Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector

Neointima formation and vascular remodelling through vascular smooth muscle cell migration and proliferation can limit the long term success of coronary interventions, for example in coronary artery bypass grafting (CABG). Ex vivo gene therapy has the potential to reduce unnecessary cell proliferation and limit neointima formation in vascular pathologies. To date the species C adenovirus serotype 5 (Ad5) has been commonly used for pre-clinical gene therapy, however its suitability is potentially limited by relatively poor tropism for vascular cells and high levels of pre-existing immunity in the population. To avoid these limitations, novel species of adenovirus are being tested; here we investigate the potential of adenovirus 49 (Ad49) for use in gene therapy. Transduction of primary human vascular cells by a range of adenovirus serotypes was assessed; Ad49 demonstrated highest transduction of both vascular smooth muscle and endothelial cells. Gene transfer with Ad49 in vascular smooth muscle and endothelial cells was possible following short exposure times (*lt;1hr) and with low MOI which is clinically relevant. Ex vivo delivery to surplus CABG tissue showed efficient gene transfer with Ad49, consistent with the in vitro findings. Luminal infusion of Ad49GFP into intact CABG samples ex vivo resulted in efficient vessel transduction. In addition, no seroprevelance rates to Ad49 were observed in a Scottish cohort of patients from cardiovascular clinics, thus circumventing issues with pre-existing immunity. Our results show Ad49 has tropism for vascular cells in vitro and ex vivo and demonstrate Ad49 may be an improved vector for local vascular gene therapy compared to current alternatives

Pion Photoproduction Amplitude Relations in the 1/N_c Expansion

We derive expressions for pion photoproduction amplitudes in the 1/N_c expansion of QCD, and obtain linear relations directly from this expansion that relate electromagnetic multipole amplitudes at all energies. The leading-order relations in 1/N_c compare favorably with available data, while the next-to-leading order relations seem to provide only a small improvement. However, when resonance parameters are compared directly, the agreement at O(1/N_c) or O(1/N_c^2) is impressive.Comment: 19 pages, ReVTeX, 50 eps files combine into 5 compound figure

Pion-Nucleon Scattering Relations at Next-to-Leading Order in 1/N_c

We obtain relations between partial-wave amplitudes for pi-N-->pi-N and pi-N-->pi-Delta directly from large N_c QCD. While linear relations among certain amplitudes holding at leading order (LO) in 1/N_c were derived in the context of chiral soliton models two decades ago, the present work employs a fully model-independent framework based on consistency with the large N_c expansion. At LO we reproduce the soliton model results; however, this method allows for systematic corrections. At next-to-leading order (NLO), most relations require additional unknown functions beyond those appearing at leading order (LO) and thus have little additional predictive power. However, three NLO relations for the pi-N-->pi-Delta reaction are independent of unknown functions and make predictions accurate at this order. The amplitudes relevant to two of these relations were previously extracted from experiment. These relations describe experiment dramatically better than their LO counterparts.Comment: 8 pages, 2 figures; references adde

Adaptable history biases in human perceptual decisions

When making choices under conditions of perceptual uncertainty, past experience can play a vital role. However, it can also lead to biases that worsen decisions. Consistent with previous observations, we found that human choices are influenced by the success or failure of past choices even in a standard two-alternative detection task, where choice history is irrelevant. The typical bias was one that made the subject switch choices after a failure. These choice history biases led to poorer performance and were similar for observers in different countries. They were well captured by a simple logistic regression model that had been previously applied to describe psychophysical performance in mice. Such irrational biases seem at odds with the principles of reinforcement learning, which would predict exquisite adaptability to choice history. We therefore asked whether subjects could adapt their irrational biases following changes in trial order statistics. Adaptability was strong in the direction that confirmed a subject's default biases, but weaker in the opposite direction, so that existing biases could not be eradicated. We conclude that humans can adapt choice history biases, but cannot easily overcome existing biases even if irrational in the current context: adaptation is more sensitive to confirmatory than contradictory statistics

Multi-language neural network language models

Recently there has been a lot of interest in neural network based language models. These models typically consist of vocabulary dependent input and output layers and one or more vocabulary independent hidden layers. One standard issue with these approaches is that large quantities of training data are needed to ensure robust parameter estimates. This poses a significant problem when only limited data is available. One possible way to address this issue is augmentation: model-based, in the form of language model interpolation, and data-based, in the form of data augmentation. However, these approaches may not always be possible to use due to vocabulary dependent input and output layers. This seriously restricts the nature of the data possible to use in augmentation. This paper describes a general solution whereby only one or more vocabulary independent hidden layers are augmented. Such approach makes it possible to examine augmentation from previously impossible domains. Moreover, this approach paves a direct way for multi-task learning with these models. As a proof of the concept this paper examines the use of multilingual data for augmenting hidden layers of recurrent neural network language models. Experiments are conducted using a set of language packs released within IARPA Babel program

Air-to-Water Heat Pumps With Radiant Delivery in Low-Load Homes

Space conditioning represents nearly 50% of average residential household energy consumption, highlighting the need to identify alternative cost-effective, energy-efficient cooling and heating strategies. As homes are better built, there is an increasing need for strategies that are particularly well suited for high performance, low load homes. ARBI researchers worked with two test homes in hot-dry climates to evaluate the in-situ performance of air-to-water heat pump (AWHP) systems, an energy efficient space conditioning solution designed to cost-effectively provide comfort in homes with efficient, safe, and durable operation. Two monitoring projects of test houses in hot-dry climates were initiated in 2010 to test this system. Both systems were fully instrumented and have been monitored over one year to capture complete performance data over the cooling and heating seasons. Results are used to quantify energy savings, cost-effectiveness, and system performance using different operating modes and strategies. A calibrated TRNSYS model was developed and used to evaluate performance in various climate regions. This strategy is most effective in tight, insulated homes with high levels of thermal mass (i.e. exposed slab floors)

Manipulating adenovirus hexon hypervariable loops dictates immune neutralisation and coagulation factor X-dependent cell interaction in vitro and in vivo

Adenoviruses are common pathogens, mostly targeting ocular, gastrointestinal and respiratory cells, but in some cases infection disseminates, presenting in severe clinical outcomes. Upon dissemination and contact with blood, coagulation factor X (FX) interacts directly with the adenovirus type 5 (Ad5) hexon. FX can act as a bridge to bind heparan sulphate proteoglycans, leading to substantial Ad5 hepatocyte uptake. FX “coating” also protects the virus from host IgM and complement-mediated neutralisation. However, the contribution of FX in determining Ad liver transduction whilst simultaneously shielding the virus from immune attack remains unclear. In this study, we demonstrate that the FX protection mechanism is not conserved amongst Ad types, and identify the hexon hypervariable regions (HVR) of Ad5 as the capsid proteins targeted by this host defense pathway. Using genetic and pharmacological approaches, we manipulate Ad5 HVR interactions to interrogate the interplay between viral cell transduction and immune neutralisation. We show that FX and inhibitory serum components can co-compete and virus neutralisation is influenced by both the location and extent of modifications to the Ad5 HVRs. We engineered Ad5-derived HVRs into the rare, native non FX-binding Ad26 to create Ad26.HVR5C. This enabled the virus to interact with FX at high affinity, as quantified by surface plasmon resonance, FX-mediated cell binding and transduction assays. Concomitantly, Ad26.HVR5C was also sensitised to immune attack in the absence of FX, a direct consequence of the engineered HVRs from Ad5. In both immune competent and deficient animals, Ad26.HVR5C hepatic gene transfer was mediated by FX following intravenous delivery. This study gives mechanistic insight into the pivotal role of the Ad5 HVRs in conferring sensitivity to virus neutralisation by IgM and classical complement-mediated attack. Furthermore, through this gain-of-function approach we demonstrate the dual functionality of FX in protecting Ad26.HVR5C against innate immune factors whilst determining liver targeting

An inability to exclude visual noise in migraine

- Purpose: People with migraine are relatively poor at judging the direction of motion of coherently moving signal dots when interspersed with noise dots drifting in random directions, a task known as motion coherence. Although this has been taken as evidence of impoverished global pooling of motion signals, it could also arise from unreliable coding of local direction (of each dot), or an inability to segment signal from noise (noise-exclusion). The aim of this study was to determine how these putative limits contribute to impoverished motion processing in migraine. - Methods: Twenty-two participants with migraine (mean age, 34.7 ± 8.3 years; 16 female) and 22 age- and sex-matched controls (mean age, 34.4 ± 6.2 years) performed a motion-coherence task and a motion-equivalent noise task, the latter quantifying local and global limits on motion processing. In addition, participants were tested on analogous equivalent noise paradigms involving judgments of orientation and size, so that the specificity of any findings (to visual dimension) could be ascertained. - Results: Participants with migraine exhibited higher motion-coherence thresholds than controls (P = 0.01, independent t-test). However, this difference could not be attributed to deficits in either local or global processing since they performed normally on all equivalent noise tasks (P > 0.05, multivariate ANOVA). - Conclusions: These findings indicate that motion perception in the participants with migraine was limited by an inability to exclude visual noise. We suggest that this is a defining characteristic of visual dysfunction in migraine, a theory that has the potential to integrate a wide range of findings in the literature

Osteoarthritis: a narrative review of molecular approaches to disease management

Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and synovium. While it is still believed to be a mechanically driven disease, the role of underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated. Post-traumatic osteoarthritis (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults and is widely used in pre-clinical models to help understand OA in general. There is an urgent need to develop new treatments as the global burden is considerable and expanding. In this review, we focus on the recent pharmacological advances in the treatment of OA and summarize the most significant promising agents based on their molecular effects. Those are classified here into broad categories: anti-inflammatory, modulation of the activity of matrix metalloproteases, anabolic, and unconventional pleiotropic agents. We provide a comprehensive analysis of the pharmacological advances in each of these areas and highlight future insights and directions in the OA field