Biomolecular imaging and electronic damage using X-ray free-electron lasers

Proposals to determine biomolecular structures from diffraction experiments using femtosecond X-ray free-electron laser (XFEL) pulses involve a conflict between the incident brightness required to achieve diffraction-limited atomic resolution and the electronic and structural damage induced by the illumination. Here we show that previous estimates of the conditions under which biomolecular structures may be obtained in this manner are unduly restrictive, because they are based on a coherent diffraction model that is not appropriate to the proposed interaction conditions. A more detailed imaging model derived from optical coherence theory and quantum electrodynamics is shown to be far more tolerant of electronic damage. The nuclear density is employed as the principal descriptor of molecular structure. The foundations of the approach may also be used to characterize electrodynamical processes by performing scattering experiments on complex molecules of known structure.Comment: 16 pages, 2 figure

A mixed reality telepresence system for collaborative space operation

This paper presents a Mixed Reality system that results from the integration of a telepresence system and an application to improve collaborative space exploration. The system combines free viewpoint video with immersive projection technology to support non-verbal communication, including eye gaze, inter-personal distance and facial expression. Importantly, these can be interpreted together as people move around the simulation, maintaining natural social distance. The application is a simulation of Mars, within which the collaborators must come to agreement over, for example, where the Rover should land and go. The first contribution is the creation of a Mixed Reality system supporting contextualization of non-verbal communication. Tw technological contributions are prototyping a technique to subtract a person from a background that may contain physical objects and/or moving images, and a light weight texturing method for multi-view rendering which provides balance in terms of visual and temporal quality. A practical contribution is the demonstration of pragmatic approaches to sharing space between display systems of distinct levels of immersion. A research tool contribution is a system that allows comparison of conventional authored and video based reconstructed avatars, within an environment that encourages exploration and social interaction. Aspects of system quality, including the communication of facial expression and end-to-end latency are reported

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Effect of Pulsed or Continuous Delivery of Salt on Sensory Perception Over Short Time Intervals

Salt in the human diet is a major risk factor for hypertension and many countries have set targets to reduce salt consumption. Technological solutions are being sought to lower the salt content of processed foods without altering their taste. In this study, the approach was to deliver salt solutions in pulses of different concentrations to determine whether a pulsed delivery profile affected sensory perception of salt. Nine different salt profiles were delivered by a Dynataste device and a trained panel assessed their saltiness using time–intensity and single-score sensory techniques. The profile duration (15 s) was designed to match eating conditions and the effects of intensity and duration of the pulses on sensory perception were investigated. Sensory results from the profiles delivered in either water or in a bouillon base were not statistically different. Maximum perceived salt intensities and the area under the time– intensity curves correlated well with the overall perceived saltiness intensity despite the stimulus being delivered as several pulses. The overall saltiness scores for profiles delivering the same overall amount of sodium were statistically not different from one another suggesting that, in this system, pulsed delivery did not enhance salt perception but the overall amount of salt delivered in each profile did affect sensory perception

That's Not Fair: Tariff Structures for Electric Utilities with Rooftop Solar

(1) Problem definition: Utility regulators are grappling to devise compensation schemes for customers who sell rooftop solar generation back to the grid, balancing environmental interests and the financial interests of utilities, solar system installers, and retail customers. This is difficult: Regulatory changes made in Nevada in 2015 to protect Nevada's utility induced SolarCity, the market leader in solar systems, to suspend local operations. We show that the choice of tariff structure is crucial to achieving socially desirable objectives. (2) Academic/Practical Relevance: It is important for regulators to understand how tariff structure interacts with social objectives. This has implications for consumers, regulators and industry. (3) Methodology: We use a sequential game to analyze the regulator's social welfare maximization problem in a market with a regulated utility, an unregulated, price-setting, profit-maximizing solar system installer, and customers who endogenously determine whether to adopt solar or not, based on utility tariffs, solar prices and their heterogeneous usage profiles and generation potentials. (4) Results: We illustrate that the effectiveness of tariff structures is not governed simply by the number of free tariff parameters, but by the functions these parameters serve. In particular, an effective tariff must discriminate among customer usage tiers between customers with and without rooftop solar to achieve socially desirable outcomes. We present a tariff structure with these two characteristics and show how it can be implemented as a simple buy-all, sell-all tariff while retaining its favorable properties. We illustrate our findings numerically using data from Nevada and New Mexico, two states grappling with this issue. (5) Managerial Implications: Many utilities in the U.S. operate tariff structures that are missing at least one of the two identified features. Regulators must overhaul these tariff structures to adequately safeguard all stake-holders

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed

Real-time delay announcement under competition

Internet-based technology enables firms to disseminate real-time delay information to delay-sensitive customers. We study how such delay announcements impact service providers in a competitive environment with two service providers who compete for market share. We model the service providers' strategies based on an endogenous timing game, investigating strategies that emerge in equilibrium. We determine the service providers' market shares under the various game outcomes by analyzing continuous-time Markov chains, which capture customers' joining decisions, and by developing a novel computational technique to analyze the intractable asymmetric Join-the-Shortest Queue system, providing bounds on the market shares. We find that only the lower capacity service provider announces its real-time delay under intermediate system loads and highly imbalanced capacities. However, for most parameter settings, the mere presence of a competitor induces both providers to announce delays in equilibrium, leaving customers better off on average. We relate our findings to the single-provider delay announcement literature by discussing the impact of competition on service providers, delay announcement technology firms, and customers

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Regular and chaotic vibration in a piezoelectric energy harvester

We examine regular and chaotic responses of a vibrational energy harvester composed of a vertical beam and a tip mass. The beam is excited horizontally by a harmonic inertial force while mechanical vibrational energy is converted to electrical power through a piezoelectric patch. The mechanical resonator can be described by single or double well potentials depending on the gravity force from the tip mass. By changing the tip mass we examine bifurcations from single well oscillations, to regular and chaotic vibrations between the potential wells. The appearance of chaotic responses in the energy harvesting system is illustrated by the bifurcation diagram, the corresponding Fourier spectra, the phase portraits, and is confirmed by the 0–1 test. The appearance of chaotic vibrations reduces the level of harvested energy