When push comes to shove - RNA polymerase and DNA-bound protein roadblocks

In recent years, transcriptional roadblocking has emerged as a crucial regulatory mechanism in gene expression, whereby other DNA-bound obstacles can block the progression of transcribing RNA polymerase (RNAP), leading to RNAP pausing and ultimately dissociation from the DNA template. In this review, we discuss the mechanisms by which transcriptional roadblocks can impede RNAP progression, as well as how RNAP can overcome these obstacles to continue transcription. We examine different DNA-binding proteins involved in transcriptional roadblocking and their biophysical properties that determine their effectiveness in blocking RNAP progression. The catalytically dead CRISPR-Cas (dCas) protein is used as an example of an engineered programmable roadblock, and the current literature in understanding the polarity of dCas roadblocking is also discussed. Finally, we delve into a stochastic model of transcriptional roadblocking and highlight the importance of transcription factor binding kinetics and its resistance to dislodgement by an elongating RNAP in determining the strength of a roadblock.Nan Hao, Alana J. Donnelly, Ian B. Dodd, Keith E. Shearwi

Photo-production of Nucleon Resonances and Nucleon Spin Structure Function in the Resonance Region

The photo-production of nucleon resonances is calculated based on a chiral constituent quark model including both relativistic corrections H{rel} and two-body exchange currents, and it is shown that these effects play an important role. We also calculate the first moment of the nucleon spin structure function g1 (x,Q^2) in the resonance region, and obtain a sign-changing point around Q^2 ~ 0.27 {GeV}^2 for the proton.Comment: 23 pages, 5 figure

Particles-vortex interactions and flow visualization in He4

Recent experiments have demonstrated a remarkable progress in implementing and use of the Particle Image Velocimetry (PIV) and particle tracking techniques for the study of turbulence in He4. However, an interpretation of the experimental data in the superfluid phase requires understanding how the motion of tracer particles is affected by the two components, the viscous normal fluid and the inviscid superfluid. Of a particular importance is the problem of particle interactions with quantized vortex lines which may not only strongly affect the particle motion, but, under certain conditions, may even trap particles on quantized vortex cores. The article reviews recent theoretical, numerical, and experimental results in this rapidly developing area of research, putting critically together recent results, and solving apparent inconsistencies. Also discussed is a closely related technique of detection of quantized vortices negative ion bubbles in He4.Comment: To appear in the J Low Temperature Physic

Exercise, Service and Support: Client Experiences of Physical Activity Referral Schemes(PARS)

Physical activity referral schemes (PARS) represent one of the most prevalent interventions in the fight against chronic illness such as coronary heart disease and obesity. Despite this, issues surrounding low retention and adherence continue to hinder the potential effectiveness of such schemes on public health. This article reports on the second stage of a larger investigation into client experiences of PARS focusing specifically on findings from five client-based focus groups and interviews with five Scheme Organisers. The resulting analysis reveals three main factors impacting participant perceptions of the quality of service and support received: the organisation of PARS provision, client engagement with the PARS community and the nature and extent of client support networks. The article demonstrates that staff have a considerable role to play in engaging clients in the PARS system and that Scheme Organisers should give serious thought to ensuring that clients have valuable and sustainable networks of support. Furthermore, it is suggested that Scheme Organisers need to facilitate a system in which staff are genuinely engaged with the needs of clients and are able to provide individualised programmes of physical activity

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved