Generalized fragility curves for bearing-supported skew bridges, for arbitrary angle of incidence of the seismic action

In a previous work by the authors and their co-workers an analytical methodology for the derivation of seismic fragility curves for bridges was proposed. Bridges were classified into three main categories according to their seismic energy dissipation mechanism: bridges with yielding piers of the column type, bridges with bearings and non-yielding piers of the wall type, and bridges with bearings and yielding piers of the column type. Then, damage states were defined using deck displacement at characteristic points of 'typical' bridge pushover curves, which are related to the seismic energy dissipation mechanism, consistently with the proposed classification scheme. Only one horizontal component of the seismic action was considered to act along the principal directions of the bridge. This methodology was subsequently extended by the authors to take into account the angle of incidence of the seismic action, considering only the single-component case. In the present work the methodology is further extended to the general case wherein the minor principal horizontal component of the earthquake is also taken into account (dual-component seismic action). Furthermore, damage states for bridges with bearings are redefined in a broader manner, to take into account biaxial shear effects, and all possible failure mechanisms of the bearings. The methodology is applied here to a skew bridge, subjected to either single- or dual-component seismic action. The main difference between straight and skew bridges is that the modal principal bridge directions are rotated with respect to the geometric principal bridge directions, for a specific angle of incidence. The proposed methodology is formulated in terms of modal principal directions. The CQC rule is used for the combination of the projections of the control point displacement and of the base shear in the single-component case, while in the dual-component case the SRSS rule is used and it is found adequate for all excitation angles. From the derived generalized fragility curves it is concluded that when the minor principal horizontal component of the earthquake is taken into account, bridge fragility is significantly increased, while it remains practically unaffected by the angle of incidence

Assessment of concrete bridges subjected to ground motion with an arbitrary angle of incidence: static and dynamic approach

A nonlinear static analysis methodology for the derivation of a set of pushover curves for any angle of incidence of the seismic action (multidirectional pushover curves) for bridges is developed, wherein the interaction between axial force and biaxial moments at critical pier sections or biaxial shear forces at the bearings is taken into account. Dynamic pushover curves (base shear vs. peak deck displacement) for arbitrary angle of incidence of the excitation, are derived for both unidirectional (single-component) and bidirectional (dualcomponent)ground motion. It is found that neglecting the minor horizontal component leads to underestimation of bridge response, especially along the bridge principal directions and that the angle of incidence of bidirectional excitation affects bridge response, but to a lesser extent than in the case of unidirectional excitation. The proposed procedure is then applied to a straight symmetric bridge, its results are checked against those from response-history analysis, and is found to be sufficiently accurate for practical application. Using the derived results it is also found that the design of the selected bridge is safe since for the design bidirectional earthquake the bridge starts to behave inelastically (the first plastic hinge forms), while its failure occurs for about four times the design seismic action

Attitudes towards Cypriot Greek and Standard Modern Greek in London’s Greek Cypriot community

Aim To investigate whether the positive attitudes towards Standard Modern Greek and the mixture of positive and negative attitudes towards Cypriot Greek that have been documented in Cyprus are also present in London's Greek Cypriot community. Approach Unlike previous quantitative works, the study reported in this article was qualitative and aimed at capturing the ways in which attitudes and attitude-driven practices are experienced by members of London's diasporic community. Data and Analysis Data were collected by means of semi-structured, sociolinguistic interviews with 28 members of the community. All participants were second-generation heritage speakers, successive bilinguals in Cypriot Greek and English, and successive bidialectal speakers in Cypriot Greek and Standard Modern Greek. The data were analysed qualitatively (thematic analysis). Findings – Positive perceptions of Standard Modern Greek and mixed perceptions, both positive and negative, of Cypriot Greek are found in the context of London. – As in Cyprus, Standard Modern Greek is perceived as a prestigious, proper and 'correct' variety of Greek. Cypriot Greek, in contrast, is described as a villagey, heavy and even broken variety. – Greek complementary schools play a key role in engendering these attitudes. – Unlike in Cyprus, in the London community, the use of Cypriot Greek is also discouraged in informal settings such as the home. Originality Papapavlou & Pavlou contended that "there are no signs of negative attitudes towards Cypriot Greek [in London]" (2001, p. 104). This research shows this claim to be false. Significance/Implications Negative attitudes towards Cypriot Greek lead to a community-wide preference for the use of Standard Modern Greek in communication with other members of the Greek Cypriot community, which poses a great threat to the intergenerational transmission and maintenance of Cypriot Greek as a heritage language in London

Language attitudes and use in a transplanted setting: Greek Cypriots in London

In this paper we explore language attitudes and use in the Greek Cypriot community in London, England. Our study is based on an earlier survey carried out in Nicosia, Cyprus and we compare attitudes to language and reported language use in the two communities. We thereby highlight the significance of sociolinguistic variables on similar groups of speakers. We further extend our investigation to include codeswitching practices in the London community. \ud Analysis of language attitudes and use within the Greek-Cypriot population of London, and comparisons with findings in Nicosia, reflect symbolic forces operating in the two contexts. Despite obvious differences between the two communities, (most obviously the official languages and distinct cultural backgrounds of the two nations), the Greek Cypriot Dialect continues to play an active role in both. English is however the ‘default choice‘ for young Cypriots in the UK and Standard Modern Greek occupies a much more limited role than in Cyprus. It is argued that differences in language attitudes and use can be interpreted in light of different market forces operating in the nation (i.e. Cyprus) and the Diaspora (i.e. UK)

Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma

We examined a panel of sporadic breast carcinomas for loss of heterozygosity (LOH) in a 10-cM interval on chromosome 10 known to encompass the PTEN gene. We detected allele loss in 27 of 70 breast tumour DNAs. Fifteen of these showed loss limited to a subregion of the area studied. The most commonly deleted region was flanked by D10S215 and D10S541 and encompasses the PTEN locus. We used a combination of denaturing gradient gel electrophoresis and single-strand conformation polymorphism analyses to investigate the presence of PTEN mutations in tumours with LOH in this region. We did not detect mutations of PTEN in any of these tumours. Our data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not. These results are consistent with loss of another unidentified tumour suppressor in this region in sporadic breast carcinoma. © 1999 Cancer Research Campaig

Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand

<p>Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials.</p> <p>The aim of the present study was to elucidate the molecular requirements involving the PAR-4 mechanism of activation by peptide analogues of its tethered-ligand.</p> <p>Eight synthetic PAR-4 tethered-ligand peptide analogues were synthesized and studied for their agonistic/antagonistic potency and selectivity toward human washed platelet aggregation, using light transmittance aggregometry. In addition, <i>in silico</i> studies were conducted to describe the receptor–peptide interactions that are developed following PAR-4 exposure to the above analogues. To provide a first structure-activity relationship rationale on the bioactivity profiles recorded for the studied analogues, molecular docking was applied in a homology model of PAR-4, derived using the crystal structure of PAR-1.</p> <p>The following peptide analogues were synthesized: AYPGKF-NH₂ (1), GYPGKF-NH₂ (2), <i>Ac-</i>AYPGKF-NH₂ (3), <i>trans-cinnamoyl-</i>AYPGKF-NH₂ (4), YPGKF-NH₂ (5), <i>Ac-</i>YPGKF-NH₂ (6), <i>trans-cinnamoyl-</i>YPGKF-NH₂ (7), and <i>caffeoyl-</i>YPGKF-NH₂ (8). Peptide (1) is a selective PAR-4 agonist inducing platelet aggregation with an IC₅₀ value of 26.2 μM. Substitution of Ala-1 with Gly-1 resulted in peptide (2), which significantly reduces the agonistic potency of peptide (1) by 25-fold. Importantly, substitution of Ala-1 with <i>trans-cinnamoyl-</i>1 resulted in peptide (7), which completely abolishes the agonistic activity of peptide (1) and renders it with a potent antagonistic activity toward peptide (1)-induced platelet aggregation. All other peptides tested were inactive. Tyr-2, residue, along with its neighboring environment was a key determinant in the PAR-4 recognition mode. When the neighboring residues to Tyr-2 provided an optimum spatial ability for the ligand to enter into the binding site of the transmembrane receptor, a biological response was propagated. These results were compared with the predicted binding poses of small molecule antagonists of PAR-4, denoted as YD-3, ML-354, and BMS-986120. π–π stacking interaction with Tyr-183 appears to be critical and common for both small molecules antagonists and the peptide <i>trans-cinnamoyl-</i>YPGKF-NH₂.</p> <p>Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.</p

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

Background Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. Objectives The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. Methods This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. Results Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). Conclusions In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status