Silencing disease genes in the laboratory and the clinic

Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology

Watch Out for the Beast: Fear Information and Attentional Bias in Children

Although valenced information about novel animals changes the implicit and explicit fear beliefs of children (Field & Lawson, 2003), how it might lead to anxiety is unknown. One possibility, based on cognitive models of anxiety, is that fear information creates attentional biases similar to those seen in anxiety disorders. Children between 7 and 9 years old were given positive information about 1 novel animal, negative information about another, and no information about the 3rd. A pictorial dot-probe task was used, immediately or with a 24-hr delay, to test for attentional biases to the different animals. The results replicated the finding that fear information changes children's fear beliefs. Regardless of whether there was a delay, children acquired an attentional bias in the left visual field toward the animal about which they held negative beliefs compared to the control animal. These results imply a possible way in which fear information might contribute to acquired fear

Paradoxical popups: Why are they hard to catch?

Even professional baseball players occasionally find it difficult to gracefully approach seemingly routine pop-ups. This paper describes a set of towering pop-ups with trajectories that exhibit cusps and loops near the apex. For a normal fly ball, the horizontal velocity is continuously decreasing due to drag caused by air resistance. But for pop-ups, the Magnus force (the force due to the ball spinning in a moving airflow) is larger than the drag force. In these cases the horizontal velocity decreases in the beginning, like a normal fly ball, but after the apex, the Magnus force accelerates the horizontal motion. We refer to this class of pop-ups as paradoxical because they appear to misinform the typically robust optical control strategies used by fielders and lead to systematic vacillation in running paths, especially when a trajectory terminates near the fielder. In short, some of the dancing around when infielders pursue pop-ups can be well explained as a combination of bizarre trajectories and misguidance by the normally reliable optical control strategy, rather than apparent fielder error. Former major league infielders confirm that our model agrees with their experiences.Comment: 28 pages, 10 figures, sumitted to American Journal of Physic

Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage

The rad2 mutant of Schizosaccharomyces pombe is sensitive to UV irradiation and deficient in the repair of UV damage. In addition, it has a very high degree of chromosome loss and/or nondisjunction. We have cloned the rad2 gene and have shown it to be a member of the Saccharomyces cerevisiae RAD2/S. pombe rad13/human XPG family. Using degenerate PCR, we have cloned the human homolog of the rad2 gene. Human cDNA has 55% amino acid sequence identity to the rad2 gene and is able to complement the UV sensitivity of the rad2 null mutant. We have thus isolated a novel human gene which is likely to be involved both in controlling the fidelity of chromosome segregation and in the repair of UV-induced DNA damage. Its involvement in two fundamental processes for maintaining chromosomal integrity suggests that it is likely to be an important component of cancer avoidance mechanisms

Damage areas on selected LDEF aluminum surfaces

With the U.S. about to embark on a new space age, the effects of the space environment on a spacecraft during its mission lifetime become more relevant. Included among these potential effects are degradation and erosion due to micrometeoroid and debris impacts, atomic oxygen and ultraviolet light exposure as well as material alteration from thermal cycling, and electron and proton exposure. This paper focuses on the effects caused by micrometeoroid and debris impacts on several LDEF aluminum plates from four different bay locations: C-12, C-10, C-01, and E-09. Each plate was coated with either a white, black, or gray thermal paint. Since the plates were located at different orientations on the satellite, their responses to the hypervelocity impacts varied. Crater morphologies range from a series of craters, spall zones, domes, spaces, and rings to simple craters with little or no spall zones. In addition, each of these crater morphologies is associated with varying damage areas, which appear to be related to their respective bay locations and thus exposure angles. More than 5% of the exposed surface area examined was damaged by impact cratering and its coincident effects (i.e., spallation, delamination and blow-off). Thus, results from this analysis may be significant for mission and spacecraft planners and designers

Diffusive transport in networks built of containers and tubes

We developed analytical and numerical methods to study a transport of non-interacting particles in large networks consisting of M d-dimensional containers C_1,...,C_M with radii R_i linked together by tubes of length l_{ij} and radii a_{ij} where i,j=1,2,...,M. Tubes may join directly with each other forming junctions. It is possible that some links are absent. Instead of solving the diffusion equation for the full problem we formulated an approach that is computationally more efficient. We derived a set of rate equations that govern the time dependence of the number of particles in each container N_1(t),N_2(t),...,N_M(t). In such a way the complicated transport problem is reduced to a set of M first order integro-differential equations in time, which can be solved efficiently by the algorithm presented here. The workings of the method have been demonstrated on a couple of examples: networks involving three, four and seven containers, and one network with a three-point junction. Already simple networks with relatively few containers exhibit interesting transport behavior. For example, we showed that it is possible to adjust the geometry of the networks so that the particle concentration varies in time in a wave-like manner. Such behavior deviates from simple exponential growth and decay occurring in the two container system.Comment: 21 pages, 18 figures, REVTEX4; new figure added, reduced emphasis on graph theory, additional discussion added (computational cost, one dimensional tubes

A Review of the Use of Massive Open Online Courses (MOOCs) in Medical Imaging Education

Purpose: The purpose of this review article is to describe the benefits and challenges associated with massive open online courses (MOOCs) and to discuss the implications specific to medical imaging education and training. Methods: Peer-reviewed journal articles pertaining to MOOCs in higher education were analyzed to identify commonalities, relationships, and possible gaps in the literature. Results: Analysis revealed several repetitive themes and concepts regarding the use of MOOCs in higher education: theory of connectivism, instructors’ and students’ perspectives, and benefits and challenges. Implications for medical imaging education and training were also discussed. Conclusions: As web-based education and technology integration continue to increase, innovative approaches, such as MOOCs, will continue to develop. As higher education institutions continue experimenting with MOOCs, opportunities to engage individuals as lifelong learners will rise. Medical imaging students can use MOOCs to refine skills to prepare for an upcoming course along with the possibility of completing continuing education requirements

Solution of voter model dynamics on annealed small-world networks

An analytical study of the behavior of the voter model on the small-world topology is performed. In order to solve the equations for the dynamics, we consider an annealed version of the Watts-Strogatz (WS) network, where long-range connections are randomly chosen at each time step. The resulting dynamics is as rich as on the original WS network. A temporal scale $\tau$ separates a quasi-stationary disordered state with coexisting domains from a fully ordered frozen configuration. $\tau$ is proportional to the number of nodes in the network, so that the system remains asymptotically disordered in the thermodynamic limit.Comment: 11 pages, 4 figures, published version. Added section with extension to generic number of nearest neighbor

2013 Nest Success and Productivity of Chesapeake Bay Osprey

The Chesapeake Bay is home to one of the largest populations of breeding Osprey now estimated between 8,000-10,000 pairs. Osprey are a key indicator for the health of the Bay ecosystem. This study continues a long-term monitoring study of osprey populations in the Bay. We visited 189 osprey nests in coastal Virginia during the 2013 breeding season to document occupancy and breeding activity. In 2013, average reproductive rates were 1.1 chicks/active nest and 1.8 chicks/successful nest. Fifty-nine osprey were banded to document survival and dispersal including 19 breeding adults and 40 nestlings. Six GPS transmitters were deployed on adult males

Low prevalence, quasi-stationarity and power-law distribution in a model of spreading

Understanding how contagions (information, infections, etc) are spread on complex networks is important both from practical as well as theoretical point of view. Considerable work has been done in this regard in the past decade or so. However, most models are limited in their scope and as a result only capture general features of spreading phenomena. Here, we propose and study a model of spreading which takes into account the strength or quality of contagions as well as the local (probabilistic) dynamics occurring at various nodes. Transmission occurs only after the quality-based fitness of the contagion has been evaluated by the local agent. The model exhibits quality-dependent exponential time scales at early times leading to a slowly evolving quasi-stationary state. Low prevalence is seen for a wide range of contagion quality for arbitrary large networks. We also investigate the activity of nodes and find a power-law distribution with a robust exponent independent of network topology. Our results are consistent with recent empirical observations.Comment: 7 pages, 8 figures. (Submitted