Novel Liquid Argon Time-Projection Chamber Readouts

Liquid argon time-projection chambers (LArTPCs) have become a prominent tool for experiments in particle physics. Recent years have yielded significant advances in the techniques used to capture the signals generated by these cryogenic detectors. This article summarizes these novel developments for detection of ionization electrons and scintillation photons in LArTPCs. New methods to capture ionization signals address the challenges of scaling traditional techniques to the large scales necessary for future experiments. Pixelated readouts improve signal fidelity and expand the applicability of LArTPCs to higher-rate environments. Methods that leverage amplification in argon enable measurements in the keV regime and below. Techniques to enhance collection of argon scintillation photons improve calorimetry and expand the physics program for very large detectors. Future efforts aim to demonstrate systems for the combined detection of both electrons and photons

Lentivirus Display: Stable Expression of Human Antibodies on the Surface of Human Cells and Virus Particles

Background: Isolation of human antibodies using current display technologies can be limited by constraints on protein expression, folding and post-translational modifications. Here we describe a discovery platform that utilizes self-inactivating (SIN) lentiviral vectors for the surface display of high-affinity single-chain variable region (scFv) antibody fragments on human cells and lentivirus particles. Methodology/Principal Findings: Bivalent scFvFc human antibodies were fused in frame with different transmembrane (TM) anchoring moieties to allow efficient high-level expression on human cells and the optimal TM was identified. The addition of an eight amino acid HIV-1 gp41 envelope incorporation motif further increased scFvFc expression on human cells and incorporation into lentiviral particles. Both antibody-displaying human cells and virus particles bound antigen specifically. Sulfation of CDR tyrosine residues, a property recently shown to broaden antibody binding affinity and antigen recognition was also demonstrated. High level scFvFc expression and stable integration was achieved in human cells following transduction with IRES containing bicistronic SIN lentivectors encoding ZsGreen when scFvFc fusion proteins were expressed from the first cassette. Up to 10[super]6-fold enrichment of antibody expressing cells was achieved with one round of antigen coupled magnetic bead pre-selection followed by FACS sorting. Finally, the scFvFc displaying human cells could be used directly in functional biological screens with remarkable sensitivity. Conclusions/Significance: This antibody display platform will complement existing technologies by virtue of providing properties unique to lentiviruses and antibody expression in human cells, which, in turn, may aid the discovery of novel therapeutic human mAbs

Collision-Induced Decay of Metastable Baby Skyrmions

Many extensions of the standard model predict heavy metastable particles which may be modeled as solitons (skyrmions of the Higgs field), relating their particle number to a winding number. Previous work has shown that the electroweak interactions admit processes in which these solitons decay, violating standard model baryon number. We motivate the hypothesis that baryon-number-violating decay is a generic outcome of collisions between these heavy particles. We do so by exploring a 2+1 dimensional theory which also possesses metastable skyrmions. We use relaxation techniques to determine the size, shape and energy of static solitons in their ground state. These solitons could decay by quantum mechanical tunneling. Classically, they are metastable: only a finite excitation energy is required to induce their decay. We attempt to induce soliton decay in a classical simulation by colliding pairs of solitons. We analyze the collision of solitons with varying inherent stabilities and varying incident velocities and orientations. Our results suggest that winding-number violating decay is a generic outcome of collisions. All that is required is sufficient (not necessarily very large) incident velocity; no fine-tuning of initial conditions is required.Comment: 24 pages, 7 figures, latex. Very small changes onl

Football in the community schemes: Exploring the effectiveness of an intervention in promoting healthful behaviour change

This study aims to examine the effectiveness of a Premier League football club’s Football in the Community (FitC) schemes intervention in promoting positive healthful behaviour change in children. Specifically, exploring the effectiveness of this intervention from the perspectives of the participants involved (i.e. the researcher, teachers, children and coaches). A range of data collection techniques were utilized including the principles of ethnography (i.e. immersion, engagement and observations), alongside conducting focus groups with the children. The results allude to the intervention merely ‘keeping active children active’ via (mostly) fun, football sessions. Results highlight the important contribution the ‘coach’ plays in the effectiveness of the intervention. Results relating to working practice (i.e. coaching practice and coach recruitment) are discussed and highlighted as areas to be addressed. FitC schemes appear to require a process of positive organizational change to increase their effectiveness in strategically attending to the health agenda

Public opinion on energy crops in the landscape: considerations for the expansion of renewable energy from biomass

Public attitudes were assessed towards two dedicated biomass crops – Miscanthus and Short Rotation Coppice (SRC), particularly regarding their visual impacts in the landscape. Results are based on responses to photographic and computer-generated images as the crops are still relatively scarce in the landscape. A questionnaire survey indicated little public concern about potential landscape aesthetics but more concern about attendant built infrastructure. Focus group meetings and interviews indicated support for biomass end uses that bring direct benefits to local communities. Questions arise as to how well the imagery used was able to portray the true nature of these tall, dense, perennial plants but based on the responses obtained and given the caveat that there was limited personal experience of the crops, it appears unlikely that wide-scale planting of biomass crops will give rise to substantial public concern in relation to their visual impact in the landscape

Networking Opportunities for Bacteria

In this post-genomic era, our capacity to explore biological networks and predict network architectures has been greatly expanded, accelerating interest in systems biology. Here, we highlight recent systems biology studies in prokaryotes, consider the challenges ahead, and suggest opportunities for future studies in bacterial models

Gyrase inhibitors induce an oxidative damage cellular death pathway

Modulation of bacterial chromosomal supercoiling is a function of DNA gyrase-catalyzed strand breakage and rejoining. This reaction is exploited by both antibiotic and proteic gyrase inhibitors, which trap the gyrase molecule at the DNA cleavage stage. Owing to this interaction, doublestranded DNA breaks are introduced and replication machinery is arrested at blocked replication forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate, through a series of phenotypic and gene expression analyses, that superoxide and hydroxyl radical oxidative species are generated following gyrase poisoning and play an important role in cell killing by gyrase inhibitors. We show that superoxide-mediated oxidation of iron-sulfur clusters promotes a breakdown of iron regulatory dynamics; in turn, iron misregulation drives the generation of highly destructive hydroxyl radicals via the Fenton reaction. Importantly, our data reveal that blockage of hydroxyl radical formation increases the survival of gyrase-poisoned cells. Together, this series of biochemical reactions appears to compose a maladaptive response, that serves to amplify the primary effect of gyrase inhibition by oxidatively damaging DNA, proteins and lipids

A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics

SummaryAntibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA

Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli

Modulation of bacterial chromosomal supercoiling is a function of DNA gyrase-catalyzed strand breakage and rejoining. This reaction is exploited by both antibiotic and proteic gyrase inhibitors, which trap the gyrase molecule at the DNA cleavage stage. Owing to this interaction, double-stranded DNA breaks are introduced and replication machinery is arrested at blocked replication forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate, through a series of phenotypic and gene expression analyses, that superoxide and hydroxyl radical oxidative species are generated following gyrase poisoning and play an important role in cell killing by gyrase inhibitors. We show that superoxide-mediated oxidation of iron–sulfur clusters promotes a breakdown of iron regulatory dynamics; in turn, iron misregulation drives the generation of highly destructive hydroxyl radicals via the Fenton reaction. Importantly, our data reveal that blockage of hydroxyl radical formation increases the survival of gyrase-poisoned cells. Together, this series of biochemical reactions appears to compose a maladaptive response, that serves to amplify the primary effect of gyrase inhibition by oxidatively damaging DNA, proteins and lipids