Single-Molecule Imaging of an in Vitro-Evolved RNA Aptamer Reveals Homogeneous Ligand Binding Kinetics

Many studies of RNA folding and catalysis have revealed conformational heterogeneity, metastable folding intermediates, and long-lived states with distinct catalytic activities. We have developed a single-molecule imaging approach for investigating the functional heterogeneity of in vitro-evolved RNA aptamers. Monitoring the association of fluorescently labeled ligands with individual RNA aptamer molecules has allowed us to record binding events over the course of multiple days, thus providing sufficient statistics to quantitatively define the kinetic properties at the single-molecule level. The ligand binding kinetics of the highly optimized RNA aptamer studied here displays a remarkable degree of uniformity and lack of memory. Such homogeneous behavior is quite different from the heterogeneity seen in previous single-molecule studies of naturally derived RNA and protein enzymes. The single-molecule methods we describe may be of use in analyzing the distribution of functional molecules in heterogeneous evolving populations or even in unselected samples of random sequences

Numerical Solution of Differential Equations by the Parker-Sochacki Method

A tutorial is presented which demonstrates the theory and usage of the Parker-Sochacki method of numerically solving systems of differential equations. Solutions are demonstrated for the case of projectile motion in air, and for the classical Newtonian N-body problem with mutual gravitational attraction.Comment: Added in July 2010: This tutorial has been posted since 1998 on a university web site, but has now been cited and praised in one or more refereed journals. I am therefore submitting it to the Cornell arXiv so that it may be read in response to its citations. See "Spiking neural network simulation: numerical integration with the Parker-Sochacki method:" J. Comput Neurosci, Robert D. Stewart & Wyeth Bair and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717378

Effects of crack tip geometry on dislocation emission and cleavage: A possible path to enhanced ductility

We present a systematic study of the effect of crack blunting on subsequent crack propagation and dislocation emission. We show that the stress intensity factor required to propagate the crack is increased as the crack is blunted by up to thirteen atomic layers, but only by a relatively modest amount for a crack with a sharp 60$^\circ$ corner. The effect of the blunting is far less than would be expected from a smoothly blunted crack; the sharp corners preserve the stress concentration, reducing the effect of the blunting. However, for some material parameters blunting changes the preferred deformation mode from brittle cleavage to dislocation emission. In such materials, the absorption of preexisting dislocations by the crack tip can cause the crack tip to be locally arrested, causing a significant increase in the microscopic toughness of the crack tip. Continuum plasticity models have shown that even a moderate increase in the microscopic toughness can lead to an increase in the macroscopic fracture toughness of the material by several orders of magnitude. We thus propose an atomic-scale mechanism at the crack tip, that ultimately may lead to a high fracture toughness in some materials where a sharp crack would seem to be able to propagate in a brittle manner. Results for blunt cracks loaded in mode II are also presented.Comment: 12 pages, REVTeX using epsfig.sty. 13 PostScript figures. Final version to appear in Phys. Rev. B. Main changes: Discussion slightly shortened, one figure remove

Load-sharing policies in parallel simulation of agent-based demographic models

Execution parallelism in agent-Based Simulation (ABS) allows to deal with complex/large-scale models. This raises the need for runtime environments able to fully exploit hardware parallelism, while jointly offering ABS-suited programming abstractions. In this paper, we target last-generation Parallel Discrete Event Simulation (PDES) platforms for multicore systems. We discuss a programming model to support both implicit (in-place access) and explicit (message passing) interactions across concurrent Logical Processes (LPs). We discuss different load-sharing policies combining event rate and implicit/explicit LPs’ interactions. We present a performance study conducted on a synthetic test case, representative of a class of agent-based models.Peer ReviewedPostprint (author's final draft

Highly Parallel Translation of DNA Sequences into Small Molecules

A large body of in vitro evolution work establishes the utility of biopolymer libraries comprising 1010 to 1015 distinct molecules for the discovery of nanomolar-affinity ligands to proteins.[1], [2], [3], [4], [5] Small-molecule libraries of comparable complexity will likely provide nanomolar-affinity small-molecule ligands.[6], [7] Unlike biopolymers, small molecules can offer the advantages of cell permeability, low immunogenicity, metabolic stability, rapid diffusion and inexpensive mass production. It is thought that such desirable in vivo behavior is correlated with the physical properties of small molecules, specifically a limited number of hydrogen bond donors and acceptors, a defined range of hydrophobicity, and most importantly, molecular weights less than 500 Daltons.[8] Creating a collection of 1010 to 1015 small molecules that meet these criteria requires the use of hundreds to thousands of diversity elements per step in a combinatorial synthesis of three to five steps. With this goal in mind, we have reported a set of mesofluidic devices that enable DNA-programmed combinatorial chemistry in a highly parallel 384-well plate format. Here, we demonstrate that these devices can translate DNA genes encoding 384 diversity elements per coding position into corresponding small-molecule gene products. This robust and efficient procedure yields small molecule-DNA conjugates suitable for in vitro evolution experiments

With or without force? : European public opinion on democracy promotion

A Large part of the education provided at colleges and universities of today requires for thestudent to be more independent in their studies. This demands that the physical space,where the students choose to study, is designed in a way that can encourage and supportlearning. It seems as though that many of the learning spaces of today don’t always meetthe students’ needs. The university library at the University of Umeå is currently planningto design new learning spaces for the students. The aim of this study is to examine how thephysical learning space can be designed to engage and encourage the students in theirlearning process. Based on literature describing learning spaces we have initially identified three mainareas to examine- Learning, Information Technology and Learning space design. Theseareas are all important features in the design of new learning spaces. With informationdrawn from that literature we conducted an empirical study at the library of the Universityof Umeå. The empirical study was carried out through observations and focus groupinterviews. To give us more insight about the students’ thoughts about the learning spacewe also compared our findings with a survey conducted by the library personnel in 2008and 2010. The result of our study shows that there are some areas to be improved in theexisting learning space. The students are working more collaboratively which requiresmore group areas. Our study also shows that flexibility, more student interaction and asocial and engaging environment are all important features in the design of new learningspaces

Instability of Democracy as Resource Curse

We suggest a dynamic game theoretic model to explain why resource abundance may lead to instability of democracy. Stationary Markov perfect equilibria of this game with four players – Politician, Oligarch, Autocrat and Public (voters) – are analyzed. Choosing a rate of resource rent tax, potential Autocrat competes with conventional Politician for the office, and Oligarch, the owner of the resource wealth, bribes Politician to influence her decisions. Actual Autocrat's tax policy may be different from the announced one. If the difference is large, then Public may revolt or Oligarch may organize a coup to throw Autocrat down. It is shown that the probability of democracy preservation is decreasing in the amount of resources if the institutional quality is low enough. It does not depend on the amount of resources, if the institutional quality is higher than a threshold. The level of the threshold, however, depends positively on the resource wealth. We have found also that under very low institutional quality, a paradoxical effect takes place: the probability of democracy preservation may decrease with small improvements of institutional quality. It is shown as well that Oligarch earns larger part of rent under democracy than under autocracy. This result conforms to empirical observation which is demonstrated in the paper: under low quality of institutions, democratization leads to higher inequality and inequality entails worsening of the attitude to democracy

Practicing Politics: technical project templates and political practice in a DFID country office

Development agencies including the UK Department for International Development (DFID) increasingly agree that if aid is to be effective, it should be politically smart and locally led. However, both the critical and the reformist literature have argued that development agencies persist with technical, template-driven programming: political analysis and practice have not been widely institutionalized. This study aims to identify why development representations are persistently technical in their form, and what blockages have existed for developing locally grounded and politically aware programmes. The article presents an ethnography of the process of developing the core elements of the governance portfolio in an (anonymized) DFID country office. Focusing on a key design workshop, the study is situated within a wider organizational ethnography. The persistently technical justifications for programmes are a result of the bureaucratic form itself, its accountability and approval processes. Political analyses represent countries in such a way that officials can prioritize selection from a repertoire of technical models. However, scepticism about the tractability of governance problems to such analyses and programming has led to an emerging understanding of politics that creates space within the bureaucratic form for politically aware practice. Politically aware programming should emphasize good operational practice over explicit analysis and should continue to emphasize technical models like the adaptive management models which create room for such practice