SVA retrotransposons as modulators of gene expression.

Endogenous mobile genetic elements can give rise to de novo germline or somatic mutations that can have dramatic consequences for genome regulation both local and possibly more globally based on the site of integration. However if we consider them as "normal genetic" components of the reference genome then they are likely to modify local chromatin structure which would have an effect on gene regulation irrelevant of their ability to further transpose. As such they can be treated as any other domain involved in a gene × environment interaction. Similarly their evolutionary appearance in the reference genome would supply a driver for species specific responses/traits. Our recent data would suggest the hominid specific subset of retrotransposons, SINE-VNTR-Alu (SVA), can function as transcriptional regulatory domains both in vivo and in vitro when analyzed in reporter gene constructs. Of particular interest in the SVA element, were the variable number tandem repeat (VNTR) domains which as their name suggests can be polymorphic. We and others have previously shown that VNTRs can be both differential regulators and biomarkers of disease based on the genotype of the repeat. Here, we provide an overview of why polymorphism in the SVA elements, in particular the VNTRs, could alter gene expression patterns that could be mechanistically associated with different traits in evolution or disease progression in humans

A Hilbertian projection method for constrained level set-based topology optimisation

We present an extension of the projection method proposed by Challis et al ($\textit{Int J Solids Struct}$. Volume $\textbf{45}$(14-15) (2008) 4130-4146) for constrained level set-based topology optimisation that harnesses the Hilbertian velocity extension-regularisation framework. Our $\textit{Hilbertian projection method}$ chooses a normal velocity for the level set function as a linear combination of: 1) an orthogonal projection operator applied to the extended optimisation objective shape sensitivity; and 2) a weighted sum of orthogonal basis functions for the extended constraint shape sensitivities. This combination aims for the best possible first-order improvement of the optimisation objective in addition to first-order improvement of the constraints. Our formulation utilising basis orthogonalisation naturally handles linearly dependent constraint shape sensitivities. Furthermore, use of the Hilbertian extension-regularisation framework ensures that the resulting normal velocity is extended away from the boundary and enriched with additional regularity. Our approach is generally applicable to any topology optimisation problem to be solved in the level set framework. We consider several benchmark constrained microstructure optimisation problems and demonstrate that our method is effective with little-to-no parameter tuning. We also find that our method performs well when compared to a Hilbertian sequential linear programming method.Comment: 23 pages, 8 figure

Fermionic field theory for directed percolation in (1+1) dimensions

We formulate directed percolation in (1+1) dimensions in the language of a reaction-diffusion process with exclusion taking place in one space dimension. We map the master equation that describes the dynamics of the system onto a quantum spin chain problem. From there we build an interacting fermionic field theory of a new type. We study the resulting theory using renormalization group techniques. This yields numerical estimates for the critical exponents and provides a new alternative analytic systematic procedure to study low-dimensional directed percolation.Comment: 20 pages, 2 figure

At the dawn of the transcriptomic medicine

Impact statement This review describes the impact of transcriptomics on experimental biology and its integration into medical practice. Transcriptomics is an essential part of modern biomedical research based on highly sophisticated and reliable technology. Transcriptomics can aid clinical practice and improve the precision of clinical diagnoses and decision-making by complementing existing clinical best practice. The power of which will be increased when combined with genomic variation from genome wide association studies and next generation sequencing. We are witnessing the implementation of RNA-based technologies in clinical practice that will eventually lead to the establishment of transcriptional medicine as a routine tool in diagnosis. Progress in genomic analytical technologies has improved our possibilities to obtain information regarding DNA, RNA, and their dynamic changes that occur over time or in response to specific challenges. This information describes the blueprint for cells, tissues, and organisms and has fundamental importance for all living organisms. This review focuses on the technological challenges to analyze the transcriptome and what is the impact of transcriptomics on precision medicine. The transcriptome is a term that covers all RNA present in cells and a substantial part of it will never be translated into protein but is nevertheless functional in determining cell phenotype. Recent developments in transcriptomics have challenged the fundamentals of the central dogma of biology by providing evidence of pervasive transcription of the genome. Such massive transcriptional activity is challenging the definition of a gene and especially the term “pseudogene” that has now been demonstrated in many examples to be both transcribed and translated. We also review the common sources of biomaterials for transcriptomics and justify the suitability of whole blood RNA as the current optimal analyte for clinical transcriptomics. At the end of the review, a brief overview of the clinical implications of transcriptomics in clinical trial design and clinical diagnosis is given. Finally, we introduce the transcriptome as a target for modern drug development as a tool for extending our capacity for precision medicine in multiple diseases

Observation of the lowest energy gamma-ray in any superdeformed nucleus : 196Bi

New results on the superdeformed $^{196}$Bi nucleus a re reported. We have observed with the EUROBALL IV $\gamma$-ray spectrometer array a superdeformed trans ition of 124 keV which is the lowest observed energy $\gamma$-ray in any superdeformed nucleus. We have de velopped microscopic cranked Hartree-Fock-Bogoliubov calculations using the SLy4 effective force and a realistic surface p airing which strongly support the $K^\pi=2^-$($\pi$[651]1/2$\otimes \nu$[752]5/2) assignment of this su perdeformed band

A numerical approach to large deviations in continuous-time

We present an algorithm to evaluate the large deviation functions associated to history-dependent observables. Instead of relying on a time discretisation procedure to approximate the dynamics, we provide a direct continuous-time algorithm, valuable for systems with multiple time scales, thus extending the work of Giardin\`a, Kurchan and Peliti (PRL 96, 120603 (2006)). The procedure is supplemented with a thermodynamic-integration scheme, which improves its efficiency. We also show how the method can be used to probe large deviation functions in systems with a dynamical phase transition -- revealed in our context through the appearance of a non-analyticity in the large deviation functions.Comment: Submitted to J. Stat. Mec

An evolutionary conserved region (ECR) in the human dopamine receptor D4 gene supports reporter gene expression in primary cultures derived from the rat cortex

<p>Abstract</p> <p>Background</p> <p>Detecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours. At a molecular level, characterisation of variation in exons has been studied as they are easily identified in the current genome annotation although the functional consequences are less well understood; however, it has been difficult to prioritise regions of non-coding DNA in which genetic variation could also have significant functional consequences. Comparison of multiple vertebrate genomes has allowed the identification of non-coding evolutionary conserved regions (ECRs), in which the degree of conservation can be comparable with exonic regions suggesting functional significance.</p> <p>Results</p> <p>We identified ECRs at the dopamine receptor D4 gene locus, an important gene for human behaviours. The most conserved non-coding ECR (D4ECR1) supported high reporter gene expression in primary cultures derived from neonate rat frontal cortex. Computer aided analysis of the sequence of the D4ECR1 indicated the potential transcription factors that could modulate its function. D4ECR1 contained multiple consensus sequences for binding the transcription factor Sp1, a factor previously implicated in DRD4 expression. Co-transfection experiments demonstrated that overexpression of Sp1 significantly decreased the activity of the D4ECR1 <it>in vitro</it>.</p> <p>Conclusion</p> <p>Bioinformatic analysis complemented by functional analysis of the DRD4 gene locus has identified a) a strong enhancer that functions in neurons and b) a transcription factor that may modulate the function of that enhancer.</p

Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus

AbstractGenome-wide association studies (GWAS) have identified a locus on chromosome 1p21.3 to be highly associated with schizophrenia. A microRNA, MIR137, within this locus has been proposed as the gene causally associated with schizophrenia, due to its known role as a regulator of neuronal development and function. However, the involvement of other genes within this region, including DPYD (dihydropyrimidine dehydrogenase), is also plausible. In this communication, we describe a previously uncharacterised, brain-expressed RNA, EU358092, within the schizophrenia-associated region at 1p21.3. As we observed for MIR137, EU358092 expression was modulated in response to psychoactive drug treatment in the human SH-SY5Y neuroblastoma cell line. Bioinformatic analysis of publically available CNS expression data indicates that MIR137 and EU358092 are often co-expressed in vivo. A potential regulatory domain for expression of EU358092 is identified by bioinformatic analysis and its regulatory function is confirmed by reporter gene assays. These data suggest a potentially important role for EU358092 in the aetiology of schizophrenia, either individually or in combination with other genes at this locus

Ancilla-based quantum simulation

We consider simulating the BCS Hamiltonian, a model of low temperature superconductivity, on a quantum computer. In particular we consider conducting the simulation on the qubus quantum computer, which uses a continuous variable ancilla to generate interactions between qubits. We demonstrate an O(N^3) improvement over previous work conducted on an NMR computer [PRL 89 057904 (2002) & PRL 97 050504 (2006)] for the nearest neighbour and completely general cases. We then go on to show methods to minimise the number of operations needed per time step using the qubus in three cases; a completely general case, a case of exponentially decaying interactions and the case of fixed range interactions. We make these results controlled on an ancilla qubit so that we can apply the phase estimation algorithm, and hence show that when N \geq 5, our qubus simulation requires significantly less operations that a similar simulation conducted on an NMR computer.Comment: 20 pages, 10 figures: V2 added section on phase estimation and performing controlled unitaries, V3 corrected minor typo