MELD-SCH: A megastudy of lexical decision in simplified Chinese.

Here we report on MELD-SCH (MEgastudy of Lexical Decision in Simplified CHinese), a dataset that contains the lexical decision data of 1,020 one-character, 10,022 two-character, 949 three-character, and 587 four-character simplified Chinese words obtained from 504 native Chinese users. It also includes a number of word-level and character-level variables. Analyses showed that the reliability of the dataset is satisfactory, as indicated by split-half correlations and comparisons with other datasets. Item-based regression showed that both word-level and character-level variables contributed significantly to the reaction times and error rates of lexical decision. Moreover, we discovered a U-shape relationship between word-length and reaction times, which has not been reported in Chinese before. MELD-SCH can facilitate research in Chinese word recognition by providing high quality normative data and information of different linguistic variables. It also encourages researchers to extend their empirical findings, which are mostly based on one-character and two-character words, to words of different lengths.

Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts.

Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher's exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.

Animal models of atherosclerosis.

Atherosclerosis is a significant cause of morbidity and mortality globally. Many animal models have been developed to study atherosclerosis, and permit experimental conditions, diet and environmental risk factors to be carefully controlled. Pathophysiological changes can be produced using genetic or pharmacological means to study the harmful consequences of different interventions. Experiments using such models have elucidated its molecular and pathophysiological mechanisms, and provided platforms for pharmacological development. Different models have their own advantages and disadvantages, and can be used to answer different research questions. In the present review article, different species of atherosclerosis models are outlined, with discussions on the practicality of their use for experimentation.

Electrophysiological mechanisms of long and short QT syndromes.

The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP) depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS) are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.

Tachycardia-bradycardia syndrome: Electrophysiological mechanisms and future therapeutic approaches (Review).

Sick sinus syndrome (SSS) encompasses a group of disorders whereby the heart is unable to perform its pacemaker function, due to genetic and acquired causes. Tachycardia­bradycardia syndrome (TBS) is a complication of SSS characterized by alternating tachycardia and bradycardia. Techniques such as genetic screening and molecular diagnostics together with the use of pre-clinical models have elucidated the electrophysiological mechanisms of this condition. Dysfunction of ion channels responsible for initiation or conduction of cardiac action potentials may underlie both bradycardia and tachycardia; bradycardia can also increase the risk of tachycardia, and vice versa. The mainstay treatment option for SSS is pacemaker implantation, an effective approach, but has disadvantages such as infection, limited battery life, dislodgement of leads and catheters to be permanently implanted in situ. Alternatives to electronic pacemakers are gene­based bio­artificial sinoatrial node and cell­based bio­artificial pacemakers, which are promising techniques whose long-term safety and efficacy need to be established. The aim of this article is to review the different ion channels involved in TBS, examine the three­way relationship between ion channel dysfunction, tachycardia and bradycardia in TBS and to consider its current and future therapies.

Mouse models of atherosclerosis: a historical perspective and recent advances.

Atherosclerosis represents a significant cause of morbidity and mortality in both the developed and developing countries. Animal models of atherosclerosis have served as valuable tools for providing insights on its aetiology, pathophysiology and complications. They can be used for invasive interrogation of physiological function and provide a platform for testing the efficacy and safety of different pharmacological therapies. Compared to studies using human subjects, animal models have the advantages of being easier to manage, with controllable diet and environmental risk factors. Moreover, pathophysiological changes can be induced either genetically or pharmacologically to study the harmful effects of these interventions. There is no single ideal animal model, as different systems are suitable for different research objectives. A good understanding of the similarities and differences to humans enables effective extrapolation of data for translational application. In this article, we will examine the different mouse models for the study and elucidation of the pathophysiological mechanisms underlying atherosclerosis. We also review recent advances in the field, such as the role of oxidative stress in promoting endoplasmic reticulum stress, mitochondrial dysfunction and mitochondrial DNA damage, which can result in vascular inflammation and atherosclerosis. Finally, novel therapeutic approaches to reduce vascular damage caused by chronic inflammation using microRNA and nano-medicine technology, are discussed.

The role of gap junctions in inflammatory and neoplastic disorders (Review).

Gap junctions are intercellular channels made of connexin proteins, mediating both electrical and biochemical signals between cells. The ability of gap junction proteins to regulate immune responses, cell proliferation, migration, apoptosis and carcinogenesis makes them attractive therapeutic targets for treating inflammatory and neoplastic disorders in different organ systems. Alterations in gap junction profile and expression levels are observed in hyperproliferative skin disorders, lymphatic vessel diseases, inflammatory lung diseases, liver injury and neoplastic disorders. It is now recognized that the therapeutic effects mediated by traditional pharmacological agents are dependent upon gap junction communication and may even act by influencing gap junction expression or function. Novel strategies for modulating the function or expression of connexins, such as the use of synthetic mimetic peptides and siRNA technology are considered.

The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches.

Gap junctions are intercellular proteins responsible for mediating both electrical and biochemical coupling through the exchange of ions, second messengers and small metabolites. They consist of two connexons, with (one) connexon supplied by each cell. A connexon is a hexamer of connexins and currently more than 20 connexin isoforms have been described in the literature thus far. Connexins have a short half-life, and therefore gap junction remodeling constantly occurs with a high turnover rate. Post-translational modification, such as phosphorylation, can modify their channel activities. In this article, the roles of connexins in wound healing and repair are reviewed. Novel strategies for modulating the function or expression of connexins, such as the use of antisense technology, synthetic mimetic peptides and bioactive materials for the treatment of skin wounds, diabetic and pressure ulcers as well as cornea wounds, are considered.

What Is the Arrhythmic Substrate in Viral Myocarditis? Insights from Clinical and Animal Studies.

Sudden cardiac death (SCD) remains an unsolved problem in the twenty-first century. It is often due to rapid onset, ventricular arrhythmias caused by a number of different clinical conditions. A proportion of SCD patients have identifiable diseases such as cardiomyopathies, but for others, the causes are unknown. Viral myocarditis is becoming increasingly recognized as a contributor to unexplained mortality, and is thought to be a major cause of SCD in the first two decades of life. Myocardial inflammation, ion channel dysfunction, electrophysiological, and structural remodeling may play important roles in generating life-threatening arrhythmias. The aim of this review article is to examine the electrophysiology of action potential conduction and repolarization and the mechanisms by which their derangements lead to triggered and reentrant arrhythmogenesis. By synthesizing experimental evidence from pre-clinical and clinical studies, a framework of how host (inflammation), and viral (altered cellular signaling) factors can induce ion electrophysiological and structural remodeling is illustrated. Current pharmacological options are mainly supportive, which may be accompanied by mechanical circulatory support. Heart transplantation is the only curative option in the worst case scenario. Future strategies for the management of viral myocarditis are discussed.

Animal models for the study of primary and secondary hypertension in humans.

Hypertension is a significant cause of morbidity and mortality worldwide. It is defined as systolic and diastolic blood pressures (SBP/DBP) >140 and 90 mmHg, respectively. Individuals with an SBP between 120 and 139, or DBP between 80 and 89 mmHg, are said to exhibit pre-hypertension. Hypertension can have primary or secondary causes. Primary or essential hypertension is a multifactorial disease caused by interacting environmental and polygenic factors. Secondary causes are renovascular hypertension, renal disease, endocrine disorders and other medical conditions. The aim of the present review article was to examine the different animal models that have been generated for studying the molecular and physiological mechanisms underlying hypertension. Their advantages, disadvantages and limitations will be discussed.

Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia. Over the last decade, plasma Epstein-Barr virus (EBV) DNA has been developed as a tumor marker for NPC. In this study, the authors investigated whether plasma EBV DNA analysis is useful for NPC surveillance. METHODS: In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow-up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC. RESULTS: Three individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow-up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2-fold increase in plasma EBV DNA on the follow-up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks. CONCLUSIONS: Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false-positive results. Cancer 2013. © 2013 American Cancer Society.

One-step expression and purification of single-chain variable antibody fragment using an improved hexahistidine tag phagemid vector.

Millions of candidate clones are commonly obtained following rounds of phage-displayed antibody library panning, and expression of those selected single-chain variable fragment (scFv) is required for secondary functional screening to identify positive clones. Large scale functional screening is often hampered by the time-consuming and labor-intensive subcloning of those candidate scFv clones into a bacterial expression vector carrying an affinity tag for scFv purification and detection. To overcome the limitations and to develop a multiplex approach, an improved hexahistidine tag phagemid vector was constructed for one-step scFv expression and purification. By using hexahistidine as an affinity tag, soluble scFvs can be rapidly and cost-effectively captured from Escherichia coli periplasmic extracts. For proof-of-concept, feasibility of the improved phagemid vector was examined against two scFvs, L17E4d targeting a cell surface antigen and L18Hh5 recognizing a monoclonal antibody (mAb). Using 1 ml of Ni-NTA agarose, 0.2-0.5 mg of soluble scFv was obtained from 1 L of bacteria culture, and the purified scFvs bound specifically to their target antigens with high affinity. Moreover, using two randomly selected hapten-specific scFv phage clones, it was demonstrated that the display of scFvs on phage surface was not affected by the hexahistidine affinity tag. These results suggest the improved phagemid vector allows the shuttle of phage-displayed antibody library panning and functional scFv production. Importantly, the improved phagemid vector can be easily adapted for multiplex screening.