Ferulic acid supplementation prevents trimethyltin-induced cognitive deficits in mice

This study's objective was to clarify the ameliorative effects ferulic acid (4-hydroxy-3-methoxycinnamic acid) has against cognitive deficits and ChAT activation in trimethyltin (TMT) induced, memory injured mice following a 28-d ferulic acid treatment. After administering TMT for 3 d, each mouse performed Y-maze and passive avoidance tests to check immediate working memory performance and cognitive function. The results showed that ferulic acid administration attenuated TMT-induced memory injury and a decline in ChAT activity in the mice. This suggests that ferulic acid might be useful for preventing cognitive dysfunction as well as for boosting the activation of ChAT in dementia.     

Technical note: Artificial Resynthesis Technology for the experimental formation of dental microwear textures

Dental microwear formation on the posterior dentition is largely attributed to an organism's diet. However, some have suggested that dietary and environmental abrasives contribute more to the formation process than food, calling into question the applicability of dental microwear to the reconstruction of diet in the fossil record. Creating microwear under controlled conditions would benefit this debate, but requires accurately replicating the oral environment. This study tests the applicability of Artificial Resynthesis Technology (ART 5) to create microwear textures while mitigating the challenges of past research. ART 5 is a simulator that replicates the chewing cycle, responds to changes in food texture, and simulates the actions of the oral cavity. Surgically extracted, occluding pairs of third molars (n = 2 pairs) were used in two chewing experiments: one with dried beef and another with sand added to the dried beef. High-resolution molds were taken at 0, 50, 100, 2500, and 5000 simulated chewing cycles, which equates to approximately 1 week of chewing. Preliminary results show that ART 5 produces microwear textures. Meat alone may produce enamel prism rod exposure at 5000 cycles, although attrition cannot be ruled out. Meat with sand accelerates the wear formation process, with enamel prism rods quickly obliterated and “pit-and-scratch” microwear forming at approximately 2500 cycles. Future work with ART 5 will incorporate a more thorough experimental protocol with improved controls, pH of the simulated oral environment, and grit measurements; however, these results indicate the potential of ART 5 in untangling the complex variables of dental microwear formation.     

Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation

Background

Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.

Methods and Findings

Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1–2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus–positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.

Conclusions

Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors'' Summary     

Male-specific genetic effect on hypertension and metabolic disorders

Genetic risk factors for hypertension may have age or gender specificity and pleiotropic effects. This study aims to measure the risk of genetic and non-genetic factors in the occurrence of hypertension and related diseases, with consideration of potential confounding factors and age-gender stratification. A discovery set of 352,228 genotyped plus 1.8 million imputed single-nucleotide polymorphisms were analyzed for 2,886 hypertensive cases and 3,440 healthy controls obtained from two community-based cohorts in Korea, and selected gene variants were replicated in the Health Examinee cohort (665 cases and 1,285 controls). Genome-wide association analyses were conducted in 12 groups stratified by age and gender after adjusting for potential covariates under three genetic models. Age, rural area residence, body mass index, family history of hypertension, male gender, current alcohol drinking status, and current smoking status were significantly associated with hypertension (P = 4 × 10^?151 to 0.011). Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 × 10^?14 to 4.46 × 10^?7 in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population. Three gene variants, rs12229654, rs17249754, and rs11066280, were significantly associated with metabolic disorders such as hyperlipidemia and diabetes (P = 0.00071 to 0.0097, respectively). Careful consideration of the potential confounding effects in future genome-wide association studies is necessary to uncover the genetic underpinnings of complex diseases.     

Enhancement of 1,3-propanediol production by expression of pyruvate decarboxylase and aldehyde dehydrogenase from Zymomonas mobilis in the acetolactate-synthase-deficient mutant of Klebsiella pneumoniae

The acetolactate synthase (als)-deficient mutant of Klebsiella pneumoniae fails to produce 1,3-propanediol (1,3-PD) or 2,3-butanediol (2,3-BD), and is defective in glycerol metabolism. In an effort to recover production of the industrially valuable 1,3-PD, we introduced the Zymomonas mobilis pyruvate decarboxylase (pdc) and aldehyde dehydrogenase (aldB) genes into the als-deficient mutant to activate the conversion of pyruvate to ethanol. Heterologous expression of pdc and aldB efficiently recovered glycerol metabolism in the 2,3-BD synthesis-defective mutant, enhancing the production of 1,3-PD by preventing the accumulation of pyruvate. Production of 1,3-PD in the pdc- and aldB-expressing als-deficient mutant was further enhanced by increasing the aeration rate. This system uses metabolic engineering to produce 1,3-PD while minimizing the generation of 2,3-BD, offering a breakthrough for the industrial production of 1,3-PD from crude glycerol.     

AKAP12 Mediates Barrier Functions of Fibrotic Scars during CNS Repair

The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12)-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO) mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT) mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process.     

Effect of E. coli MutL on the steady-state ATPase activity of MutS in the presence of short blocked end DNAs

The effect of wild-type and mutant MutL on the steady-state ATPase activity of MutS from Escherichia coli has been investigated in the absence and presence of 22, 50, and 75 base pair hetero- and homoduplex DNAs with open and blocked ends. The steady-state ATPase activity of MutS has been measured at 37 °C using a spectrophotometric method. The presence of MutL did not affect appreciably on the ATPase activity of MutS in the absence of DNA or in the presence of blocked end homoduplex DNAs. However, the addition of MutL affected oppositely on the ATPase activity of MutS in the presence of G-T mismatched DNAs depending on their end status. We have also found that only the ATPase active forms of MutL increased the ATPase activity of MutS in the presence of G-T mismatched DNAs with blocked ends. The results suggest that MutL ATPase activity is required to catalyze dissociation of the MutS sliding clamps.