Yi-Kuan Tseng

Risk of dementia after anaesthesia and surgery

BACKGROUND The potential relationship between anaesthesia, surgery and onset of dementia remains elusive. AIMS To determine whether the risk of dementia increases after surgery with anaesthesia, and to evaluate possible associations among age, mode of anaesthesia, type of surgery and risk of dementia. METHOD The study cohort comprised patients aged 50 years and older who were anaesthetised for the first time since 1995 between 1 January 2004 and 31 December 2007, and a control group of randomly selected patients matched for age and gender. Patients were followed until 31 December 2010 to identify the emergence of dementia. RESULTS Relative to the control group, patients who underwent anaesthesia and surgery exhibited an increased risk of dementia (hazard ratio = 1.99) and a reduced mean interval to dementia diagnosis. The risk of dementia increased in patients who received intravenous or intramuscular anaesthesia, regional anaesthesia and general anaesthesia. CONCLUSIONS The results of our nationwide, population-based study suggest that patients who undergo anaesthesia and surgery may be at increased risk of dementia.

The change of microbial community from chlorinated solvent-contaminated groundwater after biostimulation using the metagenome analysis.

The compositions of bacterial community in one site contaminated with PCE/TCE after the slow polycolloid-releasing substrate (SPRS) (contained vegetable oil, cane molasses, and surfactants) addition were analyzed. Results show that SPRS caused a rapid enhancement of reductive dechlorination of TCE. The transformation of PCE/TCE into ethene was observed after 20 days of operation. To compare the change of bacterial communities before and after SPRS addition, 16S rRNA amplicon sequencing using the metagenome analysis was performed. Results demonstrated the detection of the increased amounts of Dehalogenimonas by 2.2-fold, Pseudomonas by 3.4-fold and Sulfuricurvum by 4-fold with the analysis of the ribosomal database project (RDP). Metagenomic DNA was extracted from PCE/TCE-contaminated groundwater after SPRS addition, and subjected to sequencing. Results obtained from metagenomic sequencing indicate that genes from Dehalococcoides mccartyi was ranked as the second abundant bacteria among all of the detected bacteria via the analysis of the lowest common ancestor (LCA). Abundance of these bacterial groups, as shown above suggests their role in TCE biodegradation. Functional analysis of the metagenome, with the specific reference to chloroalkane and chloroalkene degradation, revealed the presence of some genes responsible for TCE biodegradation. Overall, results of this study provided new insights for a better understanding of the potential of biostimulation on TCE-contaminated sites.

Alanyl-tRNA synthetase genes of Vanderwaltozyma polyspora arose from duplication of a dual-functional predecessor of mitochondrial origin

In eukaryotes, the cytoplasmic and mitochondrial forms of a given aminoacyl-tRNA synthetase (aaRS) are typically encoded by two orthologous nuclear genes, one of eukaryotic origin and the other of mitochondrial origin. We herein report a novel scenario of aaRS evolution in yeast. While all other yeast species studied possess a single nuclear gene encoding both forms of alanyl-tRNA synthetase (AlaRS), Vanderwaltozyma polyspora, a yeast species descended from the same whole-genome duplication event as Saccharomyces cerevisiae, contains two distinct nuclear AlaRS genes, one specifying the cytoplasmic form and the other its mitochondrial counterpart. The protein sequences of these two isoforms are very similar to each other. The isoforms are actively expressed in vivo and are exclusively localized in their respective cellular compartments. Despite the presence of a promising AUG initiator candidate, the gene encoding the mitochondrial form is actually initiated from upstream non-AUG codons. A phylogenetic analysis further revealed that all yeast AlaRS genes, including those in V. polyspora, are of mitochondrial origin. These findings underscore the possibility that contemporary AlaRS genes in V. polyspora arose relatively recently from duplication of a dual-functional predecessor of mitochondrial origin.

An Insertion Peptide in Yeast Glycyl-tRNA Synthetase Facilitates both Productive Docking and Catalysis of Cognate tRNAs

ABSTRACT The yeast Saccharomyces cerevisiae possesses two distinct glycyl-tRNA synthetase (GlyRS) genes: GRS1 and GRS2. GRS1 is dually functional, encoding both cytoplasmic and mitochondrial activities, while GRS2 is dysfunctional and not required for growth. The protein products of these two genes, GlyRS1 and GlyRS2, are much alike but are distinguished by an insertion peptide of GlyRS1, which is absent from GlyRS2 and other eukaryotic homologues. We show that deletion or mutation of the insertion peptide modestly impaired the enzymes catalytic efficiency in vitro (with a 2- to 3-fold increase in Km and a 5- to 8-fold decrease in kcat). Consistently, GRS2 can be conveniently converted to a functional gene via codon optimization, and the insertion peptide is dispensable for protein stability and the rescue activity of GRS1 at 30°C in vivo. A phylogenetic analysis further showed that GRS1 and GRS2 are paralogues that arose from a gene duplication event relatively recently, with GRS1 being the predecessor. These results indicate that GlyRS2 is an active enzyme essentially resembling the insertion peptide-deleted form of GlyRS1. Our study suggests that the insertion peptide represents a novel auxiliary domain, which facilitates both productive docking and catalysis of cognate tRNAs.

Efficient Estimation for a Semiparametric Extended Hazards Model

We propose an alternative estimation for an extended hazards (EH) model by maximizing a kernel-smoothed profile likelihood function. The EH model includes the proportional hazards (PH) model and the accelerated failure time (AFT) model as special cases. Maximization is realized using conventional gradient-search methods. The nested structure of the EH model allows one to construct a goodness-of-fit for the PH model or the AFT model through a likelihood ratio test. We also establish asymptotic theories of the resulting estimators and the likelihood ratio test statistic.

A semiparametric extended hazard regression model with time-dependent covariates

We introduce a general class of semiparametric hazard regression models, called extended hazard (EH) models, that are designed to accommodate various survival schemes with time-dependent covariates. The EH model contains both the Cox model and the accelerated failure time (AFT) model as its subclasses so that we can use this nested structure to perform model selection between the Cox model and the AFT model. A class of estimating equations using counting process and martingale techniques is developed to estimate the regression parameters of the proposed model. The performance of the estimating procedure and the impact of model misspecification are assessed through simulation studies. Two data examples, Stanford heart transplant data and Mediterranean fruit flies, egg-laying data, are used to demonstrate the usefulness of the EH model.

A Comparison between Linear and Nonlinear Forecasts for Nonlinear AR Models

In this paper the relative forecast performance of nonlinear models to linear models is assessed by the conditional probability that the absolute forecast error of the nonlinear forecast is smaller than that of the linear forecast. The comparison probability is explicitly expressed and is shown to be an increasing function of the distance between nonlinear and linear forecasts under certain conditions. This expression of the comparison probability may not only be useful in determining the predictor, which is either a more accurate or a simpler forecast, to be used but also provides a good explanation for an odd phenomenon discussed by Pemberton. The relative forecast performance of a nonlinear model to a linear model is demonstrated to be sensitive to its forecast origins. A new forecast is thus proposed to improve the relative forecast performance of nonlinear models based on forecast origins. #1997 John Wiley & Sons, Ltd.

Molecular mechanisms of 3,3′-dichlorobenzidine-mediated toxicity in HepG2 cells

3,3′‐Dichlorobenzidine (DCB) (CAS 91–94‐1), a synthetic, chlorinated, primary aromatic amine, is typically used as an intermediate in the manufacturing of pigments for printing inks, textiles, paints, and plastics. In this study, we found that DCB could significantly inhibit the cell viability of HepG2 cells in a concentration‐dependent manner. Flow cytometry revealed that DCB induced G2/M‐phase arrest and apoptosis in HepG2 cells. DCB treatment dramatically induced the dissipation of mitochondrial membrane potential (Δψm) and enhanced the enzymatic activities of caspase‐9 and caspase‐3 whilst hardly affecting caspase‐8 activity. Furthermore, Western blotting indicated that DCB‐induced apoptosis was accompanied by the down‐regulation of Bcl‐2/Bax ratio. These results suggested that DCB led to cytotoxicity involving activation of mitochondrial‐dependent apoptosis through Bax/Bcl‐2 pathways in HepG2 cells. Furthermore, HepG2 cells treated with DCB showed significant DNA damage as supported by the concentration‐dependent increase in olive tail moments as determined by the comet assay and by concentration‐ and time‐dependent increase in histone H2AX phosphorylation (γ‐H2AX). Two‐dimensional‐difference gel electrophoresis (2D‐DIGE), combined with mass spectrometry (MS), was used to unveil the differences in protein expression between cells exposed to 25 µM or 100 µM of DCB for 24 hr and the control cells. Twenty‐seven differentially expressed proteins involved in DNA repair, unfolded protein response, metabolism, cell signaling, and apoptosis were identified. Among these, 14‐3‐3 theta, CGI‐46, and heat‐shock 70 protein 4 were confirmed using Western blot assay. Taken together, these data suggest that DCB is capable of inducing DNA damage and some cellular stress responses in HepG2 cells, thus eventually leading to cell death by apoptosis. Environ. Mol. Mutagen. 55:407–420, 2014.

Modulating the structure and function of an aminoacyl-tRNA synthetase cofactor by biotinylation

Arc1p is a yeast-specific tRNA-binding protein that forms a ternary complex with glutamyl-tRNA synthetase (GluRSc) and methionyl-tRNA synthetase (MetRS) in the cytoplasm to regulate their catalytic activities and subcellular distributions. Despite Arc1p not being involved in any known biotin-dependent reaction, it is a natural target of biotin modification. Results presented herein show that biotin modification had no obvious effect on the growth-supporting activity, subcellular distribution, tRNA binding, or interactions of Arc1p with GluRSc and MetRS. Nevertheless, biotinylation of Arc1p was temperature dependent; raising the growth temperature from 30 to 37 °C drastically reduced its biotinylation level. As a result, Arc1p purified from a yeast culture that had been grown overnight at 37 °C was essentially biotin free. Non-biotinylated Arc1p was more heat stable, more flexible in structure, and more effective than its biotinylated counterpart in promoting glutamylation activity of the otherwise inactive GluRSc at 37 °C in vitro. Our study suggests that the structure and function of Arc1p can be modulated via biotinylation in response to temperature changes.

A Kernel Smooth Approach for Joint Modeling of Accelerated Failure Time and Longitudinal Data

Joint likelihood approaches have been widely used to handle survival data with time-dependent covariates. In construction of the joint likelihood function for the accelerated failure time (AFT) model, the unspecified baseline hazard function is assumed to be a piecewise constant function in the literature. However, there are usually no close form formulas for the regression parameters, which require numerical methods in the EM iterations. The nonsmooth step function assumption leads to very spiky likelihood function which is very hard to find the globe maximum. Besides, due to nonsmoothness of the likelihood function, direct search methods are conducted for the maximization which are very inefficient and time consuming. To overcome the two disadvantages, we propose a kernel smooth pseudo-likelihood function to replace the nonsmooth step function assumption. The performance of the proposed method is evaluated by simulation studies. A case study of reproductive egg-laying data is provided to demonstrate the usefulness of the new approach.