Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups

he design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups

Effect of mattress deflection on CPR quality assessment for older children and adolescents

Appropriate chest compression (CC) depth is associated with improved CPR outcome. CCs provided in hospital are often conducted on a compliant mattress. The objective was to quantify the effect of mattress compression on the assessment of CPR quality in children. Methods: A force and deflection sensor (FDS) was used during CPR in the Pediatric Intensive Care Unit and Emergency Department of a children's hospital. The sensor was interposed between the chest of the patient and hands of the rescuer and measured CC depth. Following CPR event, each event was reconstructed with a manikin and an identical mattress/backboard/patient configuration. CCs were performed using FDS on the sternum and a reference accelerometer attached to the spine of the manikin, providing a means to Calculate the mattress deflection. Results: Twelve CPR events with 14,487 CC (11 patients, median age 14.9 years) were recorded and reconstructed: 9 on ICU beds (9296 CC), 3 on stretchers (5191 CC). Measured mean CC depth during CPR was 47 +/- 8 mm on ICU beds, and 45 +/- 7 mm on stretcher beds with overestimation of 13 +/- 4 mm and 4 +/- 1 mm, respectively, due to mattress compression. After adjusting for this, the proportion of CC that met the CPR guidelines decreased from 88.4 to 31.8% on ICU beds (p < 0.001), and 86.3 to 64.7% on stretcher (p < 0.001 The proportion of appropriate depth CC was significantly smaller on ICU beds (p < 0.001). Conclusion: CC conducted on a non-rigid surface may not be deep enough. FDS may overestimate CC depth by 28% on ICU beds, and 10% on stretcher beds

Medium effects in high energy heavy-ion collisions

The change of hadron properties in dense matter based on various theoretical approaches are reviewed. Incorporating these medium effects in the relativistic transport model, which treats consistently the change of hadron masses and energies in dense matter via the scalar and vector fields, heavy-ion collisions at energies available from SIS/GSI, AGS/BNL, and SPS/CERN are studied. This model is seen to provide satisfactory explanations for the observed enhancement of kaon, antikaon, and antiproton yields as well as soft pions in the transverse direction from the SIS experiments. In the AGS heavy-ion experiments, it can account for the enhanced $K^+/\pi^+$ ratio, the difference in the slope parameters of the $K^+$ and $K^-$ transverse kinetic energy spectra, and the lower apparent temperature of antiprotons than that of protons. This model also provides possible explanations for the observed enhancement of low-mass dileptons, phi mesons, and antilambdas in heavy-ion collisions at SPS energies. Furthermore, the change of hadron properties in hot dense matter leads to new signatures of the quark-gluon plasma to hadronic matter transition in future ultrarelativistic heavy-ion collisions at RHIC/BNL.Comment: RevTeX, 65 pages, including 25 postscript figures, invited topical review for Journal of Physics G: Nuclear and Particle Physic

Disparities in the analysis of morphological disparity

Analyses of morphological disparity have been used to characterize and investigate the evolution of variation in the anatomy, function and ecology of organisms since the 1980s. While a diversity of methods have been employed, it is unclear whether they provide equivalent insights. Here, we review the most commonly used approaches for characterizing and analysing morphological disparity, all of which have associated limitations that, if ignored, can lead to misinterpretation. We propose best practice guidelines for disparity analyses, while noting that there can be no ‘one-size-fits-all’ approach. The available tools should always be used in the context of a specific biological question that will determine data and method selection at every stage of the analysis

Event shapes in e+e- annihilation and deep inelastic scattering

This article reviews the status of event-shape studies in e+e- annihilation and DIS. It includes discussions of perturbative calculations, of various approaches to modelling hadronisation and of comparisons to data.Comment: Invited topical review for J.Phys.G; 40 pages; revised version corrects some nomenclatur

Adaptation and Convergent Evolution within the Jamesonia-Eriosorus Complex in High-Elevation Biodiverse Andean Hotspots

The recent uplift of the tropical Andes (since the late Pliocene or early Pleistocene) provided extensive ecological opportunity for evolutionary radiations. We test for phylogenetic and morphological evidence of adaptive radiation and convergent evolution to novel habitats (exposed, high-altitude páramo habitats) in the Andean fern genera Jamesonia and Eriosorus. We construct time-calibrated phylogenies for the Jamesonia-Eriosorus clade. We then use recent phylogenetic comparative methods to test for evolutionary transitions among habitats, associations between habitat and leaf morphology, and ecologically driven variation in the rate of morphological evolution. Páramo species (Jamesonia) display morphological adaptations consistent with convergent evolution in response to the demands of a highly exposed environment but these adaptations are associated with microhabitat use rather than the páramo per se. Species that are associated with exposed microhabitats (including Jamesonia and Eriorsorus) are characterized by many but short pinnae per frond whereas species occupying sheltered microhabitats (primarily Eriosorus) have few but long pinnae per frond. Pinnae length declines more rapidly with altitude in sheltered species. Rates of speciation are significantly higher among páramo than non-páramo lineages supporting the hypothesis of adaptation and divergence in the unique Páramo biodiversity hotspot

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Structure and binding affinity in DNA minor groove binders

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effect of mattress deflection on CPR quality assessment for older children and adolescents

Appropriate chest compression (CC) depth is associated with improved CPR outcome. CCs provided in hospital are often conducted on a compliant mattress. The objective was to quantify the effect of mattress compression on the assessment of CPR quality in children. Methods: A force and deflection sensor (FDS) was used during CPR in the Pediatric Intensive Care Unit and Emergency Department of a children's hospital. The sensor was interposed between the chest of the patient and hands of the rescuer and measured CC depth. Following CPR event, each event was reconstructed with a manikin and an identical mattress/backboard/patient configuration. CCs were performed using FDS on the sternum and a reference accelerometer attached to the spine of the manikin, providing a means to Calculate the mattress deflection. Results: Twelve CPR events with 14,487 CC (11 patients, median age 14.9 years) were recorded and reconstructed: 9 on ICU beds (9296 CC), 3 on stretchers (5191 CC). Measured mean CC depth during CPR was 47 +/- 8 mm on ICU beds, and 45 +/- 7 mm on stretcher beds with overestimation of 13 +/- 4 mm and 4 +/- 1 mm, respectively, due to mattress compression. After adjusting for this, the proportion of CC that met the CPR guidelines decreased from 88.4 to 31.8% on ICU beds (p < 0.001), and 86.3 to 64.7% on stretcher (p < 0.001 The proportion of appropriate depth CC was significantly smaller on ICU beds (p < 0.001). Conclusion: CC conducted on a non-rigid surface may not be deep enough. FDS may overestimate CC depth by 28% on ICU beds, and 10% on stretcher beds

Amide isosteres in structure-activity studies of antibacterial minor groove binders

Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis