⁵NH₄⁺ oxidation rates, but correlated with Nitrospina (r²=0.246, P<0.05) and NO₂⁻ concentrations (r²=0.276, P<0.05). Our findings suggest that Nitrospina have a quantitatively important role in NO₂⁻ oxidation and N cycling in the ETNP, and provide new insight into their ecology and interactions with other N-cycling processes in this biogeochemically important region of the ocean.     

Association of the interleukin-10 − 592A/C, − 1082G/A and − 819T/C gene polymorphisms with type 2 diabetes: A meta-analysis

There is more evidence that interleukin-10 (IL-10), as a multifunctional regulatory cytokine of inflammatory responses, may have an important role in type 2 diabetes (T2D). However, genetic association studies that evaluated the relationship between IL-10 gene variants and T2D have produced conflicting results. The aim of this study was to determine whether the IL-10 gene polymorphisms (− 592A/C, − 1082G/A, − 819T/C) conferred susceptibility to T2D through a meta-analysis. A comprehensive search was conducted to examine all the eligible studies. A total of 9 studies involving 2838 T2D patients and 2773 controls were considered in the meta-analysis. Overall, there was no significant association between IL-10 − 592A/C and T2D (A vs C: OR = 0.93, P = 0.625; AA + AC vs CC: OR = 0.89, P = 0.511; AA vs AC + CC: OR = 0.93, P = 0.821). We failed to find the association between the IL-10 − 1082G allele and T2D (OR = 1.04, P = 0.430), but the genotypes of the IL-10 − 1082G/A polymorphism conferred a risk for the development of T2D (GA vs AA: OR = 1.21, P = 0.027; GG + GA vs AA: OR = 1.17, P = 0.048). Analysis of the − 819T/C polymorphism revealed no significant association with T2D (T vs C: OR = 1.04, P = 0.853; TT + TC vs CC: OR = 1.07, P = 0.834; TT vs TC + CC: OR = 1.08, P = 0.824). In conclusion, the present meta-analysis suggests association between the IL-10 − 1082G/A polymorphism and T2D. However, additional well-designed and larger scale primary studies are required to further evaluate the IL-10 gene polymorphisms and T2D.     

NQO1 609C > T polymorphism interaction with tobacco smoking and alcohol drinking increases colorectal cancer risk in a Chinese population

Background

NAD (P)H:quinone oxidoreductase (NQO1) catalyzes the activation of some environmental procarcinogens present in tobacco smoke or the diet. We conducted a hospital-based case–control study to evaluate the potential association between NQO1 609C > T polymorphisms and colorectal cancer risk in a Chinese population.

Methods

The study population comprised 672 histologically confirmed colorectal cancer patients and 672 frequency-matched control subjects without cancer or systemic illness. We used PCR restriction fragment length polymorphism-based methods for genotyping analyses and unconditional logistic regression model for statistical evaluations.

Results

The risk of colorectal cancer increased with the level of smoking and decreased with the consumption of tea, fresh fruits, and vegetables. In addition, we found that the NQO1 609 CT and TT genotypes were associated with an increased risk of colorectal cancer (CT: adjusted OR = 2.02, 95% CI = 1.55–2.57; TT: adjusted OR = 2.51, 95% CI = 1.82–3.47), compared with the CC genotype. Moreover, NQO1 609C > T appeared to have a multiplicative joint effect with both tobacco smoking and alcoholic drinking (P for multiplicative interactions were 0.0001 and 0.013, respectively) on colorectal cancer risk.

Conclusion

Our findings suggest that the NQO1 609C > T polymorphism plays an important role in the development of colorectal cancer in the Chinese population, which is strengthened by alcohol drinking or tobacco smoking.     

10-Å CryoEM Structure and Molecular Model of the Myriapod (Scutigera) 6 × 6mer Hemocyanin: Understanding a Giant Oxygen Transport Protein

Oxygen transport in Myriapoda is maintained by a unique 6 × 6mer hemocyanin, that is, 36 subunits arranged as six hexamers (1 × 6mers). In the sluggish diplopod Spirostreptus, the 1 × 6mers seem to operate as almost or fully independent allosteric units (h ∼ 1.3; P₅₀ ∼ 5 torr), whereas in the swift centipede Scutigera, they intensively cooperate allosterically (h ∼ 10; P₅₀ ∼ 50 torr). Here, we show the chemomechanical basis of this differential behavior as deduced from hybrid 6 × 6mer structures, obtained by single-particle cryo-electron microscopy of the Scutigera 6 × 6mer (10.0 Å resolution according to the 0.5 criterion) and docking of homology-modeled subunits from Scutigera and two diplopods, Spirostreptus and Polydesmus. The Scutigera 6 × 6mer hemocyanin is a trigonal antiprism assembled from six smaller trigonal antiprisms (1 × 6mers), thereby exhibiting D3 point group symmetry. It can be described as two staggered 3 × 6mers or three oblique 2 × 6mers. Topologically, the 6 × 6mer is subdivided into six subunit zones, thereby exhibiting a mantle (24 subunits) and a core (12 subunits). The six hexamers are linked by 21 bridges, subdivided into five types: two within each 3 × 6mer and three between both 3 × 6mers. The molecular models of the 6 × 6mer reveal intriguing amino acid appositions at these inter-hexamer interfaces. Besides opportunities for salt bridges, we found pairs of carboxylate residues for possible bridging via a Ca²⁺ or Mg²⁺ ion. Moreover, we detected histidine clusters, notably in Scutigera, allowing us to advance hypotheses as to how the hexamers are allosterically coupled in centipede hemocyanin and why they act more independently in diplopod hemocyanin.     

The interleukin-4 − 589C/T polymorphism and the risk of asthma: A meta-analysis including 7345 cases and 7819 controls

Background

A number of studies assessed the association of − 589C/T polymorphism in the promoter region of interleukin-4 (IL-4) with asthma in different populations. However, the results were contradictory. A meta-analysis was conducted to investigate the association between polymorphism in the IL-4 and asthma susceptibility.

Methods

Databases including Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Thirty-four studies involving 7345 cases and 7819 controls were included. Overall, significant association between − 589C/T polymorphism and asthma was observed for TT + CT vs. CC (OR = 1.26; 95% CI 1.12–1.42; P = 0.0001; I² = 26%). In the subgroup analysis by ethnicity, significant associations were found among Asians (OR = 1.36; 95% CI 1.07–1.73; P = 0.01; I² = 0%) and Caucasians (OR = 1.30; 95% CI 1.09–1.54; P = 0.004; I² = 53%) but not among African Americans (OR = 1.20; 95% CI 0.72–2.00; P = 0.48; I² = 48%). In the subgroup analysis by atopic status, no significant association was found among atopic asthma patients (OR = 1.20; 95% CI 0.92–1.34; P = 0.27; I² = 6%) and non-atopic asthma patients (OR = 0.97; 95% CI 0.73–1.28; P = 0.81; I² = 0%).

Conclusions

This meta-analysis suggested that the IL-4 − 589C/T polymorphism was a risk factor of asthma.     

GALNT11 as a new molecular marker in chronic lymphocytic leukemia

Aberrant mucin O-glycosylation often occurs in different cancers and is characterized by immature expression of simple mucin-type carbohydrates. At present, there are some controversial reports about the Tn antigen (GalNAcα-O-Ser/Thr) expression and there is a great lack of information about the [UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts)] expression in chronic lymphocytic leukemia (CLL). To gain insight in these issues we evaluated the Tn antigen expression in CLL patient samples using two Tn binding proteins with different fine specificity. We also studied the expression from 14 GalNAc-Ts genes in CLL patients by RT-PCR. Our results have provided additional information about the expression level of the Tn antigen, suggesting that a low density of Tn residues is expressed in CLL cells. We also found that GALNT11 was expressed in CLL cells and normal T cell whereas little or no expression was found in normal B cells. Based on these results, GALNT11 expression was assessed by qPCR in a cohort of 50 CLL patients. We found significant over-expression of GALNT11 in 96% of B–CLL cells when compared to normal B cells. Moreover, we confirmed the expression of this enzyme at the protein level. Finally we found that GALNT11 expression was significantly associated with the mutational status of the immunoglobulin heavy chain variable region (IGHV), [?²(1) = 18.26; P < 0.0001], lipoprotein lipase expression [?²(1) = 13.72; P = 0.0002] and disease prognosis [?²(1) = 15.49; P < 0.0001]. Our evidence suggests that CLL patient samples harbor aberrant O-glycosylation highlighted by Tn antigen expression and that the over-expression of GALNT11 constitutes a new molecular marker for CLL.     

The variant hERG/R148W associated with LQTS is a mutation that reduces current density on co-expression with the WT

Background

A variant of the ether-à-go-go related channel (hERG), p.Arg148Trp (R148W) was found at heterozygous state in two infants who died from sudden infant death syndrome (SIDS), one with documented prolonged QTc and Torsade de Pointes (TdP), and in an adult woman with QTc > 500 ms, atrioventricular block and TdP. This variant was previously reported in cases of severe ventricular arrhythmia but very rarely in control subjects. Its classification as mutation or polymorphism awaited electrophysiological characterization.

Methods

The properties of this N-terminal, proximal domain, hERG variant were explored in Xenopus oocytes injected with the same amount of RNA encoding for either hERG/WT or hERG/R148W or their equimolar mixture. The human ventricular cell (TNNP) model was used to test the effects of changes in hERG current.

Results

R148W alone produced a current similar to the WT (369 ± 76 nA (mean ± SEM), n = 13 versus 342 ± 55 nA in WT, n = 13), while the co-expression of 1/2 WT + 1/2 R148W lowered the current by 29% versus WT (243 ± 35 nA, n = 13, p < 0.05). The voltage dependencies of steady-state activation and inactivation were not changed in the variant alone or in co-expression with the WT. The time constants of fast recovery from inactivation and of fast and slow deactivation analyzed between − 120 and + 20 mV were not changed. The voltage-dependent distribution of the current amplitudes among fast-, slow- and non-deactivating fractions was unaltered. A 6.6% increase in APD90 from 323.5 ms to 345 ms was observed using the human cardiac ventricular myocyte model.

Conclusions

Such a decrease in hERG current as evidenced here when co-expressing the hERG/R148W variant with the WT may have predisposed to the observed long QT syndrome and associated TdP. Therefore, the heterozygous carriers of hERG/R148W may be at risk of cardiac sudden death.     

A genetic variant in the promoter of APE1 gene (− 656 T > G) is associated with breast cancer risk and progression in a Chinese population

Background/aims

APE1 is an important DNA repair protein in the base excision repair pathway. Genetic variations in APE1 have been suggested to influence individuals' susceptibility to human malignancies. The present study was aimed to investigate the associations between two functional polymorphisms in APE1 (− 656 T > G and 1349 T>G) and breast cancer risk.

Methods

We genotyped the two polymorphisms in a case-control study of 500 breast cancer patients and 799 age-matched cancer-free controls using the TaqMan method. Unconditional logistic regression adjusted for potential confounding factors was used to assess the associations.

Results

We found that the variant genotypes of the − 656 T>G were significantly associated with decreased breast cancer risk, compared with the wild genotype [TG/GG vs. TT: adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.56–0.91], and the protective effect of this polymorphism was more predominant among the subgroups of younger subjects (< 52 years) (OR = 0.65, 95% CI = 0.46–0.92). Besides, we found that the variant genotypes were associated with less frequent lymph node metastasis (P = 0.020, OR = 0.64, 95% CI = 0.44–0.94). We did not observe any significant association between the 1349 T>G polymorphism and breast cancer risk.

Conclusion

Our results suggest that the APE1 − 656 T>G but not the 1349 T>G polymorphism may influence the susceptibility and progression of breast cancer in the Chinese population. Large population-based prospective studies are required to validate these findings.     

Proliferation and copy number variation of BEL-like long terminal repeat retrotransposons within the Diabrotica virgifera virgifera genome

The proliferation of retrotransposons within a genome can contribute to increased size and affect the function of eukaryotic genes. BEL/Pao-like long-terminal repeat (LTR) retrotransposons were annotated from the highly adaptable insect species Diabrotica virgifera virgifera, the Western corn rootworm, using survey sequences from bacterial artificial chromosome (BAC) inserts and contigs derived from a low coverage next-generation genome sequence assembly. Eleven unique D. v. virgifera BEL elements were identified that contained full-length gag–pol coding sequences, whereas 88 different partial coding regions were characterized from partially assembled elements. Estimated genome copy number for full and partial BEL-like elements ranged from ~ 8 to 1582 among individual contigs using a normalized depth of coverage (DOC) among Illumina HiSeq reads (total genome copy number ~ 8821). BEL element copy number was correlated among different D. v. virgifera populations (R² = 0.9846), but individual element numbers varied ≤ 1.68-fold and the total number varied by ~ 527 copies. These data indicate that BEL element proliferation likely contributed to a large genome size, and suggest that differences in copy number are a source of genetic variability among D. v. virgifera.     

Functional polymorphisms in FAS and FASL contribute to risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese population

Accumulating evidences indicate that the functional FAS− 1377G > A, − 670A > G and FASL− 844T > C polymorphisms affect the risk of several kinds of cancers. However, their roles in the development of larynx and hypopharynx squamous cell carcinoma (SCC) were still unknown in the Chinese. In the current study, we examined whether these functional genetic variants were associated with the risk of larynx and hypopharynx squamous SCC in a Han Chinese population. The FAS and FASL polymorphisms were genotyped in 300 patients with laryngeal and hypopharyngeal SCC and 300 control subjects by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that subjects carrying the FASL–844CT or TT genotype had a significantly decreased risk of developing laryngeal and hypopharyngeal SCC [odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.51–0.93; P = 0.016; or, OR = 0.41; 95% CI = 0.20–0.86; P = 0.009] compared with those carrying the CC genotype. Joint gene-smoking and gene-drinking effects were also observed, with the OR of CC genotype for smokers or drinkers were 5.15 (95%CI = 3.24–8.97) or 12.52 (95%CI = 7.31–22.47), respectively. Therefore, the FASL− 844T > C polymorphism is associated with genetic susceptibility of developing laryngeal and hypopharyngeal SCC in a Han Chinese population.     

The impact of GGH -401C > T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer

Aims

Cervical cancer is the third most frequent cancer in women worldwide, mostly treated with cisplatin-based chemoradiotherapy. Since it is known that folate metabolism might interfere with cisplatin effectiveness, we intended to study the influence of the Gamma Glutamyl Hydrolase -401C > T polymorphism in treatment response in cervical cancer.

Methods

We retrospectively reviewed the clinical data of 167 patients with bulky cervical cancer submitted to cisplatin-based chemoradiotherapy. The genotypes of GGH -401C > T SNP were determined by real-time PCR and statistical analysis was performed by χ² test and survival analysis.

Results

The genotypes of GGH-401C > T were significantly associated with the response to platinum-based chemoradiotherapy. Treatment response was higher in patients carrying the CC genotype, who presented a significant increased chance of treatment response (survival time in months/genotype: 91 for CC Vs 72 for CT/TT; p = 0.035, log rank test). A Cox regression analysis accordingly showed that the presence of the T allele was significantly linked to a worse treatment response (HR = 3.036; CI 95% 1.032-8.934, p = 0.044).

Conclusions

The results of our study suggested the potential interest of GGH -401C > T as a predictive factor of the outcome of cervical carcinoma treated with cisplatin-based chemoradiotherapy.     

Ni[TCNE]2 · zCH2Cl2 (Tc = 13 K) and VxNi1 − x[TCNE]y · zCH2Cl2 solid solution room temperature magnets

Magnetically ordered Ni[TCNE]₂ · zCH₂Cl₂ (T_c = 13 K) is reported for the first time from the reaction of Ni(CO)₄ with tetracyanoethylene (TCNE). A family of new solid solution room temperature magnets of V_xNi_1 − x[TCNE]_y · zCH₂Cl₂ (0 ? x < 1; y ? 2) composition has been characterized by IR spectrometry, elemental analysis, and magnetic measurements (ac and dc susceptibility). Substitution of Ni^II for V^II in V[TCNE]_y · zCH₂Cl₂ does not alter the T_c significantly for x ? 0.05 and does not alter H_cr significantly for x > 0; however, the magnitude of M increases with x, as does the broadness of the peaks in the χ′(T) and χ″(T) ac susceptibilities. Hence, the magnetic properties of the room temperature V[TCNE]_y · zCH₂Cl₂ magnet can be finely tuned via synthetic chemistry methodology, making this material more amenable in future technologies.     

Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib

Aim

As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib.

Methods

One hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan–Meier methods. Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS).

Results

After the median 16.6 months of follow-up, the unfavorable EGFR rs2293347AA or GA genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0 months; hazard ratio (HR) = 2.44, 95% confidence interval (CI) = 1.06–5.56; P = 0.036; GA vs. GG: 15.0 vs. 21.0 months; HR = 1.75, 95%CI = 1.08–2.86, P = 0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS = 24.6 vs. 14.9 months, HR = 0.29, 95%CI = 0.10–0.83, P = 0.021). No significant associations were found among other EGFR SNPs and survival.

Conclusion

EGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib.