Ultra Bright LED Light Injection Calibration System for MINOS

We describe here a proposal for a light injection calibration system for the MINOS detectors based on ultra bright blue LEDs as the light source. We have shown that these LEDs are bright enough to span over two orders of magnitude in light intensity, commensurate with that expected in a single scintillator strip in the MINOS neutrino detectors.Comment: 9 pages, 13 figures, Submitted to NI

A finite dimensional approach to Donaldson's J-flow

Consider a projective manifold with two distinct polarisations $L_1$ and $L_2$. From this data, Donaldson has defined a natural flow on the space of Kähler metrics in $c_1$($L_1$), called the J-flow. The existence of a critical point of this flow is closely related to the existence of a constant scalar curvature Kähler metric in $c_1$($L_1$) for certain polarisations $L_2$. Associated to a quantum parameter $k$ $\gg$ 0, we define a flow over Bergman type metrics, which we call the J-balancing flow. We show that in the quantum limit $k$ → +∞, the rescaled J-balancing flow converges towards the J-flow. As corollaries, we obtain new proofs of uniqueness of critical points of the J-flow and also that these critical points achieve the absolute minimum of an associated energy functional. We show that the existence of a critical point of the J-flow implies the existence of J-balanced metrics for $k$ $\gg$ 0. Defining a notion of Chow stability for linear systems, we show that this in turn implies the linear system |$L_2$| is asymptotically Chow stable. Asymptotic Chow stability of |$L_2$| implies an analogue of K-semistability for the J-flow introduced by Lejmi-Székelyhidi, which we call J-semistability. We prove also that Jstability holds automatically in a certain numerical cone around $L_2$, and that if $L_2$ is the canonical class of the manifold that J-semistability implies K-stability. Eventually, this leads to new K-stable polarisations of surfaces of general type.The first author was funded by a studentship associated to an EPSRC Career Acceleration Fellowship (EP/J002062/1). The work of the second author has been carried out in the framework of the Labex Archimede (ANR-11-LABX-0033) and of the A*MIDEX project (ANR-11-IDEX- 0001-02), funded by the “Investissements d’Avenir” French Government programme managed by the French National Research Agency (ANR). The second author was also partially supported by supported by the ANR project EMARKS, decision No ANR-14-CE25-0010

Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat by Pyrrole-Imidazole Polyamides

The host factor LSF represses the human immunodeficiency virus type 1 long terminal repeat (LTR) by mediating recruitment of histone deacetylase. We show that pyrrole-imidazole polyamides targeted to the LTR can specifically block LSF binding both in vitro and within cells via direct access to chromatin, resulting in increased LTR expression

Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5′-WGGWWW-3′ and 5′GGGWWW-3′. The compound is capable of binding to κB sites and reducing the expression of various NF-κB–driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α–inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists

Upgrade to the Birmingham Irradiation Facility

The Birmingham Irradiation Facility was developed in 2013 at the University of Birmingham using the Medical Physics MC40 cyclotron. It can achieve High Luminosity LHC (HL-LHC) fluences of 1015 (1 MeV neutron equivalent (neq)) cm-2 in 80 s with proton beam currents of 1 μA and so can evaluate effectively the performance and durability of detector technologies and new components to be used for the HL-LHC. Irradiations of silicon sensors and passive materials can be carried out in a temperature controlled cold box which moves continuously through the homogenous beamspot. This movement is provided by a pre-configured XY-axis Cartesian robot scanning system. In 2014 the cooling system and cold box were upgraded from a recirculating glycol chiller system to a liquid nitrogen evaporative system. The new cooling system achieves a stable temperature of -50 °C in 30 min and aims to maintain sub-0 °C temperatures on the sensors during irradiations. This paper reviews the design, development, commissioning and performance of the new cooling system

Sequence-specific fluorescence detection of DNA by polyamide-thiazole orange conjugates

Fluorescent methods to detect specific double-stranded DNA sequences without the need for denaturation may be useful in the field of genetics. Three hairpin pyrrole-imidazole polyamides 2-4 that target their respective sequences 5'-WGGGWW-3', 5'-WGGCCW-3', and 5'-WGWWCW-3' (W = A or T) were conjugated to thiazole orange dye at the C-termini to examine their fluorescence properties in the presence and absence of match duplex DNA. The conjugates fluoresce weakly in the absence of DNA but showed significant enhancement (>1000-fold) upon the addition of 1 equiv of match DNA and only slight enhancement with the addition of mismatch DNA. The polyamide-dye conjugates bound specific DNA sequences with high affinity (Ka > 10(8) M(-1)) and unwound the DNA duplex through intercalation (unwinding angle, phi, approximately 8 degrees). This new class of polyamides provides a method to specifically detect DNA sequences without denaturation

Design of a sequence-specific DNA bisintercalator

Programmable bisintercalators: Symmetric synthetic DNA bisintercalators (see picture) based on the H-pin polyamide motif afford high affinity and programmable sequence specificity

Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-l, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity, The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication

Microwave Assisted Synthesis of Py-Im Polyamides

Microwave synthesis was utilized to rapidly build Py-Im polyamides in high yields and purity using Boc-protection chemistry on Kaiser oxime resin. A representative polyamide targeting the 5′-WGWWCW-3′ (W = A or T) subset of the consensus Androgen and Glucocorticoid Response Elements was synthesized in 56% yield after 20 linear steps and HPLC purification. It was confirmed by Mosher amide derivatization of the polyamide that a chiral α-amino acid does not racemize after several additional coupling steps