ApoE gene therapy: an overview and update

Atherosclerosis remains the leading cause of death in industrialized societies. Apolipoprotein E (ApoE) is an attractive candidate to treat hypercholesterolemia and coronary heart disease, as it is a circulating protein with pleiotropic atheroprotective actions. Here, we describe several "gene addition" approaches and on-going developments to achieve efficient delivery and long-term expression. The use of recombinant viruses is discussed, including adeno-associated viral vectors (AAV) where technological advances now allow the cross-packaging of different AAV serotypes. Nonviral delivery systems are also described, including plasmids and cell-based therapy. Finally, a radical, alternative technology to gene addition, which has the potential for permanent cure in many genetic diseases, is reviewed: "targeted gene repair", which aims to correct underlying point mutations in-situ. Synthetic oligonucleotides are designed to bind specifically to defective DNA, enabling the cell's own mismatch machinery to recognize and repair the faulty DNA. Although such gene editing technology has great potential it remains inconsistent and difficult to reproduce

Vibration of a beam on continuous elastic foundation with nonhomogeneous stiffness and damping under a harmonically excited mass

In this paper, a method of analysis of a beam that is continuously supported on a linear nonhomogeneous elastic foundation and subjected to a harmonically excited mass is presented. The solution is obtained by decomposing the nonhomogeneous foundation properties and the beam displacement response into double Fourier summations which are solved in the frequency–wavenumber domain, from which the space–time domain response can be obtained. The method is applied to railway tracks with step variation in foundation properties. The validity of this method is checked, through examples, against existing methods for both homogeneous and nonhomogeneous foundation parameters. The effect of inhomogeneity and the magnitude of the mass are also investigated. It is found that a step variation in foundation properties leads to a reduction in the beam displacement and an increase in the resonance frequency for increasing step change, with the reverse occurring for decreasing step change. Furthermore, a beam on nonhomogeneous foundation may exhibit multiple resonances corresponding to the foundation stiffness of individual sections, as the mass moves through the respective sections along the beam

Experimental investigation on the dynamic response of RC flat slabs after a sudden column loss

To prevent disproportionate collapse under an extreme loading event, a sudden column loss scenario is often used to ensure the structure has suitable robustness. This study aims to investigate experimentally the dynamic response of reinforced concrete flat slabs after a sudden column loss. Seven 1/3 scale reinforced concrete flat slabs were tested under static load increases or dynamic column removal cases with different supports removed. Reaction forces and deflections were recorded throughout, along with reinforcement strains and concrete cracking patterns. During dynamic tests, a high speed camera was used to capture the dynamic motion. The experiments demonstrated that flat slabs, in general, are able to redistribute their loading effectively after a column loss. Although large levels of damage were observed, collapse due to flexural failure did not occur. However, punching shear was shown to be an issue due to the additional vertical loading on the adjacent supports. The inclusion of continuous bottom reinforcement through a column did not significantly improve the capacity, as the new load path is not primarily through the removed column location. The results also indicate that the dynamic effects due to a sudden column loss can be significant as deflections of up to 1.5 times the static case were measured within the elastic range. It is also shown that the Dynamic Amplification Factor (DAF) reduces when nonlinear damaging effects are included, which implies conventional code-based design methods for flat slab structures may be over conservative. Additionally, the increase in material strength due the strain rates is not viewed to be significant

An investigation of plate-type windborne debris flight using coupled CFD–RBD models. Part I: Model development and validation

AbstractThe development of a coupled computational fluid-dynamics rigid body (CFD–RBD) model is presented. The RBD model deploys rotational quaternions, which are free from the gimbal lock that is associated with Euler rotational matrix. The quaternion model means that the complex 3D spinning flight modes associated with the flight of plate-type windborne debris can be modelled robustly. This paper attempts to determine the accuracy of the CFD–RBD model by comparing the predicted trajectories from a large number of debris simulations with experimentally derived equations of best fit. Agreement is found to be good and, based on the findings, an alternative form for the dimensionless flight distance is presented, which extends the range of the experimental study to longer flight times.The predictions from the CFD–RBD model are then compared against two quasi-steady analytical debris flight models. The second model is based on modified force and moment coefficients, which are informed by the findings from the CFD–RBD model. For plates that have attained a stable, autorotational flight mode, the CFD–RBD and analytical models are in good agreement. Their predictions differ during the initial stages of flight, where the complex non-linear interactions between the plate and its wake are not captured by the analytical models

Dynamic column loss analysis of reinforced concrete flat slabs

The sudden column loss idealisation is a useful design tool to assess structures for progressive collapse. As such an event is a dynamic problem, suitable account must be taken of these effects. This can either be achieved by a full dynamic analysis of the structure or a simplified static approach, with correction factors for the dynamic influence. This study aims to investigate the response of Reinforced Concrete (RC) flat slab structures after a column loss using experimentally validated Finite Element (FE) models. The nonlinear dynamic response of a structure after such an event is considered, including the redistribution of loads and displacement profile. These results are then compared to equivalent static cases in order to determine the Dynamic Amplification Factor (DAF). For the range of structures considered, the DAF was calculated as between 1.39 and 1.62 for displacements, with lower factors associated with a higher nonlinear response or slower column removal. Additionally, the shear forces in remaining columns may exceed 200% of their fully supported condition, with a different associated DAF. The effects of increasing the tensile strength of concrete due to high strain rates are also considered. Typical Dynamic Increase Factors (DIFs) based on the strain rates were up to 1.23, however, this only applied for a short time period, and in a limited area. Therefore, such effects do not significantly influence the response

Differences in photosynthesis and terpene content in leaves and roots of wild-type and transgenic Arabidopsis thaliana plants

We investigated the hypotheses that two different varieties of Arabidopsis thaliana show differences in physiology and terpene production. The two varieties of A. thaliana used in this study were wild-type (WT) and transgenic line (CoxIV-FaNES I) genetically modified to emit nerolidol with linalool/nerolidol synthase (COX). Photosynthetic rate, electron transport rate, fluorescence, leaf volatile terpene contents and root volatile terpene contents were analyzed. For both types, we found co-eluting α-pinene+β-ocimene, limonene, and humulene in leaves; and in the roots we found co-eluting α-pinene+β-ocimene, sabinene+β-pinene, β-myrcene, limonene, and humulene. At the end of the growing cycle, COX plants tended to have lower pools of terpene compounds in their leaves, with 78.6% lower photosynthesis rates and 30.8% lower electron transport rates, compared with WT plants at that time. The maximal photochemical efficiency Fv/Fm was also significantly lower (25.5%) in COX plants, indicating that these varieties were more stressed than WT plants. However, COX plants had higher (239%) root terpene contents compared to WT plants. COX plants appear to favor root production of volatile terpenes rather than leaf production. Thus we conclude that there were significant differences between COX and WT plants in terms of terpenoid pools, stress status and physiology

A comparison between the use of straight and curved beam elements for modelling curved railway tracks

A major environmental concern related to railway traffic is vibration. A lot of re- search has been carried out to understand vibration of straight tracks, with less attention been paid to curved tracks. Modelling the dynamic behaviour of a curved railway track is important to understand the physics of generation and propagation of vibration fromtrains at non-straight sections of tracks. Modelling is also important to assess the current and any alternative track designs from an environmental point of view. In this paper a curved track is modelled and the effect of curvature is investigated. Two models have been developed and their results have been compared. In the first, the curved track is modelled using straight beam elements. In the second curved beam elements are used. For both, the Euler-Bernoulli beam theory has been adopted to describe their bending behaviour. The elements have 12 degrees of freedom accounting for displacements and rotations in the lateral, transverse and longitudinal directions. The excitation comes from an axle traversing the rails with subcritical velocity, accounting for the wheel-rail contact forces. The describedmodels are solved using the Finite Element Method. The time domain response of the versine of the curved track due to the passage of the axle is computed. A comparison is made on the efficiency of the two models for different curve radii and frequencies. The two models provide very similar results showing that the piecewise straight beam approximation represents the behaviour of the curved track accurately. Also the curved beam model used in this study shows some limitations for the specific application and therefore the straight element method is recommende

3D LES simulations of a static and vertically free-to-oscillate 4:1 rectangular cylinder: Effects of the grid resolution

Vortex induced vibration (VIV) is an important phenomenon which appears in flexible structures immersed in a moving fluid. This oscillation is self-sustained and self-limited, but VIV might cause fatigue damage and affect the structure's serviceability.In the present study, the aerodynamics of the flow fields around a static and vertically free-to-oscillate 4:1 rectangular cylinder are analysed by means of 3D LES simulations, adopting the OneEqEddy viscosity model. Integral parameters, pressure distributions, amplitudes of oscillation, coherences and correlations are obtained and compared with the available experimental data. Aiming to ascertain the impact of the boundary conditions and the grid resolution on the accuracy of results, five cases adopting 3 different meshes including two different spanwise discretisations have been considered. When studying the aerodynamics of the cylinder in static conditions, the influence of the spatial discretisation is very limited, and the agreement with experimental data is fairly good. On the other hand, for the free-to-oscillate cylinder, the structural response is dramatically dependent on the spanwise discretisation. The maximum amplitude of the structural response decreases as the mesh resolution increases, providing a closer fit with the experimental data. Also, the spanwise correlation of pressures is studied, finding remarkable differences depending on the level of spatial discretisation

Ipsilateral breast tumour relapse: local recurrence versus new primary and the effect of whole breast radiotherapy on the rate of new primaries

PurposeThe justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT.Methods and MaterialsWe retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up.ResultsAt a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC.ConclusionsThis analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy

Experimental identification of the lateral human–structure interaction mechanism and assessment of the inverted-pendulum biomechanical model

Within the context of crowd-induced lateral bridge vibration, human–structure interaction (HSI) is a widely studied phenomenon. Central to this study is the self-excited component of the ground reaction force (GRF). This force harmonic, induced by a walking pedestrian, resonates with lateral deck motion, irrespective of the pedestrian׳s pacing frequency. Its presence can lead to positive feedback between pedestrian GRFs and structural motion. Characterisation of the self-excited force as equivalent structural mass and damping has greatly improved the understanding of HSI and its role in developing lateral dynamic instability. However, despite this evolving understanding, a key question has remained unanswered; what are the features of a pedestrian׳s balance response to base motion that gives rise to the self-excited force? The majority of the literature has focussed on the effects of HSI with the underlying mechanism receiving comparatively little attention. This paper presents data from experimental testing in which 10 subjects walked individually on a laterally oscillating treadmill. Lateral deck motion as well as the GRFs imposed by the subject was recorded. Three-dimensional motion capture equipment was used to track the position of visual markers mounted on the subject. Thus whole body response to base motion was captured in addition to the GRFs generated. The data presented herein supports the authors’ previous findings that the self-excited force is a frequency sideband harmonic resulting from amplitude modulation of the lateral GRF. The gait behaviour responsible for this amplitude modulation is a periodic modulation of stride width in response to a sinusoidally varying inertia force induced by deck motion. In a separate analysis the validity of the passive inverted pendulum model, stabilised by active control of support placement was confirmed. This was established through comparison of simulated and observed frontal plane CoM motion. Despite the relative simplicity of this biomechanical model, remarkable agreement was observed