Decoding coalescent hidden Markov models in linear time

In many areas of computational biology, hidden Markov models (HMMs) have been used to model local genomic features. In particular, coalescent HMMs have been used to infer ancient population sizes, migration rates, divergence times, and other parameters such as mutation and recombination rates. As more loci, sequences, and hidden states are added to the model, however, the runtime of coalescent HMMs can quickly become prohibitive. Here we present a new algorithm for reducing the runtime of coalescent HMMs from quadratic in the number of hidden time states to linear, without making any additional approximations. Our algorithm can be incorporated into various coalescent HMMs, including the popular method PSMC for inferring variable effective population sizes. Here we implement this algorithm to speed up our demographic inference method diCal, which is equivalent to PSMC when applied to a sample of two haplotypes. We demonstrate that the linear-time method can reconstruct a population size change history more accurately than the quadratic-time method, given similar computation resources. We also apply the method to data from the 1000 Genomes project, inferring a high-resolution history of size changes in the European population.Comment: 18 pages, 5 figures. To appear in the Proceedings of the 18th Annual International Conference on Research in Computational Molecular Biology (RECOMB 2014). The final publication is available at link.springer.co

Telescoper: de novo assembly of highly repetitive regions.

MotivationWith advances in sequencing technology, it has become faster and cheaper to obtain short-read data from which to assemble genomes. Although there has been considerable progress in the field of genome assembly, producing high-quality de novo assemblies from short-reads remains challenging, primarily because of the complex repeat structures found in the genomes of most higher organisms. The telomeric regions of many genomes are particularly difficult to assemble, though much could be gained from the study of these regions, as their evolution has not been fully characterized and they have been linked to aging.ResultsIn this article, we tackle the problem of assembling highly repetitive regions by developing a novel algorithm that iteratively extends long paths through a series of read-overlap graphs and evaluates them based on a statistical framework. Our algorithm, Telescoper, uses short- and long-insert libraries in an integrated way throughout the assembly process. Results on real and simulated data demonstrate that our approach can effectively resolve much of the complex repeat structures found in the telomeres of yeast genomes, especially when longer long-insert libraries are used.AvailabilityTelescoper is publicly available for download at sourceforge.net/p/[email protected] informationSupplementary data are available at Bioinformatics online

Irreducible pseudo 2-factor isomorphic cubic bipartite graphs

A bipartite graph is {\em pseudo 2--factor isomorphic} if all its 2--factors have the same parity of number of circuits. In \cite{ADJLS} we proved that the only essentially 4--edge-connected pseudo 2--factor isomorphic cubic bipartite graph of girth 4 is $K_{3,3}$, and conjectured \cite[Conjecture 3.6]{ADJLS} that the only essentially 4--edge-connected cubic bipartite graphs are $K_{3,3}$, the Heawood graph and the Pappus graph. There exists a characterization of symmetric configurations $n_3$ %{\bf decide notation and how to use it in the rest of the paper} due to Martinetti (1886) in which all symmetric configurations $n_3$ can be obtained from an infinite set of so called {\em irreducible} configurations \cite{VM}. The list of irreducible configurations has been completed by Boben \cite{B} in terms of their {\em irreducible Levi graphs}. In this paper we characterize irreducible pseudo 2--factor isomorphic cubic bipartite graphs proving that the only pseudo 2--factor isomorphic irreducible Levi graphs are the Heawood and Pappus graphs. Moreover, the obtained characterization allows us to partially prove the above Conjecture

BioNetGen 2.2: Advances in Rule-Based Modeling

BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation, and analysis of larger and more complex models than previously possible.Comment: 3 pages, 1 figure, 1 supplementary text file. Supplementary text includes a brief discussion of the RK-PLA along with a performance analysis, two tables listing all new actions/arguments added in BioNetGen 2.2, and the "BioNetGen Quick Reference Guide". Accepted for publication in Bioinformatic

Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

Anomalous CO2 Ice Toward HOPS-68: A Tracer of Protostellar Feedback

We report the detection of a unique CO2 ice band toward the deeply embedded, low-mass protostar HOPS-68. Our spectrum, obtained with the Infrared Spectrograph onboard the Spitzer Space Telescope, reveals a 15.2 micron CO2 ice bending mode profile that cannot modeled with the same ice structure typically found toward other protostars. We develop a modified CO2 ice profile decomposition, including the addition of new high-quality laboratory spectra of pure, crystalline CO2 ice. Using this model, we find that 87-92% of the CO2 is sequestered as spherical, CO2-rich mantles, while typical interstellar ices show evidence of irregularly-shaped, hydrogen-rich mantles. We propose that (1) the nearly complete absence of unprocessed ices along the line-of-sight is due to the flattened envelope structure of HOPS-68, which lacks cold absorbing material in its outer envelope, and possesses an extreme concentration of material within its inner (10 AU) envelope region and (2) an energetic event led to the evaporation of inner envelope ices, followed by cooling and re-condensation, explaining the sequestration of spherical, CO2 ice mantles in a hydrogen-poor mixture. The mechanism responsible for the sublimation could be either a transient accretion event or shocks in the interaction region between the protostellar outflow and envelope. The proposed scenario is consistent with the rarity of the observed CO2 ice profile, the formation of nearly pure CO2 ice, and the production of spherical ice mantles. HOPS-68 may therefore provide a unique window into the protostellar feedback process, as outflows and heating shape the physical and chemical structure of protostellar envelopes and molecular clouds.Comment: Accepted to the Astrophysical Journal, 2013 February 15: 14 pages, 9 figures, 3 table

The OPERA trial: protocol for a randomised trial of an exercise intervention for older people in residential and nursing accommodation

Abstract Background: Depression is common in residents of Residential and Nursing homes (RNHs). It is usually undetected and often undertreated. Depression is associated with poor outcomes including increased morbidity and mortality. Exercise has potential to improve depression, and has been shown in existing trials to improve outcomes among younger and older people. Existing evidence comes from trials that are short, underpowered and not from RNH settings. The aim of the OPERA trial is to establish whether exercise is effective in reducing the prevalence of depression among older RNH residents. Method: OPERA is a cluster randomised controlled trial. RNHs are randomised to one of two groups with interventions lasting 12 months Intervention group: a depression awareness and physical activity training session for care home staff, plus a whole home physical activation programme including twice weekly physiotherapist-led exercise groups. The intervention lasts for one year from randomisation, or Control group: a depression awareness training session for care home staff. Participants are people aged 65 or over who are free of severe cognitive impairment and willing to participate in the study. Our primary outcome is the prevalence of depressive symptoms, a GDS-15 score of five or more, in all participants at the end of the one year intervention period. Our secondary depression outcomes include remission of depressive symptoms and change in GDS-15 scores in those with depressive symptoms prior to randomisation. Other secondary outcomes include, fear of falling, mobility, fractures, pain, cognition, costs and health related quality of life. We aimed to randomise 77 RNHs. Discussion: Home recruitment was completed in May 2010; 78 homes have been randomised. Follow up will finish in May 2011 and results will be available late 2011. Trial Registration: [ISRCTN: ISRCTN43769277

Dune formation on the present Mars

We apply a model for sand dunes to calculate formation of dunes on Mars under the present Martian atmospheric conditions. We find that different dune shapes as those imaged by Mars Global Surveyor could have been formed by the action of sand-moving winds occuring on today's Mars. Our calculations show, however, that Martian dunes could be only formed due to the higher efficiency of Martian winds in carrying grains into saltation. The model equations are solved to study saltation transport under different atmospheric conditions valid for Mars. We obtain an estimate for the wind speed and migration velocity of barchan dunes at different places on Mars. From comparison with the shape of bimodal sand dunes, we find an estimate for the timescale of the changes in Martian wind regimes.Comment: 16 pages, 12 figure