The effect of pH on PAMAM dendrimer-siRNA complexation:endosomal considerations as determined by molecular dynamics simulation

Intracellular degradation of genes, most notably within the endo-lysosomal compartment is considered a significant barrier to (non-viral) gene delivery in vivo. Previous reports based on in vitro studies claim that carriers possessing a mixture of primary, secondary and tertiary amines are able to buffer the acidic environment within the endosome, allowing for timely release of their contents, leading to higher transfection rates. In this report, we adopt an atomistic molecular dynamics (MD) simulation approach, comparing the complexation of 21-bp siRNA with low-generation polyamidoamine (PAMAM) dendrimers (G0 and G1) at both neutral and acidic pHs, the latter of which mimics the degradative environment within maturing 'late-endosomes'. Our simulations reveal that the time taken for the dendrimer-gene complex (dendriplex) to reach equilibrium is appreciably longer at low pH and this is accompanied by more compact packaging of the dendriplex, as compared to simulations performed at neutral pH. We also note larger absolute values of calculated binding free energies of the dendriplex at low pH, indicating a higher dendrimer-nucleic acid affinity in comparison with neutral pH. These novel simulations provide a more detailed understanding of low molecular-weight polymer-siRNA behavior, mimicking the endosomal environment and provide input of direct relevance to the "proton sponge theory", thereby advancing the rational design of non-viral gene delivery systems.

Switching and generation of ultrashort pulses using all-fibre devices

Serial and parallel interconnection of photonic devices is integral to the construction of any all-optical data processing system. This thesis presents results from a series of experiments centering on the use of the nonlinear-optical loop mirror (NOLM) switch in architectures for the manipulation and generation of ultrashort pulses. Detailed analysis of soliton switching in a single NOLM and cascade of two NOLM's is performed, centering on primary limitations to device operation, effect of cascading on amplitude response, and impact of switching on the characteristics of incident pulses. By using relatively long input pulses, device failure due to stimulated Raman generation is postponed to demonstrate multiple-peaked switching for the first time. It is found that while cascading leads to a sharpening of the overall switching characteristic, pulse spectral and temporal integrity is not significantly degraded, and emerging pulses retain their essential soliton character. In addition, by including an asymmetrically placed in-fibre Bragg reflector as a wavelength selective loss element in the basic NOLM configuration, both soliton self-switching and dual-wavelength control-pulse switching are spectrally quantised. Results are presented from a novel dual-wavelength laser configuration generating pulse trains with an ultra-low rms inter-pulse-stream timing jitter level of 630fs enabling application in ultrafast switching environments at data rates as high as 130GBits/s. In addition, the fibre NOLM is included in architectures for all-optical memory, demonstrating storage and logical inversion of a 0.5kByte random data sequence; and ultrafast phase-locking of a gain-switched distributed feedback laser at 1.062GHz, the fourteenth harmonic of the system baseband frequency. The stringent requirements for environmental robustness of these architectures highlight the primary weaknesses of the NOLM in its fibre form and recommendations to overcome its inherent drawbacks are presented.

Efficacy and safety of second-generation antipsychotic long-acting injections (SGA LAIs) in maintenance treatment of bipolar disorder:protocol for a systematic review and meta-analysis

INTRODUCTION: Bipolar disorder requires long-term treatment but non-adherence is a common problem. Antipsychotic long-acting injections (LAIs) have been suggested to improve adherence but none are licensed in the UK for bipolar. However, the use of second-generation antipsychotics (SGA) LAIs in bipolar is not uncommon albeit there is a lack of systematic review in this area. This study aims to systematically review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar disorder. METHODS AND ANALYSIS: The protocol is based on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only randomised controlled trials comparing SGA LAIs in bipolar. PubMed, EMBASE, CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, http://www.clinicaltrials.gov will be searched, with no language restriction, from 2000 to January 2016 as first SGA LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or reduction in hospitalisation and primary safety outcomes are drop-out rates, all-cause discontinuation and discontinuation due to adverse events. Qualitative reporting of evidence will be based on 21 items listed on standards for reporting qualitative research (SRQR) focusing on study quality (assessed using the Jadad score, allocation concealment and data analysis), risk of bias and effect size. Publication bias will be assessed using funnel plots. If sufficient data are available meta-analysis will be performed with primary effect size as relative risk presented with 95% CI. Sensitivity analysis, conditional on number of studies and sample size, will be carried out on manic versus depressive symptoms and monotherapy versus adjunctive therapy.

The effect of slow passage in the pulse-pumped quantum dot laser

In recent years, quantum-dot (QD) semiconductor lasers attract significant interest in many practical applications due to their advantages such as high-power pulse generation because to the high gain efficiency. In this work, the pulse shape of an electrically pumped QD-laser under high current is analyzed. We find that the slow rise time of the pulsed pump may significantly affect the high intensity output pulse. It results in sharp power dropouts and deformation of the pulse profile. We address the effect to dynamical change of the phase-amplitude coupling in the proximity of the excited state (ES) threshold. Under 30ns pulse pumping, the output pulse shape strongly depends on pumping amplitude. At lower currents, which correspond to lasing in the ground state (GS), the pulse shape mimics that of the pump pulse. However, at higher currents the pulse shape becomes progressively unstable. The instability is greatest when in proximity to the secondary threshold which corresponds to the beginning of the ES lasing. After the slow rise stage, the output power sharply drops out. It is followed by a long-time power-off stage and large-scale amplitude fluctuations. We explain these observations by the dynamical change of the alpha-factor in the QD-laser and reveal the role of the slowly rising pumping processes in the pulse shaping and power dropouts at higher currents. The modeling is in very good agreement with the experimental observations. © 2014 SPIE.

Effect of Rayleigh-scattering distributed feedback on multiwavelength Raman fiber laser generation

We experimentally demonstrate a Raman fiber laser based on multiple point-action fiber Bragg grating reflectors and distributed feedback via Rayleigh scattering in an ∼22-km-long optical fiber. Twenty-two lasing lines with spacing of ∼100 GHz (close to International Telecommunication Union grid) in the C band are generated at the watt level. In contrast to the normal cavity with competition between laser lines, the random distributed feedback cavity exhibits highly stable multiwavelength generation with a power-equalized uniform distribution, which is almost independent on power. © 2011 Optical Society of America.

Effect of Rayleigh-scattering distributed feedback on multiwavelength Raman fiber laser generation

We experimentally demonstrate a Raman fiber laser based on multiple point-action fiber Bragg grating (FBG) reflectors and distributed feedback via Rayleigh scattering in a ∼22 km long optical fiber. Twenty two lasing lines with spacing of ∼100 GHz (close to ITU grid) in C-band are generated at Watts power level. In contrast to the normal cavity with competition between laser lines, the random distributed feedback cavity exhibits highly stable multiwavelength generation with a power-equalized uniform distribution which is almost independent on power. The current set up showing the capability of generating Raman gain of about 100-nm wide giving the possibility of multiwavelength generation at different bands. © 2011 SPIE.

Comparison of cost- and energy-efficient signal modulations for next generation passive optical networks

Extensive numerical investigations are undertaken to analyze and compare, for the first time, the performance, techno-economy, and power consumption of three-level electrical Duobinary, optical Duobinary, and PAM-4 modulation formats as candidates for high-speed next-generation PONs supporting downstream 40 Gb/s per wavelength signal transmission over standard SMFs in C-band. Optimization of transceiver bandwidths are undertaken to show the feasibility of utilizing low-cost and band-limited components to support next-generation PON transmissions. The effect of electro-absorption modulator chirp is examined for electrical Duobinary and PAM-4. Electrical Duobinary and optical Duobinary are powerefficient schemes for smaller transmission distances of 10 km SMFs and optical Duobinary offers the best receiver sensitivity albeit with a relatively high transceiver cost. PAM-4 shows the best power budget and costefficiency for larger distances of around 20 km, although it consumes more power. Electrical Duobinary shows the best trade-off between performance, cost and power dissipation.

An investigation of location effect on trip production using artificial neural networks

As traffic congestion exuberates and new roadway construction is severely constrained because of limited availability of land, high cost of land acquisition, and communities' opposition to the building of major roads, new solutions have to be sought to either make roadway use more efficient or reduce travel demand. There is a general agreement that travel demand is affected by land use patterns. However, traditional aggregate four-step models, which are the prevailing modeling approach presently, assume that traffic condition will not affect people's decision on whether to make a trip or not when trip generation is estimated. Existing survey data indicate, however, that differences exist in trip rates for different geographic areas. The reasons for such differences have not been carefully studied, and the success of quantifying the influence of land use on travel demand beyond employment, households, and their characteristics has been limited to be useful to the traditional four-step models. There may be a number of reasons, such as that the representation of influence of land use on travel demand is aggregated and is not explicit and that land use variables such as density and mix and accessibility as measured by travel time and congestion have not been adequately considered. This research employs the artificial neural network technique to investigate the potential effects of land use and accessibility on trip productions. Sixty two variables that may potentially influence trip production are studied. These variables include demographic, socioeconomic, land use and accessibility variables. Different architectures of ANN models are tested. Sensitivity analysis of the models shows that land use does have an effect on trip production, so does traffic condition. The ANN models are compared with linear regression models and cross-classification models using the same data. The results show that ANN models are better than the linear regression models and cross-classification models in terms of RMSE. Future work may focus on finding a representation of traffic condition with existing network data and population data which might be available when the variables are needed to in prediction.

Economic Growth and Recession Time Periods: Their Effect Upon Pleasure Travelers Visiting Florida Theme Parks

Two tourism-oriented travel samples were drawn from recent time periods that represented economic growth (expansion) and recession cycles in the O: S. economy. Analysis suggests that during the recession period, a greater percentage of theme park visitors chose to travel by air. Second, theme park travelers were more likely to visit friends or fami4 during the recession period. Third, recession theme park travelers were 10 years older, on the average, than their rapid growth counterparts. The average age difference of theme park visitors was found to be significantly different during cyclical economic periods. Research findings support the need for additional studies that segment using generational markets

Different generation regimes of mode-locked all-positive-dispersion all-fiber Yb laser

Different generation modes of all-positive-dispersion all-fibre Yb laser mode-locked due to effect of non-linear polarization evolution are investigated. For the first time we realized in the same laser both generation of single picoseconds pulse train and a newly observed lasing regime where generated are picosecond wave-packets, each being a train of femtosecond sub-pulses. Using both experimental results and numerical modeling we discuss in detail the mechanisms of laser mode-locking and switching of generation regimes and show a strong dependence of output laser characteristics on configuration of polarization controllers. A good qualitative agreement between experimental results and numerical modeling is demonstrated. © 2010 Copyright SPIE - The International Society for Optical Engineering.

Investigation of factors driving the costs of operating the 2020 Irish power system with large-scale wind generation

The main goal of this work is to determine the true cost incurred by the Republic of Ireland and Northern Ireland in order to meet their EU renewable electricity targets. The primary all-island of Ireland policy goal is that 40% of electricity will come from renewable sources in 2020. From this it is expected that wind generation on the Irish electricity system will be in the region of 32-37% of total generation. This leads to issues resulting from wind energy being a non-synchronous, unpredictable and variable source of energy use on a scale never seen before for a single synchronous system. If changes are not made to traditional operational practices, the efficient running of the electricity system will be directly affected by these issues in the coming years. Using models of the electricity system for the all-island grid of Ireland, the effects of high wind energy penetration expected to be present in 2020 are examined. These models were developed using a unit commitment, economic dispatch tool called PLEXOS which allows for a detailed representation of the electricity system to be achieved down to individual generator level. These models replicate the true running of the electricity system through use of day-ahead scheduling and semi-relaxed use of these schedules that reflects the Transmission System Operator's of real time decision making on dispatch. In addition, it carefully considers other non-wind priority dispatch generation technologies that have an effect on the overall system. In the models developed, three main issues associated with wind energy integration were selected to be examined in detail to determine the sensitivity of assumptions presented in other studies. These three issues include wind energy's non-synchronous nature, its variability and spatial correlation, and its unpredictability. This leads to an examination of the effects in three areas: the need for system operation constraints required for system security; different onshore to offshore ratios of installed wind energy; and the degrees of accuracy in wind energy forecasting. Each of these areas directly impact the way in which the electricity system is run as they address each of the three issues associated with wind energy stated above, respectively. It is shown that assumptions in these three areas have a large effect on the results in terms of total generation costs, wind curtailment and generator technology type dispatch. In particular accounting for these issues has resulted in wind curtailment being predicted in much larger quantities than had been previously reported. This would have a large effect on wind energy companies because it is already a very low profit margin industry. Results from this work have shown that the relaxation of system operation constraints is crucial to the economic running of the electricity system with large improvements shown in the reduction of wind curtailment and system generation costs. There are clear benefits in having a proportion of the wind installed offshore in Ireland which would help to reduce variability of wind energy generation on the system and therefore reduce wind curtailment. With envisaged future improvements in day-ahead wind forecasting from 8% to 4% mean absolute error, there are potential reductions in wind curtailment system costs and open cycle gas turbine usage. This work illustrates the consequences of assumptions in the areas of system operation constraints, onshore/offshore installed wind capacities and accuracy in wind forecasting to better inform the true costs associated with running Ireland's changing electricity system as it continues to decarbonise into the near future. This work also proposes to illustrate, through the use of Ireland as a case study, the effects that will become ever more prevalent in other synchronous systems as they pursue a path of increasing renewable energy generation.

Effect of reaction mechanism on precursor exposure time in atomic layer deposition of silicon oxide and silicon nitride

Atomic layer deposition (ALD) of highly conformal, silicon-based dielectric thin films has become necessary because of the continuing decrease in feature size in microelectronic devices. The ALD of oxides and nitrides is usually thought to be mechanistically similar, but plasma-enhanced ALD of silicon nitride is found to be problematic, while that of silicon oxide is straightforward. To find why, the ALD of silicon nitride and silicon oxide dielectric films was studied by applying ab initio methods to theoretical models for proposed surface reaction mechanisms. The thermodynamic energies for the elimination of functional groups from different silicon precursors reacting with simple model molecules were calculated using density functional theory (DFT), explaining the lower reactivity of precursors toward the deposition of silicon nitride relative to silicon oxide seen in experiments, but not explaining the trends between precursors. Using more realistic cluster models of amine and hydroxyl covered surfaces, the structures and energies were calculated of reaction pathways for chemisorption of different silicon precursors via functional group elimination, with more success. DFT calculations identified the initial physisorption step as crucial toward deposition and this step was thus used to predict the ALD reactivity of a range of amino-silane precursors, yielding good agreement with experiment. The retention of hydrogen within silicon nitride films but not in silicon oxide observed in FTIR spectra was accounted for by the theoretical calculations and helped verify the application of the model.

The application of next generation sequencing to profile microbe related cheese quality defects

High throughput next generation sequencing, together with advanced molecular methods, has considerably enhanced the field of food microbiology. By overcoming biases associated with culture dependant approaches, it has become possible to achieve novel insights into the nature of food-borne microbial communities. In this thesis, several different sequencing-based approaches were applied with a view to better understanding microbe associated quality defects in cheese. Initially, a literature review provides an overview of microbe-associated cheese quality defects as well as molecular methods for profiling complex microbial communities. Following this, 16S rRNA sequencing revealed temporal and spatial differences in microbial composition due to the time during the production day that specific commercial cheeses were manufactured. A novel Ion PGM sequencing approach, focusing on decarboxylase genes rather than 16S rRNA genes, was then successfully employed to profile the biogenic amine producing cohort of a series of artisanal cheeses. Investigations into the phenomenon of cheese pinking formed the basis of a joint 16S rRNA and whole genome shotgun sequencing approach, leading to the identification of Thermus species and, more specifically, the pathway involved in production of lycopene, a red coloured carotenoid. Finally, using a more traditional approach, the effect of addition of a facultatively heterofermentative Lactobacillus (Lactobacillus casei) to a Swiss-type cheese, in which starter activity was compromised, was investigated from the perspective of its ability to promote gas defects and irregular eye formation. X-ray computed tomography was used to visualise, using a non-destructive method, the consequences of the undesirable gas formation that resulted. Ultimately this thesis has demonstrated that the application of molecular techniques, such as next generation sequencing, can provide a detailed insight into defect-causing microbial populations present and thereby may underpin approaches to optimise the quality and consistency of a wide variety of cheeses.

Supporting the Model-Driven Development of Real-time Embedded Systems with Run-Time Monitoring and Animation via Highly Customizable Code Generation

This paper presents a vision that allows the combined use of model-driven engineering, run-time monitoring, and animation for the development and analysis of components in real-time embedded systems. Key building block in the tool environment supporting this vision is a highly-customizable code generation process. Customization is performed via a configuration specification which describes the ways in which input is provided to the component, the ways in which run-time execution information can be observed, and how these observations drive animation tools. The environment is envisioned to be suitable for different activities ranging from quality assurance to supporting certification, teaching, and outreach and will be built exclusively with open source tools to increase impact. A preliminary prototype implementation is described.

The Effect of Residence Time on the Tensile Properties of Superelastic and Thermal Activated Ni-Ti Orthodontic Wires

Since the 1980s, different devices based on superelastic alloys have been developed to fulfill orthodontic applications. Particularly in the last decades several researches have been carried out to evaluate the mechanical behavior of Ni-Ti alloys, including their tensile, torsion and fatigue properties. However, studies regarding the dependence of elastic properties on residence time of Ni-Ti wires in the oral cavity are scarce. Such approach is essential since metallic alloys are submitted to mechanical stresses during orthodontic treatment as well as pH and temperature fluctuations. The goal of the present contribution is to provide elastic stress-strain results to guide the orthodontic choice between martensitic thermal activated and austenitic superelastic Ni-Ti alloys. From the point of view of an orthodontist, the selection of appropriate materials and the correct maintenance of the orthodontic apparatus are essential needs during clinical treatment. The present work evaluated the elastic behavior of Ni-Ti alloy wires with diameters varying from 0.014 to 0.020 inches, submitted to hysteresis tensile tests with 8% strain. Tensile tests were performed after periods of use of 1, 2 and 3 months in the oral cavity of patients submitted to orthodontic treatment. The results from the hysteresis tests allowed to exam the strain range covered by isostress lines upon loading and unloading, as well as the residual strain after unloading for both superelastic and thermal activated Ni-Ti wires. Superelastic Ni-Ti wires exhibited higher load isostress values compared to thermal activated wires. It was found that such differences in the load isostress values can increase with increasing residence time.