The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.

Non-invasive respiratory monitoring using long-period fiber grating sensors

In non-invasive ventilation, continuous monitoring of respiratory volumes is essential. Here, we present a method for the measurement of respiratory volumes by a single fiber-grating sensor of bending and provide the proof-of-principle by applying a calibration-test measurement procedure on a set of 18 healthy volunteers. Results establish a linear correlation between a change in lung volume and the corresponding change in a local thorax curvature. They also show good sensor accuracy in measurements of tidal and minute respiratory volumes for different types of breathing. The proposed technique does not rely on the air flow through an oronasal mask or the observation of chest movement by a clinician, which distinguishes it from the current clinical practice. © 2014 Optical Society of America.

Ultra-long laser cavities for non-repeated fibre transmission

We propose the use of ultra-long laser cavities for non-repeated fibre communication. We perform a comparison based on nonlinearity management theory between the performance of ultra-long cavities and other amplification schemes for non-repeated transmission.

Pain management programmes for non-English-speaking black and minority ethnic groups with long-term or chronic pain

Increasing ethnic diversity in the UK means that there is a growing need for National Health Service care to be delivered to non-English-speaking patients. The aims of the present systematic review were to: (1) better understand the outcomes of chronic pain management programmes (PMPs) for ethnic minority and non-English-speaking patients and (2) explore the perspectives on and experiences of chronic pain for these groups. A systematic review identified 26 papers meeting the inclusion criteria; no papers reported on the outcomes of PMPs delivered in the UK. Of the papers obtained, four reported on PMPs conducted outside the UK; eight reported on ethnic differences in patients seeking support from pain management services in America; and the remaining papers included literature reviews, an experimental pain study, a collaborative enquiry, and a survey of patient and clinician ratings of pain. The findings indicate a lack of research into UK-based pain management for ethnic minorities and non-English-speaking patients. The literature suggests that effective PMPs must be tailored to meet cultural experiences of pain and beliefs about pain management. There is a need for further research to explore these cultural beliefs in non-English-speaking groups in the UK. Culturally sensitive evaluations of interpreted PMPs with long-term follow-up are needed to assess the effectiveness of current provision. Copyright © 2015 John Wiley & Sons, Ltd.

Highly refractive index sensitive femtosecond laser inscribed long period gratings

The distinct behaviour of femtosecond laser inscribed long period gratings, with a non-uniform index perturbation within the optical fibre core, has been studied experimentally. The non-uniform laser-induced perturbation results in light coupling from the core mode to a greater number of cladding modes than is the case with their UV laser inscribed counterparts, and this is made evident from the surrounding refractive index (SRI) grating response. Femtosecond inscribed long period gratings are shown to simultaneously couple to multiple sets of cladding modes. A 400μm LPG is shown to result in attenuation peaks that have both blue and red wavelength shifts over a 1250nm to 1700nm wavelength range. This gives rise to SRI sensitivities far greater than anything achievable by monitoring a single attenuation peak. The maximum sensitivity produced by monitoring a single attenuation peak was 1106nm/RIU, whereas monitoring opposing wavelength shifts resulted in a significantly improved sensitivity of 1680nm/RIU. © 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells

The delicately orchestrated process of bone fracture healing is not always successful and long term non union of fractured bone occurs in 5-20% of all cases. Atrophic fracture non unions have been described as the most difficult to treat and this is thought to arise through a cellular and local failure of osteogenesis. However, little is known about the presence and osteogenic proficiency of cells in the local area of non union tissue. We have examined the growth and differentiation potential of cells isolated from human non union tissues compared with normal human bone marrow mesenchymal stromal cells (BMSC). We report the isolation and culture expansion of a population of non union stromal cells (NUSC) which have a CD profile similar to that of BMSC, i.e. CD34-ve, CD45-ve and CD105+ve. The NUSC demonstrated multipotentiality and differentiated to some extent along chondrogenic, adipogenic and osteogenic lineages. However, and importantly, the NUSC showed significantly reduced osteogenic differentiation and mineralization in vitro compared to BMSC. We also found increased levels of cell senescence in NUSC compared to BMSC based on culture growth kinetics and cell positivity for senescence associated beta galactosidase (SA-beta-Gal) activity. The reduced capacity of NUSC to form osteoblasts was associated with significantly elevated secretion of Dickkopf-1 (Dkk-1) which is an important inhibitor of Wnt signalling during osteogenesis, compared to BMSC. Conversely, treating BMSC with levels of rhDkk-1 that were equivalent to those levels secreted by NUSC inhibited the capacity of BMSC to undergo osteogenesis. Treating BMSC with NUSC conditioned medium also inhibited the capacity of the BMSC to undergo osteogenic differentiation when compared to their treatment with BMSC conditioned medium. Our results suggest that the development of fracture non union is linked with a localised reduced capacity of cells to undergo osteogenesis, which in turn is associated with increased cell senescence and Dkk-1 secretion.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Molecular phase space transport in water:non-stationary random walk model

Molecular transport in phase space is crucial for chemical reactions because it defines how pre-reactive molecular configurations are found during the time evolution of the system. Using Molecular Dynamics (MD) simulated atomistic trajectories we test the assumption of the normal diffusion in the phase space for bulk water at ambient conditions by checking the equivalence of the transport to the random walk model. Contrary to common expectations we have found that some statistical features of the transport in the phase space differ from those of the normal diffusion models. This implies a non-random character of the path search process by the reacting complexes in water solutions. Our further numerical experiments show that a significant long period of non-stationarity in the transition probabilities of the segments of molecular trajectories can account for the observed non-uniform filling of the phase space. Surprisingly, the characteristic periods in the model non-stationarity constitute hundreds of nanoseconds, that is much longer time scales compared to typical lifetime of known liquid water molecular structures (several picoseconds).

Measured sensitivity of arc-induced long-period grating sensors in photonic crystal fibre

Reported are experimental results from investigations of the sensing properties of long-period gratings (LPGs) recorded in two different geometries of photonic crystal fibre (PCF): a large-mode area PCF and an endlessly single mode PCF. The LPGs have been characterised for their sensitivity to temperature, bending, surrounding index and strain. The LPGs in both fibres have been found to have negligible temperature sensitivity whilst exhibiting useful strain sensitivities. Strong directional bend sensitivity is shown by one PCF whilst the other shows good non-directional bend sensitivity. The fibres exhibit differing sensitivities to surrounding refractive index.

Nonlinearly regenerated long haul data transmission

This thesis experimentally examines the use of different techniques for optical fibre transmission over ultra long haul distances. Its format firstly examines the use of dispersion management as a means of achieving long haul communications. Secondly, examining the use concatenated NOLMs for DM autosoliton ultra long haul propagation, by comparing their performance with a generic system without NOLMs. Thirdly, timing jitter in concatenated NOLM system is examined and compared to the generic system and lastly issues of OTDM amplitude non-uniformity from channel to channel in a saturable absorber, specifically a NOLM, are raised. Transmission at a rate of 40Gbit/s is studied in an all-Raman amplified standard fibre link with amplifier spacing of the order of 80km. We demonstrate in this thesis that the detrimental effects associated with high power Raman amplification can be minimized by dispersion map optimization. As a result, a transmission distance of 1600 km (2000km including dispersion compensating fibre) has been achieved in standard single mode fibre. The use of concatenated NOLMs to provide a stable propagation regime has been proposed theoretically. In this thesis, the observation experimentally of autosoliton propagation is shown for the first time in a dispersion managed optical transmission system. The system is based on a strong dispersion map with large amplifier spacing. Operation at transmission rates of 10, 40 and 80Gbit/s is demonstrated. With an insertion of a stabilizing element to the NOLM, the transmission of a 10 and 20Gbit/s data stream was extended and demonstrated experimentally. Error-free propagation over 100 and 20 thousand kilometres has been achieved at 10 and 20Gbit/s respectively, with terrestrial amplifier spacing. The monitor of timing jitter is of importance to all optical systems. Evolution of timing jitter in a DM autosoliton system has been studied in this thesis and analyzed at bit ranges from 10Gbit/s to 80Gbit/s. Non-linear guiding by in-line regenerators considerably changes the dynamics of jitter accumulation. As transmission systems require higher data rates, the use of OTDM will become more prolific. The dynamics of switching and transmission of an optical signal comprising individual OTDM channels of unequal amplitudes in a dispersion-managed link with in-line non-linear fibre loop mirrors is investigated.

Ultra-long haul optical fibre transmission systems

This thesis examines experimentally options for optical fibre transmission over oceanic distances. Its format follows the chronological evolution of ultra-long haul optical systems, commencing with opto-electronic regenerators as repeaters, progressing to optically amplified NRZ systems and finally solitonic propagation. In each case recirculating loop techniques are deployed to simplify the transmission experiments. Advances in high speed electronics have allowed regenerators operating at 10 Gbit/s to become a practical reality. By augmenting such devices with optical amplifiers it is possible to greatly enhance the repeater spacing. Work detailed in this thesis has culminated in the propagation of 10 Gbit/s data over 400,000 km with a repeater spacing of 160 km. System reliability and robustness are enhanced by the use of a directly modulated DFB laser transmitter and total insensitivity of the system to the signal state of polarisation. Optically amplified ultra-long haul NRZ systems have taken on particular importance with the impending deployment of TAT 12/13 and TPC 5. The performance of these systems is demonstrated to be primarily limited by analogue impairments such as the accumulation of amplifier noise, polarisation effects and optical non-linearities. These degradations may be reduced by the use of appropriate dispersion maps and by scrambling the transmitted state of signal polarisation. A novel high speed optically passive polarisation scrambler is detailed for the first time. At bit rates in excess of 10 Gbit/s it is shown that these systems are severely limited and do not offer the advantages that might be expected over regenerated links. Propagation using solitons as the data bits appears particularly attractive since the dispersive and non-linear effects of the fibre allow distortion free transmission. However, the generation of pure solitons is difficult but must be achieved if the uncontrolled transmission distance is to be maximised. This thesis presents a new technique for the stabilisation of an erbium fibre ring laser that has aUowed propagation of 2.5 Gbit/s solitons to the theoretical limit of ~ 18,000 km. At higher bit rates temporal jitter becomes a significant impairment and to aUow an increase in the aggregate line rate multiplexing in both time and polarisation domains has been proposed. These techniques are shown to be of only limited benefit in practical systems and ultimately some form of soliton transmission control is required. The thesis demonstrates synchronous retiming by amplitude modulation that has allowed 20 Gbit/s data to propagate 125,000 km error free with an amplifier spacing approaching the soliton period. Ultimately the speed of operation of such systems is limited by the electronics used and, thus, a new form of soliton control is demonstrated using all optical techniques to achieve synchronous phase modulation.

The spatial distribution and temporal dynamics of brain regions activated during the perception of object and non-object patterns

Both animal and human studies suggest that the efficiency with which we are able to grasp objects is attributable to a repertoire of motor signals derived directly from vision. This is in general agreement with the long-held belief that the automatic generation of motor signals by the perception of objects is based on the actions they afford. In this study, we used magnetoencephalography (MEG) to determine the spatial distribution and temporal dynamics of brain regions activated during passive viewing of object and non-object targets that varied in the extent to which they afforded a grasping action. Synthetic Aperture Magnetometry (SAM) was used to localize task-related oscillatory power changes within specific frequency bands, and the time course of activity within given regions-of-interest was determined by calculating time-frequency plots using a Morlet wavelet transform. Both single subject and group-averaged data on the spatial distribution of brain activity are presented. We show that: (i) significant reductions in 10-25 Hz activity within extrastriate cortex, occipito-temporal cortex, sensori-motor cortex and cerebellum were evident with passive viewing of both objects and non-objects; and (ii) reductions in oscillatory activity within the posterior part of the superior parietal cortex (area Ba7) were only evident with the perception of objects. Assuming that focal reductions in low-frequency oscillations (< 30 Hz) reflect areas of heightened neural activity, we conclude that: (i) activity within a network of brain areas, including the sensori-motor cortex, is not critically dependent on stimulus type and may reflect general changes in visual attention; and (ii) the posterior part of the superior parietal cortex, area Ba7, is activated preferentially by objects and may play a role in computations related to grasping. © 2006 Elsevier Inc. All rights reserved.

Transmission of non-uniform OTDM channels in nonlinearly-guided dispersion-managed fibre system

The effects of channel inequality on nonlinear signal switching in a nonlinear optical fiber loop mirror (NOLM) were investigated. It was found that the channel-to-channel amplitude differences in optical time division multiplexing (OTDM) have strong impact on swiching behavior of individual channels in a 2R regenerator. The optical pulses in different channels face either suppression of the amplitude noise or increase in noise, depending on the inter-channel amplitude difference. It was stated that appropriate control of the channel uniformity in the OTDM transmitters is required to support stable long-haul transmission in 2R regenerated systems.

Global non-dynamic refinement of radial orbit error for altimetric earth satellites

The accuracy of altimetrically derived oceanographic and geophysical information is limited by the precision of the radial component of the satellite ephemeris. A non-dynamic technique is proposed as a method of reducing the global radial orbit error of altimetric satellites. This involves the recovery of each coefficient of an analytically derived radial error correction through a refinement of crossover difference residuals. The crossover data is supplemented by absolute height measurements to permit the retrieval of otherwise unobservable geographically correlated and linearly combined parameters. The feasibility of the radial reduction procedure is established upon application to the three day repeat orbit of SEASAT. The concept of arc aggregates is devised as a means of extending the method to incorporate longer durations, such as the 35 day repeat period of ERS-1. A continuous orbit is effectively created by including the radial misclosure between consecutive long arcs as an infallible observation. The arc aggregate procedure is validated using a combination of three successive SEASAT ephemerides. A complete simulation of the 501 revolution per 35 day repeat orbit of ERS-1 is derived and the recovery of the global radial orbit error over the full repeat period is successfully accomplished. The radial reduction is dependent upon the geographical locations of the supplementary direct height data. Investigations into the respective influences of various sites proposed for the tracking of ERS-1 by ground-based transponders are carried out. The potential effectiveness on the radial orbital accuracy of locating future tracking sites in regions of high latitudinal magnitude is demonstrated.

Tuneable compensator of dispersion and slope using non-uniformly strained chirped fibre grating

Summary form only given. A novel method for tuning the second and the third order dispersion using a simple multi-point bending device has been demonstrated. A simple model has been developed that allows to calculate the exact bending profile required for compensation for the given values of dispersion and dispersion slope.