Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy may facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands

The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographicaly diverse populations

Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report

Novel methods of Lamb wave detection for material damage detection and location

We describe and compare two novel methods of detecting ultrasonic Lamb waves used for damage detection and location, and then go on to compare their characteristics with those of more conventional PZT transducers. The two methods are measurements of the change in polarization state of the light in an optical fibre and the changes in reflected power from a fibre Bragg grating. Since different transducers measure different properties of Lamb waves by different methods, their relative sensitivities to the S0 and A0 modes can also vary. This can be of interest because, for instance, the A0 mode is more sensitive to the presence of delaminations in a sheet due to the larger shear strain component that this mode contains. We also describe the directional properties of the sensors and demonstrate the ways in which these can be used to advantage in the detection and location of damage

Damage detection in structural materials using a polarimetric fiber optic sensor

We describe a novel but simple method of detecting Lamb waves through the measurement of the changes in the polarimetric state of light propagating through an optical fibre which has been either embedded into or bonded onto the plate to be tested. The directional properties of the sensor are described, as is its ability to detect a hole produced in the plate. We also show how the relative sizes of the detected signal amplitudes from the source PZT and from the hole vary according to the alignment of the source with the sensor axis

Fibre optic sensors for lamb wave detection

An increasing interest has been shown in the use of Lamb waves for structural health monitoring. Since they propagate along, rather than normal to (as in the case of C-scanning), the plane of a plate, these waves can be used to interrogate a large area of the sample without the need to scan the source and detection transducers. The conventional way of detecting these waves is by the use of PZT transducers similar to those used to generate the ultrasound. Here we describe and contrast two different methods of using fibre optic sensors for this application. Firstly, a polarimetric method is demonstrated that uses analysis of the birefringence induced in an embedded optical fibre. This is a technique that requires only basic, inexpensive optical equipment and standard telecommunications grade optical fibre. The directional properties of this sensor can be utilised by optimising the relative positions of the acoustic source and the fibre so as to maximise the damage-to-transmitter source signal ratio. Secondly, the use of fibre Bragg gratings for ultrasound detection is described, together with a discussion on the importance of optimising various parameters, such as grating length and strength, fibre recoating material, bonding technique and interrogation method. It is shown that if three FBGs are configured into a rosette formation, the relative amplitudes of the signal in each sensor can be used to obtain the direction from which an acoustic wave is arriving. If an array of two or more rosettes is employed, the location of the source can be determined by calculating the intersection of the two wave propagation directions. This idea is further developed to show that if the damage signals can be effectively separated from the transmitter source signals, then the location of the damage can be similarly obtained. Experimental results are shown that demonstrate the successful practical implementation of all the above concepts

Comparison of point and integrated fibre optic sensing techniques for ultrasound detection and location of damage

In this paper we describe and compare two methods for detecting Lamb waves used for damage detection. One is a polarimetric sensor that integrates the pressure effects of the acoustic wave along its length, whilst the other is the Bragg grating that measures linear strain and is in effect a point sensor. Both sensors are highly directional, which gives benefits in damage signal detection and source location. We demonstrate both the detection and location of damage and discuss the advantages and disadvantages of the two sensors

Fibre Bragg gratings as arrays detecting ultrasound in structural assessment

This paper looks at Fibre Bragg gratings as arrays detecting ultrasound in structural assessmen

Fibre optic polarimetric detection of Lamb waves

In this paper we describe the detection of Lamb waves by monitoring the changes in the polarimetric state of the light emerging from an optical fibre which has been either bonded to, or incorporated into, a sample plate. Results have been obtained using both isotropic materials, such as polymer sheets, or anisotropic materials such as carbon fibre composites. These results demonstrate that polarimetric analysis has the potential to provide an alternative method of detecting Lamb waves and also provides a possible method for investigating the nature of the interaction between the acoustic wave and the light propagating through the fibre

Optical generation and detection of ultrasound

This is a review of the optical generation and detection of ultrasound on work carried out in different optical detection techniques at the Strathclyde University. We start by pointing out some limitations of conventional ultrasonic transducers and show how the use of optical-based transducers can overcome them. After explaining how laser generation of ultrasound works, we will describe and compare the advantages and disadvantages of three optical detection techniques. Finally, we describe applications in which optical ultrasound techniques appear to have a promising future