Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

Pre-mRNA splicing, a dynamic process of intron removal and exon joining, is governed by a combinatorial control exerted by overlapping cis-elements that are unique to each exon and its flanking intronic sequences. Splicing cis-elements are usually 4-to-8-nucleotide-long linear motifs that provide binding sites for specific proteins. Pre-mRNA splicing is also influenced by secondary and higher order RNA structures that affect accessibility of splicing cis-elements. Antisense oligonucleotides (ASOs) that block splicing cis-elements and/or affect RNA structure have been shown to modulate splicing in vivo. Therefore, ASO-based strategies have emerged as a powerful tool for therapeutic manipulation of splicing in pathological conditions. Here we describe an ASO-based approach to increase the production of the full-length SMN2 mRNA in spinal muscular atrophy patient cells

A model of Bˉ0→D∗+ωπ−\bar{B}^0\to D^{*+}\omega\pi^- decay

We suggest a parameterization of the matrix element for $\bar{B}^0\to D^{*+}\omega\pi^-$ decay using kinematic variables convenient for experimental analysis. The contributions of intermediate $\omega\pi$- and $D^{**}$-states up to spin 3 have been taken into account. The angular distributions for each discussed hypothesis have been obtained and analysed using Monte-Carlo simulation.Comment: 24 pages, 9 figures, 1 table; V2: text in some places improved and acknowledgments adde

Fr-TM-align: a new protein structural alignment method based on fragment alignments and the TM-score

©2008 Pandit and Skolnick; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article is available from: http://www.biomedcentral.com/1471-2105/9/531doi:10.1186/1471-2105-9-531Background: Protein tertiary structure comparisons are employed in various fields of contemporary structural biology. Most structure comparison methods involve generation of an initial seed alignment, which is extended and/or refined to provide the best structural superposition between a pair of protein structures as assessed by a structure comparison metric. One such metric, the TM-score, was recently introduced to provide a combined structure quality measure of the coordinate root mean square deviation between a pair of structures and coverage. Using the TM-score, the TM-align structure alignment algorithm was developed that was often found to have better accuracy and coverage than the most commonly used structural alignment programs; however, there were a number of situations when this was not true. Results: To further improve structure alignment quality, the Fr-TM-align algorithm has been developed where aligned fragment pairs are used to generate the initial seed alignments that are then refined using dynamic programming to maximize the TM-score. For the assessment of the structural alignment quality from Fr-TM-align in comparison to other programs such as CE and TMalign, we examined various alignment quality assessment scores such as PSI and TM-score. The assessment showed that the structural alignment quality from Fr-TM-align is better in comparison to both CE and TM-align. On average, the structural alignments generated using Fr-TM-align have a higher TM-score (~9%) and coverage (~7%) in comparison to those generated by TM-align. Fr- TM-align uses an exhaustive procedure to generate initial seed alignments. Hence, the algorithm is computationally more expensive than TM-align. Conclusion: Fr-TM-align, a new algorithm that employs fragment alignment and assembly provides better structural alignments in comparison to TM-align. The source code and executables of Fr- TM-align are freely downloadable at: http://cssb.biology.gatech.edu/skolnick/files/FrTMalign/

Numerical instability of the Akhmediev breather and a finite-gap model of it

In this paper we study the numerical instabilities of the NLS Akhmediev breather, the simplest space periodic, one-mode perturbation of the unstable background, limiting our considerations to the simplest case of one unstable mode. In agreement with recent theoretical findings of the authors, in the situation in which the round-off errors are negligible with respect to the perturbations due to the discrete scheme used in the numerical experiments, the split-step Fourier method (SSFM), the numerical output is well-described by a suitable genus 2 finite-gap solution of NLS. This solution can be written in terms of different elementary functions in different time regions and, ultimately, it shows an exact recurrence of rogue waves described, at each appearance, by the Akhmediev breather. We discover a remarkable empirical formula connecting the recurrence time with the number of time steps used in the SSFM and, via our recent theoretical findings, we establish that the SSFM opens up a vertical unstable gap whose length can be computed with high accuracy, and is proportional to the inverse of the square of the number of time steps used in the SSFM. This neat picture essentially changes when the round-off error is sufficiently large. Indeed experiments in standard double precision show serious instabilities in both the periods and phases of the recurrence. In contrast with it, as predicted by the theory, replacing the exact Akhmediev Cauchy datum by its first harmonic approximation, we only slightly modify the numerical output. Let us also remark, that the first rogue wave appearance is completely stable in all experiments and is in perfect agreement with the Akhmediev formula and with the theoretical prediction in terms of the Cauchy data.Comment: 27 pages, 8 figures, Formula (30) at page 11 was corrected, arXiv admin note: text overlap with arXiv:1707.0565

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

Meditation on the Soles of the Feet Practice Provides Some Control of Aggression for Individuals with Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative condition that affects cognition, mental and physical health, and functionality of older people. As the disease progresses from the mild to moderate stage, there is a concomitant increase in several behavioral variables, chiefly agitation, anger, and aggression. Currently, there are no evidence-based treatments for these behaviors in this population. Three individuals with moderate Alzheimer’s disease were taught an informal mindfulness practice, meditation on the Soles of the Feet (SoF), as a self-management strategy within a multiple-baseline design across participants. All three were able to learn and use the SoF practice to manage their verbal and physical aggression. Their use of the SoF practice was correlated with decreased perceived psychological stress for their spouses and caregivers, as well as for the participants, but to a much smaller degree. In terms of social validity, the participants, their spouses, and caregivers rated the SoF practice as acceptable, effective, with no unintended effects, and indicated that they would recommend the practice to others. However, they also rated SoF as effortful for the participants because it involves the participants remembering to use the practice with rising anger, a requirement particularly challenging for those with memory problems. The SoF practice may enable individuals in the early stages of dementia to manage their anger and aggression. The data were derived from an internally valid experimental design, suggestive of initial proof-of-concept, but needs to be replicated before any clinical implications can be imputed from this study

Shock waves in strongly coupled plasmas

Shock waves are supersonic disturbances propagating in a fluid and giving rise to dissipation and drag. Weak shocks, i.e., those of small amplitude, can be well described within the hydrodynamic approximation. On the other hand, strong shocks are discontinuous within hydrodynamics and therefore probe the microscopics of the theory. In this paper we consider the case of the strongly coupled N=4 plasma whose microscopic description, applicable for scales smaller than the inverse temperature, is given in terms of gravity in an asymptotically $AdS_5$ space. In the gravity approximation, weak and strong shocks should be described by smooth metrics with no discontinuities. For weak shocks we find the dual metric in a derivative expansion and for strong shocks we use linearized gravity to find the exponential tail that determines the width of the shock. In particular we find that, when the velocity of the fluid relative to the shock approaches the speed of light $v\to 1$ the penetration depth $\ell$ scales as $\ell\sim (1-v^2)^{1/4}$. We compare the results with second order hydrodynamics and the Israel-Stewart approximation. Although they all agree in the hydrodynamic regime of weak shocks, we show that there is not even qualitative agreement for strong shocks. For the gravity side, the existence of shock waves implies that there are disturbances of constant shape propagating on the horizon of the dual black holes.Comment: 47 pages, 8 figures; v2:typos corrected, references adde

Disorder Effects on Exciton-Polariton Condensates

The impact of a random disorder potential on the dynamical properties of Bose Einstein condensates is a very wide research field. In microcavities, these studies are even more crucial than in the condensates of cold atoms, since random disorder is naturally present in the semiconductor structures. In this chapter, we consider a stable condensate, defined by a chemical potential, propagating in a random disorder potential, like a liquid flowing through a capillary. We analyze the interplay between the kinetic energy, the localization energy, and the interaction between particles in 1D and 2D polariton condensates. The finite life time of polaritons is taken into account as well. In the first part, we remind the results of [G. Malpuech et al. Phys. Rev. Lett. 98, 206402 (2007).] where we considered the case of a static condensate. In that case, the condensate forms either a glassy insulating phase at low polariton density (strong localization), or a superfluid phase above the percolation threshold. We also show the calculation of the first order spatial coherence of the condensate versus the condensate density. In the second part, we consider the case of a propagating non-interacting condensate which is always localized because of Anderson localization. The localization length is calculated in the Born approximation. The impact of the finite polariton life time is taken into account as well. In the last section we consider the case of a propagating interacting condensate where the three regimes of strong localization, Anderson localization, and superfluid behavior are accessible. The localization length is calculated versus the system parameters. The localization length is strongly modified with respect to the non-interacting case. It is infinite in the superfluid regime whereas it is strongly reduced if the fluid flows with a supersonic velocity.Comment: chapter for a book "Exciton Polaritons in Microcavities: New Frontiers" by Springer (2012), the original publication is available at http://www.springerlink.co