Kinetic Accessibility of Buried DNA Sites in Nucleosomes

Using a theoretical model for spontaneous partial DNA unwrapping from histones, we study the transient exposure of protein-binding DNA sites within nucleosomes. We focus on the functional dependence of the rates for site exposure and reburial on the site position, which is measurable experimentally and pertinent to gene regulation. We find the dependence to be roughly described by a random walker model. Close inspection reveals a surprising physical effect of flexibility-assisted barrier crossing, which we characterize within a toy model, the "semiflexible Brownian rotor."Comment: final version as published in Phys. Rev. Let

What Makes Educational Campaings Succeed?

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Ozone Depletion from Nearby Supernovae

Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time, improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made in theoretical modeling of supernovae and of the resultant gamma-ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma-rays and cosmic rays. We find that for the combined ozone depletion roughly to double the ``biologically active'' UV flux received at the surface of the Earth, the supernova must occur at <8 pc. Based on the latest data, the time-averaged galactic rate of core-collapse supernovae occurring within 8 pc is ~1.5/Gyr. In comparing our calculated ozone depletions with those of previous studies, we find them to be significantly less severe than found by Ruderman (1974), and consistent with Whitten et al. (1976). In summary, given the amplitude of the effect, the rate of nearby supernovae, and the ~Gyr time scale for multicellular organisms on Earth, this particular pathway for mass extinctions may be less important than previously thought.Comment: 24 pages, 4 Postscript figures, to appear in The Astrophysical Journal, 2003 March 10, vol. 58

Target search on a dynamic DNA molecule

We study a protein-DNA target search model with explicit DNA dynamics applicable to in vitro experiments. We show that the DNA dynamics plays a crucial role for the effectiveness of protein "jumps" between sites distant along the DNA contour but close in 3D space. A strongly binding protein that searches by 1D sliding and jumping alone, explores the search space less redundantly when the DNA dynamics is fast on the timescale of protein jumps than in the opposite "frozen DNA" limit. We characterize the crossover between these limits using simulations and scaling theory. We also rationalize the slow exploration in the frozen limit as a subtle interplay between long jumps and long trapping times of the protein in "islands" within random DNA configurations in solution.Comment: manuscript and supplementary material combined into a single documen

Optimal flexibility for conformational transitions in macromolecules

Conformational transitions in macromolecular complexes often involve the reorientation of lever-like structures. Using a simple theoretical model, we show that the rate of such transitions is drastically enhanced if the lever is bendable, e.g. at a localized "hinge''. Surprisingly, the transition is fastest with an intermediate flexibility of the hinge. In this intermediate regime, the transition rate is also least sensitive to the amount of "cargo'' attached to the lever arm, which could be exploited by molecular motors. To explain this effect, we generalize the Kramers-Langer theory for multi-dimensional barrier crossing to configuration dependent mobility matrices.Comment: 4 pages, 4 figure

Is osteopathic manipulation effective for headaches?

Spinal manipulative therapy (SMT), a component of osteopathy, has been shown to be variably effective for the treatment of headaches. For the prophylactic treatment of cervicogenic headaches and for acute tension headaches, SMT is superior to placebo. For tension headache prophylaxis, research shows a trend toward better outcomes with amitriptyline than with SMT. For migraine prophylaxis, SMT has an effect similar to amitriptyline (strength of recommendation: B, based on a systematic review of various quality studies)

Primary Phagocytosis of Neurons by Inflamed Microglia: Potential Roles in Neurodegeneration

Microglial phagocytosis of dead or dying neurons can be beneficial by preventing the release of damaging and/or pro-inflammatory intracellular components. However, there is now evidence that under certain conditions, such as inflammation, microglia can also phagocytose viable neurons, thus executing their death. Such phagocytic cell death may result from exposure of phosphatidylserine (PS) or other eat-me signals on otherwise viable neurons as a result of physiological activation or sub-toxic insult, and neuronal phagocytosis by activated microglia. In this review, we discuss the mechanisms of phagocytic cell death and its potential roles in Alzheimer’s Disease, Parkinson’s Disease, and Frontotemporal Dementia

Physical and digital phantoms for validating tractography and assessing artifacts

Fiber tractography is widely used to non-invasively map white-matter bundles in vivo using diffusion-weighted magnetic resonance imaging (dMRI). As it is the case for all scientific methods, proper validation is a key prerequisite for the successful application of fiber tractography, be it in the area of basic neuroscience or in a clinical setting. It is well-known that the indirect estimation of the fiber tracts from the local diffusion signal is highly ambiguous and extremely challenging. Furthermore, the validation of fiber tractography methods is hampered by the lack of a real ground truth, which is caused by the extremely complex brain microstructure that is not directly observable non-invasively and that is the basis of the huge network of long-range fiber connections in the brain that are the actual target of fiber tractography methods. As a substitute for in vivo data with a real ground truth that could be used for validation, a widely and successfully employed approach is the use of synthetic phantoms. In this work, we are providing an overview of the state-of-the-art in the area of physical and digital phantoms, answering the following guiding questions: “What are dMRI phantoms and what are they good for?”, “What would the ideal phantom for validation fiber tractography look like?” and “What phantoms, phantom datasets and tools used for their creation are available to the research community?”. We will further discuss the limitations and opportunities that come with the use of dMRI phantoms, and what future direction this field of research might take