Hydroxylation of quinocetone and carbadox is mediated by CYP1As in the chicken (Gallus gallus)

Quinoxaline derivatives (quinoxalines) comprise a class of drugs that have been widely used as animal antimicrobial agents and feed additives. Although the metabolism of quinoxaline drugs has been mostly studied using chicken liver microsomes, the biochemical mechanism of biotransformation of these chemicals in the chicken has yet to be characterized. In this study, using bacteria produced enzymes, we demonstrated that both CYP1A4 and CYP1A5 participate in the oxidative metabolism of quinoxalines. For CYP1A5, three hydroxylated metabolites of quinocetone were generated. In addition, CYP1A5 is able to hydroxylate carbadox. For CYP1A4, only one hydroxylated product of quinocetone on the phenyl ring was identified. Neither CYP1A5 nor CYP1A4 showed hydroxylation activity towards mequindox and cyadox. Our results suggest that CYP1A4 and CYP1A5 have different and somewhat overlapping substrate specificity in quinoxaline metabolism, and CYP1A5 represents a crucial enzyme in hydroxylation of both quinocetone and carbadox.     

Spatial and temporal population genetic variation and structure of Nothotsuga longibracteata (Pinaceae), a relic conifer species endemic to subtropical China

Nothotsuga longibracteata, a relic and endangered conifer species endemic to subtropical China, was studied for examining the spatial-temporal population genetic variation and structure to understand the historical biogeographical processes underlying the present geographical distribution. Ten populations were sampled over the entire natural range of the species for spatial analysis, while three key populations with large population sizes and varied age structure were selected for temporal analyses using both nuclear microsatellites (nSSR) and chloroplast microsatellites (cpSSR). A recent bottleneck was detected in the natural populations of N. longibracteata. The spatial genetic analysis showed significant population genetic differentiation across its total geographical range. Notwithstanding, the temporal genetic analysis revealed that the level of genetic diversity between different age class subpopulations remained constant over time. Eleven refugia of the Last Glacial Maximum were identified, which deserve particular attention for conservation management.     

Reduced Regional Homogeneity in Bilateral Frontostriatal System Relates to Higher Impulsivity Behavior in Codeine-Containing Cough Syrups Dependent Individuals

Background

In the past twenty years, codeine-containing cough syrups (CCS) was recognized as a new type of addictive drugs. However, the exact neurobiologic mechanisms underlying CCS-dependence are still ill-defined. The aims of this study are to identify CCS-related modulations of neural activity during the resting-state in CCS-dependent individuals and to investigate whether these changes of neural activity can be related to duration of CCS use, the first age of CCS use and impulse control deficits in CCS-dependent individuals. We also want to observe the impact of gray matter deficits on these functional results.

Methodology/Principal Findings

Thirty CCS-dependent individuals and 30 control subjects participated. Resting-state functional MRI was performed by using gradient-echo echo-planar imaging sequence. Regional homogeneity (ReHo) was calculated by using REST software. Voxel-based analysis of the ReHo maps between controls and CCS-dependent groups was performed using two-sample t tests (p<0.05, corrected for multiple comparisons). The Barratt Impulsiveness Scale 11 (BIS.11) was surveyed to assess participants'' impulsivity trait soon after MR examination. Abnormal clusters revealed by group comparison were extracted and correlated with impulsivity, duration of CCS use, and age of first CCS use. ReHo was diminished in the bilateral medial orbitofrontal cortex (mOFC) and left dorsal striatum in CCS-dependent individuals. There were negative correlations between mean ReHo in the bilateral medial OFC, left dorsal striatum and duration of CCS use, BIS.11 total scores, and the subscale of attentional impulsivity in CCS-dependent individuals. There was a significantly positive correlation between mean ReHo in the left dorsal striatum and age of first CCS use in CCS-dependent individuals. Importantly, these results still remain significant after statistically controlling for the regional gray matter deficits.

Conclusion

Resting-state abnormalities in CCS-dependent individuals revealed in the present study may further improve our understanding about the neural substrates of impulse control dysfunction in CCS-dependent individuals.     

GNB3, eNOS,and Mitochondrial DNA Polymorphisms Correlate to Natural Longevity in a Xinjiang Uygur Population

Background

In centenarian populations, application of the positive biology approach (examination of positive phenotypes in aging) has revealed that mitochondrial DNA (mtDNA) mutation accumulation may be linked to human longevity; however, the role of guanine nucleotide-binding protein (G protein) abnormalities modulated by G-protein beta-3 (GNB3) and nitrate (NO2) production associated with endothelial nitric oxide synthase (eNOS), commonly appearing in age-related diseases, remains undetermined.

Objective

The association between the mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS polymorphisms and longevity in a Uygur population (Xinjiang region, China) were investigated.

Methods

A total of 275 experimental subjects aged ≥100 or with 4 generations currently living were screened for inclusion in the centenarian (>100 years) and nonagenarian groups (90–100 years), and 112 65–70 year old control subjects were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS. Associations between polymorphic loci, genotypes, and longevity were analyzed.

Results

165 included subjects (M∶F = 107∶58; mean age = 97±3 years; mean age 100–113 years) were assigned to the centenarian (M∶F = 46/19; n = 65) and nonagenarian groups (M∶F = 61/39; n = 100). Associations between mtDNA C5178A and A10398G polymorphisms with longevity in the centenarian group with mtDNA genotype frequencies 5178A and 10398G were 66.79% and 36.8%.

Conclusions

Applying the overwhelming longevity observed in Uygur populations, these findings demonstrate that mtDNA 5178A/C and 10398A/G, GNB3 C825T, and eNOS polymorphisms are useful as a genetic basis for longevity.     

Drivers of Echinococcus multilocularis Transmission in China: Small Mammal Diversity,Landscape or Climate?

Background

Human alveolar echinococcocosis (AE) is a highly pathogenic zoonotic disease caused by the larval stage of the cestode E. multilocularis. Its life-cycle includes more than 40 species of small mammal intermediate hosts. Therefore, host biodiversity losses could be expected to alter transmission. Climate may also have possible impacts on E. multilocularis egg survival. We examined the distribution of human AE across two spatial scales, (i) for continental China and (ii) over the eastern edge of the Tibetan plateau. We tested the hypotheses that human disease distribution can be explained by either the biodiversity of small mammal intermediate host species, or by environmental factors such as climate or landscape characteristics.

Methodology/findings

The distributions of 274 small mammal species were mapped to 967 point locations on a grid covering continental China. Land cover, elevation, monthly rainfall and temperature were mapped using remotely sensed imagery and compared to the distribution of human AE disease at continental scale and over the eastern Tibetan plateau. Infection status of 17,589 people screened by abdominal ultrasound in 2002–2008 in 94 villages of Tibetan areas of western Sichuan and Qinghai provinces was analyzed using generalized additive mixed models and related to epidemiological and environmental covariates. We found that human AE was not directly correlated with small mammal reservoir host species richness, but rather was spatially correlated with landscape features and climate which could confirm and predict human disease hotspots over a 200,000 km² region.

Conclusions/Significance

E. multilocularis transmission and resultant human disease risk was better predicted from landscape features that could support increases of small mammal host species prone to population outbreaks, rather than host species richness. We anticipate that our study may be a starting point for further research wherein landscape management could be used to predict human disease risk and for controlling this zoonotic helminthic.     

Directed Forgetting of Negative Self-Referential Information Is Difficult: An fMRI Study

A large body of evidence suggested that both emotion and self-referential processing can enhance memory. However, it remains unclear how these two factors influence directed forgetting. This study speculates that directed forgetting of negative self-referential memory is more difficult than forgetting of other-referential memory. To verify this speculation, we combined the directed forgetting paradigm with the self-reference task. The behavioral result suggested that although both self-referential and other-referential information can be directly forgotten, less self-referential information can be forgotten than other-referential information. At the neural level, the forget instruction strongly activated the frontal cortex, suggesting that directed forgetting is not memory decay but an active process. In addition, compared with the negative other-referential information, forgetting of the negative self-referential information were associated with a more widespread activation, including the orbital frontal gyrus (BA47), the inferior frontal gyrus (BA45, BA44), and the middle frontal gyrus. Our results suggest that forgetting of the self-referential information seems to be a more demanding and difficult process.     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.