bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated siRNA design based on surveying of features associated with high RNAi effectiveness
Authors: Gong Wuming , Ren Yongliang , Xu Qiqi , Wang Yejun , Lin Dong , Zhou Haiyan , Li Tongbin
Published: November 2006

Background

Short interfering RNAs have allowed the development of clean and easily regulated methods for disruption of gene expression. However, while these methods continue to grow in popularity, designing effective siRNA experiments can be challenging. The various existing siRNA design guidelines suffer from two problems: they differ considerably from each other, and they produce high levels of false-positive predictions when tested on data of independent origins.

Results

Using a distinctly large set of siRNA efficacy data assembled from a vast diversity of origins (thesiRecordsdata, containing records of 3,277 siRNA experiments targeting 1,518 genes, derived from 1,417 independent studies), we conducted extensive analyses of all known features that have been implicated in increasing RNAi effectiveness. A number of features having positive impacts on siRNA efficacy were identified. By performing quantitative analyses on cooperative effects among these features, then applying adisjunctive rule merging(DRM) algorithm, we developed a bundle of siRNA design rule sets with the false positive problem well curbed. A comparison with 15 online siRNA design tools indicated that some of the rule sets we developed surpassed all of these design tools commonly used in siRNA design practice in positive predictive values (PPVs).

Conclusion

The availability of the large and diverse siRNA dataset fromsiRecordsand the approach we describe in this report have allowed the development of highly effective and generally applicable siRNA design rule sets. Together with ever improving RNAi lab techniques, these design rule sets are expected to make siRNAs a more useful tool for molecular genetics, functional genomics, and drug discovery studies.
Novel mutation of the PRNPgene of a clinical CJD case
Authors: Kotta Konstantia , Paspaltsis Ioannis , Bostantjopoulou Sevasti , Latsoudis Helen , Plaitakis Andreas , Kazis Dimitrios , Collinge John , Sklaviadis Theodoros
Published: November 2006

Background

Transmissible spongiform encephalopathies (TSEs), a group of neurodegenerative diseases, are thought to be caused by an abnormal isoform of a naturally occurring protein known as cellular prion protein, PrPC. The abnormal form of prion protein, PrPSc accumulates in the brain of affected individuals. Both isoforms are encoded by the same prion protein gene (PRNP), and the structural changes occur post-translationally. Certain mutations in the PRNP gene result in genetic TSEs or increased susceptibility to TSEs.

Case presentation

A 70 year old woman was admitted to the hospital with severe confusion and inability to walk. Relatives recognized memory loss, gait and behavioral disturbances over a six month period prior to hospitalization. Neurological examination revealed Creutzfeldt-Jakob disease (CJD) related symptoms such as incontinence, Babinski sign and myoclonus. EEG showed periodic sharp waves typical of sporadic CJD and cerebrospinal fluid analysis (CSF) was positive for the presence of the 14-3-3-protein. As the disease progressed the patient developed akinetic mutism and died in the tenth month after onset of the disease symptoms. Unfortunately, no autopsy material was available. PRNP sequencing showed the occurrence of a point mutation on one allele at codon 193, which is altered from ACC, coding for a threonine, to ATC, encoding an isoleucine (T193I).

Conclusion

Here we report a novel mutation of the PRNP gene found in an elderly female patient resulting in heterozygosity for isoleucine and threonine at codon 193, in which normally homozygosity for threonine is expected (T193). The patient presented typical clinical symptoms of CJD. EEG findings and the presence of the 14-3-3 protein in the CSF, contributed to CJD diagnosis, allowing the classification of this case as a probable CJD according to the World Health Organization (WHO) accepted criteria.
Relationship between Tonic Inhibitory Currents and Phasic Inhibitory Activity in the Spinal Cord Lamina II Region of Adult Mice
Authors: Ataka Toyofumi , Gu Jianguo G
Published: November 2006

Phasic and tonic inhibitions are two types of inhibitory activities involved in inhibitory processing in the CNS. In the spinal cord dorsal horn, phasic inhibition is mediated by both GABAergic and glycinergic inhibitory postsynaptic currents. In contrast to phasic inhibitory currents, using patch-clamp recording technique on spinal cord slices prepared from adult mice we revealed that tonic inhibitory currents were mediated by GABAA receptors but not by glycine receptors in dorsal horn lamina II region. We found that there was a linear relationship (r = 0.85) between the amplitude of tonic inhibitory currents and the frequency of GABAergic inhibitory postsynaptic currents. Analysis of charge transfer showed that the charges carried by tonic inhibitory currents were about 6 times of charges carried by phasic inhibitory currents. The prominent charge transfer by tonic inhibitory currents and their synaptic activity dependency suggest a significant role of tonic inhibition in sensory processing.
Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health
Authors: Kamphuis Sylvia , Hrafnkelsdóttir Kolbrún , Klein Mark R , de Jager Wilco , Haverkamp Margje H , van Bilsen Jolanda HM , Albani Salvatore , Kuis Wietse , Wauben Marca HM , Prakken Berent J
Published: November 2006

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.
Early changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-negative sepsis
Authors: Giamarellos-Bourboulis Evangelos J , Tsaganos Thomas , Spyridaki Ekaterini , Mouktaroudi Maria , Plachouras Diamantis , Vaki Ilia , Karagianni Vassiliki , Antonopoulou Anastasia , Veloni Vassiliki , Giamarellou Helen
Published: November 2006

Introduction

Our aim was to define early changes of lymphocytes and of NK cells in severe sepsis and to correlate them with serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1).

Methods

Blood was sampled from 49 patients with proven highly suspected infection by Gram-negative pathogens, within 12 hours of the advent of severe sepsis, and was also sampled from six healthy volunteers. White blood cells were targeted with monoclonal antibodies and were analyzed by flow cytometry. The concentrations of sTREM-1 were estimated by ELISA.

Results

The presence of CD3/CD4 cells was significantly lower (P < 0.0001) and that of NK cells significantly higher among patients with sepsis compared with controls (P = 0.011). The proportions (median ± standard error) of ANNEXIN-V/CD4/CD3-positive cells, of ANNEXIN-V/CD8/CD3-positive cells and of ANNEXIN-V/CD14-positive cells of the patient population were 7.41 ± 2.26%, 7.69 ± 3.42% and 1.96 ± 4.22%, respectively. Patients with NK cells >20% survived longer compared with those patients with NK cells ≤20% (P = 0.041), and patients with sTREM-1 concentrations >180 pg/ml survived longer compared with those patients with sTREM-1 concentrations ≤180 pg/ml (P = 0.042). A negative correlation was found between the percentages of ANNEXIN-V/CD4/CD3-positive cells and of CD3/CD4 cells (rs = -0.305, P = 0.049), and a positive correlation was found between the serum sTREM-1 concentration and the percentage of NK cells (rs = +0.395, P = 0.014). NK cells isolated from two healthy volunteers released sTREM-1 upon triggering with endotoxins.

Conclusion

Early severe sepsis is characterized by CD4-lymphopenia and increased NK cells, providing a survival benefit for the septic patient at percentages >20%. The survival benefit resulting from elevated NK cells might be connected to elevated serum levels of sTREM-1.
Cofilin plays a critical role in IL-8-dependent chemotaxis of neutrophilic HL-60 cells through changes in phosphorylation
Authors: Hirayama Akiko , Adachi Reiko , Otani Saki , Kasahara Tadashi , Suzuki Kazuhiro
Published: November 2006

Cofilin is a ubiquitous, actin-binding protein. Only unphosphorylated cofilin binds actin and severs or depolymerizes filamentous actin (F-actin), and the inactive form of cofilin is phosphorylated at Ser 3. We reported recently that cofilin plays a regulatory role in superoxide production and phagocytosis by leukocytes, and in the present study, we investigated the role of cofilin in the chemotaxis of neutrophilic HL-60 cells. IL-8 is a potent, physiological chemokine, and it triggers a rapid, transient increase in F-actin beneath the plasma membrane and rapid dephosphorylation and subsequent rephosphorylation of cofilin. In this study, cofilin phosphorylation was found to be inhibited by S3-R peptide, which consists of a peptide corresponding to part of the phosphorylation site of cofilin and a membrane-permeable arginine polymer. When S3-R peptide was introduced into the neutrophilic cells, their chemotactic activity was enhanced, whereas a control peptide that contained an inverted sequence of the phosphorylation site of cofilin had no enhancing effect. Cofilin small interfering RNA (siRNA) decreased cofilin expression by about half and inhibited chemotaxis. In IL-8-stimulated cells, unphosphorylated cofilin accumulated around F-actin, and colocalization of F-actin and phosphorylated cofilin was observed, but these changes in cofilin localization were less prominent in cofilin siRNA-treated cells. The inhibitors of PI-3K wortmannin and LY294002 inhibited the chemotaxis and suppressed IL-8-evoked dephosphorylation and rephosphorylation of cofilin. These results suggested that unphosphorylated cofilin plays a critical role in leukocyte chemotaxis and that PI-3K is involved in the control of the phosphorylation/dephosphorylation cycle of cofilin.
Immunolocalization of Monocyte Chemoattractant Protein‐1 in Islets of NOD Mice during Cyclophosphamide Administration
Authors: REDDY SHIVA , BAI YAN , ROBINSON ELIZABETH , ROSS JACQUELINE
Published: November 2006

Abstract:  The molecular processes that initiate insulitis in type 1 diabetes remain unclear. Chemokines, such as monocyte chemoattractant protein‐1 (MCP‐1), mediate chemotaxis and leukocyte migration to inflammatory sites. Although MCP‐1 mRNA has been shown in islets isolated from NOD mice at 2 weeks of age and at later stages, the cellular sources of this chemokine, at the protein level, and its role in insulitis are unclear. The aims of the present study were to employ immunohistochemical techniques to examine the expression of MCP‐1 and quantify its cellular sources in islets of NOD mice both after cyclophosphamide (Cy) administration and in spontaneous diabetes. Tissues were examined at days 1 (=day 73, first day of Cy), 4, 7, 11, and 14 and in age‐matched control NOD mice. Pancreatic sections from NOD mice without Cy administration were also studied between days 21–65 and at onset of diabetes and from adult CD‐1 mice. In the Cy group, a small number of peri‐islet macrophages were immunopositive for MCP‐1 at day 1 whereas at day 4, the number declined but increased subsequently at day 7. In the same group, it increased markedly at days 11 and 14 compared with age‐matched control NOD mice. In young NOD mice, MCP‐1 was present in selective macrophages in islets with early insulitis (day 45) but was absent at diabetes onset. MCP‐1 was undetectable in beta cells and in most T cells. Islets from adult CD‐1 mice did not show immunostaining for MCP‐1. We conclude that MCP‐1 is expressed in a proportion of islet and exocrine macrophages. This expression increases during the later stages of Cy‐induced diabetes. Thus, MCP‐1 positive macrophages that migrate to the islet periphery during the early stages of Cy‐induced diabetes and preceding spontaneous diabetes may augment insulitis by further attracting macrophages and T cells.
Eicosanoid Imbalance in the NOD Mouse Is Related to a Dysregulation in Soluble Epoxide Hydrolase and 15‐PGDH Expression
Authors: RODRIGUEZ MICHELLE , CLARE‐SALZLER MICHAEL
Published: November 2006

Abstract:  Eicosanoids promote or resolve inflammation depending on the class produced. Macrophage from nonobese diabetic (NOD) mouse produce increased proinflammatory lipid mediators and low levels of antiinflammatory lipoxin A4 (LXA4). The enhanced proinflammatory eicosanoids is secondary to increased cyclooxygenase‐2 (Cox‐2) expression and low levels of prostaglandin/leukotriene catabolic enzyme, 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH). Deficient LXA4 production is not due to deficient lipoxygenase (LO) activity, but is related to increased soluble epoxide hydrolase (sEH), involved in metabolism of anti‐inflammatory epoxyeicosatrienoic acids (EET). These aberrations in eicosanoid biology suggest that inflammation in the NOD mouse is likely to be prolonged and robust and may contribute to type 1 diabetes (T1D) pathogenesis.
Characterization of PAF‐AH Ib1 in NOD Mice
Authors: MI QING‐SHENG , ZHOU LI , GRATTAN MARSHA , WANG ZAI‐ZHAO , SIVILOTTI M. , SHE JING‐XIANG , DELOVITCH TERRY L.
Published: November 2006

Abstract:  We recently mapped Idd4 to a 5.2 cM interval on chromosome 11 with two subloci, Idd4.1 and Idd4.2, in nonobese diabetic (NOD) mice. Based on the localization of platelet‐activating factor acetylhydrolase Ib1 (PAF‐AHIb1) and the decreased activity of PAF‐AH in type 1 diabetes (T1D) patients, we hypothesized that PAF‐AHIb1 in Idd4.1 is a candidate gene. The PAF‐AHIb1 gene in NOD mice was cloned and sequenced, and its expression and function were studied. No polymorphisms were detected in PAF‐AHIb1 cDNA between NOD and B6 mice. The expression of PAF‐AH Ib1 at the mRNA and protein levels was found to be similar in different tissues between NOD and B6 mice. PAF‐AH activity does not differ in the pancreatic islets or spleen between NOD and B6 mice. Our findings suggest that PAF‐AH Ib1 may not be a diabetes‐susceptibility gene in the Idd4.1 sublocus.
Normal T Cell Development in the Absence of Thymic Insulin Expression
Authors: CARLSÉN MARIA , CILIO CORRADO M.
Published: November 2006

Abstract:  Ectopic expression of insulin in thymus has been suggested to be involved in tolerance induction against pancreatic β cells and in type 1 diabetes (T1D) pathogenesis. However, it is not known whether thymic insulin expression would also influence thymocyte maturation and differentiation. To address these questions, we have used mice that are insulin deficient. Early fetal thymi were cultured in fetal thymic organ cultures (FTOCs) and the development of thymocytes was studied by flow cytometry. The results revealed no significant difference in thymocyte maturation in the absence of thymic insulin. Taken together, these data do not support a role for thymic insulin in thymocyte differentiation and growth.
MHC Class I Chain‐Related Gene‐A Is Associated with IA2 and IAA but Not GAD in Swedish Type 1 Diabetes Mellitus
Authors: GUPTA MANU , GRAHAM JINKO , McNEENY BRIAN , ZARGHAMI MARIAN , LANDIN‐OLSSON MONA , HAGOPIAN WILLIAM A. , PALMER JERRY , LERNMARK ÅKE , SANJEEVI CARANI B.
Published: November 2006

Abstract: In type 1 diabetes mellitus (T1DM), the frequency of antibodies against insulin (IAA), glutamic acid decarboxylase‐65 (GAD65), ICA512/IA2 (IA2), and islet cell antigens (ICA) vary with human leukocyte antigen (HLA) composition of the patient. IAA, IA2 autoantibodies, and ICA are increased in DQ8 positives; GAD65 antibodies are increased in DQ2 positives. MHC class I chain‐related gene‐A (MICA) is another genetic marker that has been proposed to be associated with T1DM. In this article, we looked at microsatellite polymorphism of MICA and its association with autoantibodies (IAA, IA2, and GAD65) in Swedish T1DM patients and if the association explains its importance in early events in autoimmune response. We studied 635 T1DM patients between 0–35 years. Frequency of MICA5/5 was positively associated with the formation of IAA and IA2 antibodies considered individually or in combination (odds ratio [OR], 95% CI,Pc: [IAA+ versus IAA–]: 4.94, 2.09–11.62, <0.0005; [IA2+ versus IA2–]: 2.65, 1.52–4.59, 0.0015; [IAA and/or IA2+ versus rest]: 9.83, 2.37–40.78, <0.0015; [IAA and IA2+ versus rest]: 3.51, 2.01–6.15, <0.0015). Also, –5.1/5.1 was increased in IAA+ patients compared to IAA– patients (2.82, 1.64–4.83, <0.0005). All patients positive for –5/5 developed at least one of the three antibodies. Frequency of MICA5.1 was decreased in IAA+ (0.54, 0.36–0.81, 0.017), in IA2A+ (0.63, 0.45–0.88, 0.04), in IAA and/or IA2A+ (0.52, 0.33–0.84, 0.044), and in IAA and IA2A+ (0.55, 0.39–0.78, 0.0055) patients when compared with patients negative for corresponding antibodies. Frequency of MICA9, 5/5.1, and 5.1/9 was decreased in IAA+ compared to IAA– patients (0.51, 0.32–0.79, 0.021; 0.22, 0.11–0.44, <0.005; and 0.39, 0.22–0.69, 0.026, respectively). Frequency of MICA9 and –5.1/9 was also decreased in IAA and/or IA2 antibody‐positive patients while MICA5/5.1 decreased in patients positive for IAA and IA2 antibody both together. IAA and IA2 antibodies are believed to appear early during the autoimmune reaction against beta cells. Thus, according to our data, MICA–5/5 and –5.1/5.1 is associated with early autoimmunity in T1DM patients. Our study suggests that MICA gene polymorphism is associated with autoantibody formation and that the polymorphism especially MICA5/5 and –5.1/5.1 are important in early events of autoimmune reaction.
Predominance of the Group A Killer Ig‐Like Receptor Haplotypes in Korean Patients With T1D
Authors: PARK YONGSOO , CHOI HEEJIN , PARK HYEWON , PARK SUKYUNG , YOO EUN‐KYUNG , KIM DUKHEE , SANJEEVI CARANI B.
Published: November 2006

Abstract:  Type 1 diabetes (T1D) is a T cell‐mediated autoimmune disease in which pancreatic β cells are selectively destroyed. Although autoimmune diseases are driven by inappropriate adaptive immunity, innate immunity may play a role in the development of T1D. To study the potential involvement of innate immunity in the pathogenesis of autoimmune disease, we investigated associations of the genes for 14 different killer Ig‐like receptors (KIRs), the well‐characterized receptors in natural killer cells, with Korean T1D patients. Genetic association analyses revealed that some of the KIR genes were associated with T1D. KIR2DL5 and 2DS2 genes were present at significantly low frequency in Korean T1D patients (P < 10−4). We did not detect any influence of ligand distribution on KIR association. With the haplotype assignments, 53% of the KIR haplotypes in the control are of type A. Compared with the control (P < 10−3) and autoantibody‐negative patients (P < 10−2), the group A haplotype predominates in Korean patients with T1D. The KIR gene is associated with T1D and distribution differences between T1D and controls were not influenced by the HLA genes (DR‐DQ‐A‐C). T1D, at least in Koreans, is associated with KIR genes, especially in the group A KIR haplotypes. There is a close relationship between innate and adaptive immunity.
Cord Blood Islet Autoantibodies Are Related to Stress in the Mother during Pregnancy
Authors: LERNMARK BARBRO , LYNCH KRISTIAN , LERNMARK Å KE ,   THE DiPiS STUDY GROUP
Published: November 2006

Abstract:  A 2‐month psychological questionnaire concerning pregnancy was answered by 20,920 nondiabetic mothers of singletons. Retrospective analysis showed increased levels of islet autoantibodies (IA) in 290 (1.4%) newborns. High IA levels in the child's cord blood correlated strongly with IA levels in the mother (GADA r= 0.91, P < 0.0001; IA‐2A r= 0.75, P= 0.0001). High IA levels were found in newborns whose mothers during pregnancy had been more worried than usual (P= 0.04), had worried that the child would be sick (P= 0.01) or not survive (P= 0.002), or had experienced serious life events, like “serious accident in the family” (P < 0.0001) or “experienced violence” (P= 0.02). Associations with increased worries by the mother remained in newborns with high type 1 diabetes mellitus (T1DM)‐human leukocyte antigen (HLA) risk, but not in non‐HLA risk children. The prospective follow‐up of these children will determine the importance of this early IA for postnatal islet autoimmunity, type 1 diabetes, or both.
Cellular Alternans
Authors: WILSON LANCE D. , WAN XIAOPING , ROSENBAUM DAVID S.
Published: November 2006

Abstract:  Essentially all previous research on alternans has been restricted to normal myocardium, whereas sudden cardiac death (SCD) occurs most commonly in patients with ventricular dysfunction (i.e., heart failure), which is associated with marked disruption of proteins responsible for normal calcium cycling in myocytes. Several lines of evidence from studies in normal hearts suggest a link between impaired calcium cycling which characterizes ventricular mechanical dysfunction and impaired calcium cycling that is responsible for alternans. In normal myocardium, cells which exhibit the slowest calcium cycling, and not the slowest repolarization, are most susceptible to alternans. Decreased expression of key calcium cycling proteins is observed in alternans‐prone cells. Sarcoplasmic reticulum ATPase (SERCA2a) expression is decreased, suggesting a mechanism for the slower sarcoplasmic reticulum (SR) calcium reuptake observed in alternans‐prone cells. In addition, diminished ryanodine receptor (RyR) function leading to abnormal calcium release from the SR is also linked to cellular alternans. Although impaired contractile function clearly predisposes to SCD, the mechanisms linking mechanical to electrophysiological dysfunction in the heart are unclear. We propose that cellular calcium alternans may be an important mechanism linking mechanical dysfunction to cardiac arrhythmogenesis.
Mechanosensitive‐Mediated Interaction, Integration, and Cardiac Control
Authors: LAB MAX J
Published: November 2006

Abstract:  This review covers aspects of the cardiac mechanotransduction field at different levels, and advocates the possibility that mechanoelectro‐chemical transduction forms part of a network of mechanically linked integration in heart—mechanically mediated integration (MMI). It assembles evidence and observations in the literature to promote this hypothesis. Mechanical components can provide the bond between interactions at molecular, cellular, and macro levels to enable the integration. Stretch‐activated channels (SACs) exist in the heart, but stresses and strains can affect other membrane channels or receptors. A cellular mechanical change can thus promote several ionic or downstream changes. Cell signal cascades have been implicated and can affect membrane electrophysiology. MMI could shape intracellular and downstream signals using the cytoskeleton and intracellular Ca2+. MMI also spans other regulatory systems and processes such as the autonomic nervous system (ANS) and operates throughout the whole heart as an integrative system. Finally, supporting the hypothesis, if elements of the normal integration become deranged it contributes to cardiovascular disease and, potentially, lethal arrhythmia.
Multiscale Modeling of Calcium Signaling in the Cardiac Dyad
Authors: WINSLOW RAIMOND L. , TANSKANEN ANTTI , CHEN MINDAO , GREENSTEIN JOSEPH L.
Published: November 2006

Abstract:  Calcium (Ca2+)‐induced Ca2+‐release (CICR) takes place in spatially restricted microdomains known as dyads. The length scale over which CICR occurs is on the order of nanometers and relevant time scales range from micro‐ to milliseconds. Quantitative understanding of CICR therefore requires development of models that are applicable over a range of spatio‐temporal scales. We will present several new approaches for multiscale modeling of CICR. First, we present a model of dyad Ca2+ dynamics in which the Fokker‐Planck equation (FPE) is solved for the probability P(x, t) that a Ca2+ ion is located at dyad position x at time t. Using this model, we demonstrate that (a) Ca2+ signaling in the dyad is mediated by approximately tens of Ca2+ ions; (b) these signaling events are noisy due to the small number of ions involved; and (c) the geometry of the RyR (ryanodine receptors) protein may function to restrict the diffusion of and to “funnel” Ca2+ ions to activation‐binding sites on the RyR, thus increasing RyR open probability and excitation‐contraction (EC) coupling gain. Simplification of this model to one in which the dyadic space is represented using a single compartment yields the stochastic local‐control model of CICR developed previously. We have shown that this model captures fundamental properties of CICR, such as graded release and voltage‐dependent gain, may be integrated within a model of the myocyte and may be simulated in reasonable times using a combination of efficient numerical methods and parallel computing, but remains too complex for general use in cell simulations. To address this problem, we show how separation of time scales may be used to formulate a model in which nearby L‐type Ca2+ channels (LCCs) and RyRs gate as a coupled system that may be described using low‐dimensional systems of ordinary differential equations, thus reducing computational complexity while capturing fundamentally important properties of CICR. The simplified model may be solved many orders of magnitude faster than can either of the more detailed models, thus enabling incorporation into tissue‐level simulations.
Modeling Cardiac Ischemia
Authors: RODRÍGUEZ BLANCA , TRAYANOVA NATALIA , NOBLE DENIS
Published: November 2006

Abstract:  Myocardial ischemia is one of the main causes of sudden cardiac death, with 80% of victims suffering from coronary heart disease. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow, glucose, and washout in the affected tissue. Cellular metabolism is impaired and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation. Due to the burden imposed by ischemia in our societies, a large body of research has attempted to unravel the mechanisms of initiation, sustenance, and termination of cardiac arrhythmias in acute ischemia, but the rapidity and complexity of ischemia‐induced changes as well as the limitations in current experimental techniques have hampered evaluation of ischemia‐induced alterations in cardiac electrical activity and understanding of the underlying mechanisms. Over the last decade, computer simulations have demonstrated the ability to provide insight, with high spatiotemporal resolution, into ischemic abnormalities in cardiac electrophysiological behavior from the ionic channel to the whole organ. This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia‐related arrhythmias and how to efficiently terminate them.
Adenylyl Cyclase Gene Transfer in Heart Failure
Authors: KIRK HAMMOND H.
Published: November 2006

Abstract:  The rationale for gene transfer of adenylyl cyclase type VI (ACVI) for clinical congestive heart failure (CHF) is based on recent experimental studies that have extended from cultured cardiac myocytes to preclinical studies in animal models of CHF. Over the past several years substantial data have indicated an unexpected and pronounced favorable effect of ACVI expression in cardiovascular disease. Preclinical studies have shown that increased cardiac AC content improves left ventricular function and attenuates deleterious remodeling in the failing heart, and reduces mortality in heart failure and in acute myocardial infarction. A brief review of the preclinical studies that have examined changes associated with increased AC expression in the heart is presented here.
Thermal history analysis of surface heating of mild steel with different laser beam geometries
Authors: Safdar S , Li L , Sheikh M A , Schmidt M J
Published: November 2006

Lasers are in use in the material processing industry for well over 30 years now. The way in which the temperature is distributed inside the material is of prime importance in laser material processing, as it directly affects the heating/cooling rates and thermal gradients. Optimization of different laser processes requires control over heating/cooling rate and thermal gradient. Different processes have different requirements of heating/cooling rate and thermal gradient. Knowing these parameters and relevant metallurgical information, one can predict the microstructure and hence control the material properties. To date, majority of laser processing is carried out by using either circular or rectangular beam. At present, the variation in temperature distribution to control the heating/cooling rates and thermal gradients is caused by the variation either in laser power or in scanning speed. Variations in these parameters are often limited by other processing conditions. Although different beam intensity distributions with circular or rectangular laser beams have been studied to improve the process, no other beam geometries have been investigated. The effect of laser beam geometry on laser processing of materials has received very little attention. This article presents an investigation of the effects of different beam geometries including circular, rectangular, and triangular shapes on heating of metallic materials. Finite-element modelling technique has been used to simulate the transient effects of a moving beam for laser surface heating of metals. The temperature distributions, cooling rates, and thermal gradients have been calculated. Some of the results have been compared with the experimental data.
Stability of circular-section bonded rubber blocks subjected to compression and bending
Authors: Horton J M , Tupholme G E
Published: November 2006

Rubber blocks of circular cross-section whose ends are bonded to rigid plates are studied under compression between either flat parallel surfaces or central parallel knife-edges. Implicit expressions are derived exactly in each case for the critical values of the loads at which the blocks begin to bend, based upon the classical theory of elasticity. Convenient very good approximate explicit representations are additionally deduced for these first critical loads. Some typical representative numerical data are compared and presented graphically in both situations.
Two-dimensional lubrication analysis and design optimization of a Scotch Yoke engine linear bearing
Authors: Wang X , Subic A , Watson H
Published: November 2006

Recent study has shown that the application of a Scotch Yoke crank mechanism to a reciprocating internal combustion engine reduces the engine's size and weight and generates sinusoidal piston motion that allows for complete balance of the engine.

This paper describes detailed investigation of the performance of a linear bearing assembly, which is one of the key components of the Scotch Yoke mechanism. The investigation starts by solving Reynolds equation for the Scotch Yoke linear bearing. The two-dimensional lubricant flow is numerically simulated and the calculated results are compared with experimental results from a linear bearing test rig. The performance characteristics and a design sensitivity analysis of the bearing are presented. Dynamic testing and analysis of an instrumented linear bearing on a test rig are used to validate the numerical simulation model. The oil supply and lubrication mechanism in the linear bearing are analysed and described in detail. This work aims to provide new insights into Scotch Yoke linear bearing design. In addition, strategies for optimization of the linear bearing are discussed.
Research on the lubrication characteristics of water hydraulic slipper friction pairs
Authors: Huanlong L , Jian K , Guozhi W , Lanying Y
Published: November 2006

The low viscosity of water makes the film of water in water hydraulic axial piston pump slipper friction pairs very thin, and which can be broken easily. By simulation, analysis, experiment, and comparison, the lubrication characteristics of the new-type water slipper friction pairs, especially its anti-turnover ability, which directly affects the working reliability of the water film, are examined by a study of water's flow pattern. On the basis of the idea of multi-groups of damping and supporting cavity, the independent stiffness adjustment is used to improve the anti-turnover ability of the water slipper friction pairs. Furthermore, on the basis of the N-S equations, the fluid lubrication characteristics of water hydraulic clearance friction pairs are examined more thoroughly and accurately, taking into account the inertia, the surface roughness etc, so as to revise the calculation and analysis results of water hydraulic slipper lubrication characteristics put forth by classical theory.
Adaptive tracking of non-linear dynamic plants, using the U-model
Authors: Butt N. R. , Shafiq M
Published: November 2006

Adaptive tracking of non-linear dynamic plants is currently an important area of research. The main difficulty being felt by the research community is the lack of a general modelling framework that can facilitate synthesis of a simplistic control law while being capable of providing accurate approximation of non-linear systems. In this study a novel technique based on the control-oriented U-model is proposed for the adaptive tracking of a wide range of stable non-linear dynamic plants using only past data. The basic scheme is based on the robust internal model control (IMC) structure. An adaptive version of the U-model is introduced for the modelling of the plant, and a simplistic control law based on polynomial root-solving is synthesized. The proposed scheme has a more general appeal than other adaptive schemes based on models such as the polynomial NARMAX (Non-linear AutoRegressive Moving Average with exogenous inputs) model. Additionally, the control law is much simpler in nature. The effectiveness of the proposed adaptive scheme is demonstrated through simulations and real-time implementation.
Candidate Gene Genotypes, Along with Conventional Risk Factor Assessment, Improve Estimation of Coronary Heart Disease Risk in Healthy UK Men
Authors: Humphries Steve E , Cooper Jackie A , Talmud Philippa J , Miller George J
Published: November 2006

Background: One of the aims of cardiovascular genetics is to test the efficacy of the use of genetic information to predict cardiovascular risk. We therefore investigated whether inclusion of a set of common variants in candidate genes along with conventional risk factor (CRF) assessment enhanced coronary heart disease (CHD)-risk algorithms.

Methods: We followed middle-aged men in the prospective Northwick Park Heart Study II (NPHSII) for 10.8 years and analyzed complete trait and genotype information available on 2057 men (183 CHD events).

Results: Of the 12 genes previously associated with CHD risk, in stepwise multivariate risk analysis, uncoupling protein 2 (UCP2; P = 0.0001), apolipoprotein E (APOE; P = 0.0003), lipoprotein lipase (LPL; P = 0.007), and apolipoprotein AIV (APOA4; P = 0.04) remained in the model. Their combined area under the ROC curve (AROC) was 0.62 (0.58–0.66) [12.6% detection rate for a 5% false positive rate (DR5)]. The AROC for the CRFs age, triglyceride, cholesterol, systolic blood pressure, and smoking was 0.66 (0.61–0.70) (DR5 = 14.2%). Combining CRFs and genotypes significantly improved discrimination (P = 0.001). Inclusion of previously demonstrated interactions of smoking with LPL, interleukin-6 (IL6), and platelet/endothelial cell adhesion molecule (PECAM1) genotypes increased the AROC to 0.72 (0.68–0.76) for a DR5 of 19.1% (P = 0.01 vs CRF combined with genotypes).

Conclusions: For a modest panel of selected genotypes, CHD-risk estimates incorporating CRFs and genotype–risk factor interactions were more effective than risk estimates that used CRFs alone.
Introduction to the special issue: Media use and selectivity
Authors: Bilandzic Helena , Krotz Friedrich , Rössler Patrick
Published: November 2006

An expanding media universe confronts readers, viewers, and users with an abundance of media content that, for the most part, will not be used by the audience, and will, in many cases, not even be considered for use. Selecting what to use and not to use is functional in avoiding information overload (Carlson, 2003) or ‘technostress’ (Rosen and Weil, 1997), but, at the same time, necessary to make use of the media environment. The selection of media initiates gratifications, serves particular functions, enables certain effects, all depending on the perspective. Media use and selectivity constitute a field of remarkable tradition in communication research. The question how individuals deal with media and why they use certain media content has been in the focus of communication research from the very beginning of empirical media research; since Lazarsfeld and his colleagues conducted their radio research projects (Lazarsfeld and Stanton, 1944), which included Herzog's (1944) widely cited study on daytime serial listeners. Thinking about media use reached a first prime with the emergence of Uses and Gratifications approaches; an abundance of studies about ‘what people do with the media’ have been published during the golden years of Uses and Gratifications in the 1970s and 1980s. Bryant and Miron (2004) identified Uses and Gratifications – along with Agenda Setting – as the approach most frequently used in three communication journals from 1956 through 2000.
Explaining and analyzing audiences: A social cognitive approach to selectivity and media use
Authors: Peters Oscar , Rickes Matthias , Jöckel Sven , Criegern Christian von , Deursen Alexander van
Published: November 2006

This study explored LaRose and Eastin's (2004) model of media attendance, within a European context. It extended the uses and gratifications (U and G) paradigm within the framework of social cognitive theory (SCT) by instituting new operational measures of gratifications sought, reconstructed as outcome expectations. Although the model of media attendance offers some promising steps forward in measuring media selectivity and usage, and to some extent is applicable to another context of media use, the relative importance of outcome expectancies in explaining media usage and selectivity is not fully supported.
The gender news use divide: Impacts of sex, gender, self-esteem, achievement, and affiliation motive on German newsreaders' exposure to news topics
Authors: Knobloch-Westerwick Silvia , Brück Julia , Hastall Matthias R
Published: November 2006

To examine the psychological origins of sex-typed news preferences, an online newsmagazine was presented to 246 German participants in a quasi-experimental design. The presented articles featured equal portions of social/interpersonal and achievement/performance topics. Newsreaders' selective news exposure was unobtrusively logged. Results show that, even when various intervening factors are eliminated, women read more about social/interpersonal topics than men did, and men spent more time on achievement/performance-related news than women. Newsreaders' self-esteem and gender role orientation influenced the preference of news content. This contribution will also discuss the effects of sex-typed news exposure.
The relevance of attention for selecting news content. An eye-tracking study on attention patterns in the reception of print and online media
Authors: Bucher Hans-Jürgen , Schumacher Peter
Published: November 2006

This article argues that a theory of media selectivity needs a theory of attention, because attention to a media stimulus is the starting point of each process of reception. Attention sequences towards media stimuli – pages of newspapers and online-newspapers – were analyzed using eye-tracking patterns from three different perspectives. First, attention patterns were compared under varying task conditions. Second, different types of media were tested. Third, attention sequences towards different forms of news with different design patterns were compared. Attention was seen as a prerequisite for reception: Its selective functions for these processes are especially important. Reception itself was examined within an action-theoretical framework and therefore described as a form of interaction between recipient and the media. Eye-tracking data were used as indicators of attention. Starting with a hypothesis on the impact of different media such as printed newspapers and online newspapers on the agenda-setting process of their audience, the study examined how the type of media and the form of news influences attention and selectivity. Our findings showed that visual cues such as salient photos or graphics and information hierarchies signalled by design and layout guide attention processes, not as an automatic process driven from the bottom up, but as stimuli for an active, intention-driven selection process. The results indicate that the form of news affects these patterns of interactive attention more than the medium itself.
Pragmatics of performance and the analysis of conversational humor
Authors: Kotthoff Helga
Published: November 2006

In this paper, I combine pragmatic theorizing with empirical interaction analysis to analyze conversational humor. By taking dialogic structures and the level of performance (utterance formulation, conversational sequencing and emergent genre construction) into consideration, I also hope to offer insights for cognitive linguistics. One key to performance analysis is that utterances always provide information, often called contextualization or framing procedures, on how they should be understood. Pragmatic modeling should take framing procedures and the reconstruction of various forms of knowledge invoked in normal, everyday communication into account to explain inferencing in humorous interaction. In most humorous activities, non-standardized inferencing forms the core of the humorous potential. It arises either from a sort of script opposition (Attardo 1994) or from playing with formulation standards and expected ways of speaking within conversational sequencing. To frustrate expectations is to invite unusual associations.

I distinguish between comical interaction modality (keying and framing) and punch-line humor. Both invite listeners to make complex inferences. Besides this, they work with allusions. The listener must draw on life-world knowledge in order to understand the allusions that are central to both sorts of humor.

I favor retaining the Gricean cooperation principle and its maxims for the analysis of humor and try to link the Gricean pragmatics of cooperation to performance analysis (framing, keying, layering, contextualization). Clark's (2004) plea to take into account the distinction between primary and collateral signals is highly suggestive of possible ways to grasp the functioning of emergent humorous interaction. In this paper, I apply pragmatic theories to two examples of emergent conversational humor not belonging to well-known conventional humor genres and consequently hard to classify using conventional folk taxonomies. Using these examples, I show what a pragmatics of performance can and should contribute to explaining how interlocutors co-construct humor and process various layers of meaning. Only when combined with a performance analysis that takes into account the layering of meaning and social and cultural knowledge can pragmatics explain the joint production of humor.
New Electrochemical Methods for the Evaluation of Localized Corrosion in Engine Coolants
Authors: Yang B , Marinho FJ , Gershun AV
Published: November 2006

Due to the need of increasing energy efficiency, reducing pollution and lessening dependency on petroleum, vehicles using more advanced propulsion technologies such as fuel cell and hybrid electric (e.g., gasoline-electric or diesel-electric hybrid) power are being developed constantly. At the same time, extensive development efforts are being devoted to research aiming to increase the use of lighter metals such as magnesium alloys in today's engines. New engine coolants are often required to meet many of these new developments and the associated changes in cooling system requirements. Since corrosion protection is one of the key performance parameters for engine coolants, new and more effective corrosion measurement methods are useful for evaluating old and developing new coolants to meet the needs of new cooling systems or having improved corrosion protection performance, or both. Particularly, new electrochemical methods capable of more reliable, quantitative, and fast (ideally, real-time) measurements of localized corrosion such as pitting, crevice, and under-deposit corrosion, and corrosion under heat rejecting conditions are highly desired. Existing ASTM test methods for engine coolants either rely on inspection of the sample after a relatively long exposure period to determine the extent of localized attack or do not yield results directly related to localized corrosion. In this paper, coupled multi-electrode sensors test and simulated localized corrosion cell technique are compared and discussed to gain new insight for facilitating the development of more effective inhibited coolants.