Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems

Systemic corticosteroid hypersensitivity in children

We describe 5 cases of immediate-type reactions to systemic corticosteroids observed during the last 2 decades in boys aged 2, 4, 8, 9, and 10 years. Symptoms ranged from generalized urticaria and angioedema to anaphylactic shock immediately after administration. Oral betamethasone was implicated in 2 cases, oral prednisolone in 2 cases, and intravenous prednisolone in 1 case. The parents of patient 5 refused the skin tests. The remaining patients underwent skin prick tests with the following undiluted corticosteroids: parenteral prednisolone, oral prednisolone, parenteral methylprednisolone, parenteral dexamethasone, parenteral hydrocortisone, and oral betamethasone. If the results were negative, intradermal tests were performed with the same drugs at increasing concentrations. Skin test results were positive for all suspect corticosteroids, thus indicating an immunoglobulin E-mediated mechanism. Two patients had positive skin test results to other corticosteroids, suggesting cross-reactivity. An oral challenge test was performed with deflazacort in 4 cases and with betamethasone in 1 case; the results were negative

Time domain add-drop multiplexing scheme enhanced using a saw-tooth pulse shaper

We experimentally demonstrate the use of saw-tooth optical pulses, which are shaped using a fiber Bragg grating, to achieve robust and high performance time-domain add-drop multiplexing in a scheme based on cross-phase (XPM) modulation in an optical fiber, with subsequent offset filtering. As compared to the use of more conventional pulse shapes, such as Gaussian pulses of a similar pulse width, the purpose-shaped saw-tooth pulses allow higher extinction ratios for the add and drop windows and significant improvements in the receiver sensitivity for the dropped and added channels

Specimen dimensions influence the measurement of material properties in tendon fascicles

Stress, strain and modulus are regularly used to characterize material properties of tissue samples. However, when comparing results from different studies it is evident the reported material properties, particularly failure strains, vary hugely. The aim of our study was to characterize how and why specimen length and cross-sectional area (CSA) appear to influence failure stress, strain and modulus in fascicles from two functionally different tendons. Fascicles were dissected from five rat tails and five bovine foot extensors, their diameters determined by a laser micrometer, and loaded to failure at a range of grip-to-grip lengths. Strain to failure significantly decreased with increasing in specimen length in both rat and bovine fascicles, while modulus increased. Specimen length did not influence failure stress in rat tail fascicles, although in bovine fascicles it was significantly lower in the longer 40 mm specimens compared to 5 and 10 mm specimens. The variations in failure strain and modulus with sample length could be predominantly explained by end-effects. However, it was also evident that strain fields along the sample length were highly variable and notably larger towards the ends of the sample than the mid-section even at distances in excess of 5 mm from the gripping points. Failure strain, stress and modulus correlated significantly with CSA at certain specimen lengths. Our findings have implications for the mechanical testing of tendon tissue: while it is not always possible to control for fascicle length and/or CSA, these parameters have to be taken into account when comparing samples of different dimensions

Using technology to improve access to specialist care in amyotrophic lateral sclerosis: A systematic review

Our objective was to review the evidence for using technology to improve access to specialist care for patients with amyotrophic lateral sclerosis (ALS) and their carers. Medline, Google Scholar and the Cochrane library were searched for articles describing technology that enabled clinical care of patients with ALS or their carers where the patient/carer and clinician were not in the same location. Two applications were identified: telemedicine to facilitate video conferencing as an alternative to outpatient consultations and telehealth monitoring for patients with respiratory failure. One randomized controlled trial using telehealth in patients with respiratory failure including 22 patients with ALS was identified. While rates of hospitalization were reduced, overall mortality was unchanged and there were too few patients with ALS in the study to detect significant benefit. In conclusion, there is limited evidence to support the use of telemedicine or telehealth in the care of patients with ALS. Future research needs to develop an understanding of the key beneficial aspects of the traditional specialist ALS service and how these factors could be delivered using technology. Successful evaluation and implementation of technologies to facilitate access to specialist care will only be possible if all the relevant impacts of an intervention are understood and measured

3-3-1 exotic quark search at CERN LEPII-LHC

The 3-3-1 electroweak model is the simplest chiral extension of the standard model which predicts single and double charged bileptons and exotic quarks carrying -4/3 and 5/3 units of the positron charge. In this paper we study the possibilities of the production and decay of one of these exotic quarks at CERN LEPII-LHC collider. For typical vector bilepton, exotic quark masses and mixing angles we obtained between 20 and 750 events per year. Angular distributions are also presented.Comment: 5 pages, RevTex 3.1, 9 eps figures, to appear in Phys. Rev.

Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12

Peer reviewe

Creation of quantum correlations between two atoms in a dissipative environment from an initial vacuum state

We have investigated the effect of counter-rotating terms on the dynamics of entanglement and quantum discord between two identical atoms interacting with a lossy single mode cavity field for a system initially in a vacuum state. The counter-rotating terms are found to lead to steady states in the long time limit which can have high quantum discord, but have no entanglement. The effect of cavity decay rate on this steady state quantum discord has been also investigated, surprisingly, the increase in cavity decay rate is found to both enhance and maximize the steady quantum discord for separable states.Comment: Effects of counter-rotating interaction terms on quantum discor