The effects of discreteness of galactic cosmic rays sources

Most studies of GeV Galactic Cosmic Rays (GCR) nuclei assume a steady state/continuous distribution for the sources of cosmic rays, but this distribution is actually discrete in time and in space. The current progress in our understanding of cosmic ray physics (acceleration, propagation), the required consistency in explaining several GCRs manifestation (nuclei, $\gamma$,...) as well as the precision of present and future space missions (e.g. INTEGRAL, AMS, AGILE, GLAST) point towards the necessity to go beyond this approximation. A steady state semi-analytical model that describes well many nuclei data has been developed in the past years based on this approximation, as well as others. We wish to extend it to a time dependent version, including discrete sources. As a first step, the validity of several approximations of the model we use are checked to validate the approach: i) the effect of the radial variation of the interstellar gas density is inspected and ii) the effect of a specific modeling for the galactic wind (linear vs constant) is discussed. In a second step, the approximation of using continuous sources in space is considered. This is completed by a study of time discreteness through the time-dependent version of the propagation equation. A new analytical solution of this equation for instantaneous point-like sources, including the effect of escape, galactic wind and spallation, is presented. Application of time and space discretness to definite propagation conditions and realistic distributions of sources will be presented in a future paper.Comment: final version, 8 figures, accepted in ApJ. A misprint in fig 8 labels has been correcte

From llama to nanobody: a streamlined workflow for the generation of functionalised VHHs

Nanobodies are recombinant antigen-specific single domain antibodies (VHHs) derived from the heavy chain–only subset of camelid immunoglobulins. Their small molecular size, facile expression, high affinity, and stability have combined to make them unique targeting reagents with numerous applications in the biomedical sciences. From our work in producing nanobodies to over sixty different proteins, we present a standardised workflow for nanobody discovery from llama immunisation, library building, panning, and small-scale expression for prioritisation of binding clones. In addition, we introduce our suites of mammalian and bacterial vectors, which can be used to functionalise selected nanobodies for various applications such as in imaging and purification

Dynamic studies of the interaction of a pH responsive, amphiphilic polymer with a DOPC lipid membrane

Deeper understanding of the molecular interactions between polymeric materials and the lipid membrane is important across a range of applications from permeation for drug delivery to encapsulation for immuno-evasion. Using highly fluidic microcavity supported lipid bilayers, we studied the interactions between amphiphilic polymer PP50 and a DOPC lipid bilayer. As the PP50 polymer is pH responsive the studies were carried out at pH 6.5, 7.05 and 7.5, corresponding to fully, partly protonated (pH = p$K_a$ = 7.05) and fully ionized states of the polymer, respectively. Fluorescence correlation spectroscopy (FCS) using both labelled lipid and polymer revealed the PP50 associates with the bilayer interface across all pHs where its diffusion along the interface is impeded. Both FCS and electrochemical impedance spectroscopy (EIS) data indicate that the PP50 does not penetrate fully into the bilayer core but rather forms a layer at the bilayer aqueous interface reflected in increased resistance and decreased capacitance of the bilayer on PP50 binding. The extent of these effects and the dynamics of binding are influenced by pH, increasing with decreasing pH. These experimental trends concurred with coarse grained Monte Carlo simulations of polymer-bilayer interactions wherein a model hydrophilic polymer backbone grafted with side chains of varying hydrophobicity, to mimic the effect of varying pH, was simulated based on the bond fluctuation model with explicit solvent. Simulation results showed that with increasing hydrophobicity, the polymer penetrated deeper into the contacting bilayer leaflet of the membrane suppressing, consistent with EIS data, solvent permeation and that a full insertion of the polymer into the bilayer core is not necessary for suppression of permeability.This material is based upon work supported by the Science Foundation Ireland under Grant No. [14/IA/2488]. T. E. K. and S. R. are grateful to the Irish Research Council for a Government of Ireland postdoctoral fellowship (GOIPD/2014/322). M. W. and V. A. B. gratefully thank the European Union’s funding of the Initial Training Network SNAL (grant agreement no. 608184) under the 7th Framework programme

An elastic second skin

We report the synthesis and application of an elastic, wearable crosslinked polymer layer (XPL) that mimics the properties of normal, youthful skin. XPL is made of a tunable polysiloxane-based material that can be engineered with specific elasticity, contractility, adhesion, tensile strength and occlusivity. XPL can be topically applied, rapidly curing at the skin interface without the need for heat- or light-mediated activation. In a pilot human study, we examined the performance of a prototype XPL that has a tensile modulus matching normal skin responses at low strain (<40%), and that withstands elongations exceeding 250%, elastically recoiling with minimal strain-energy loss on repeated deformation. The application of XPL to the herniated lower eyelid fat pads of 12 subjects resulted in an average 2-grade decrease in herniation appearance in a 5-point severity scale. The XPL platform may offer advanced solutions to compromised skin barrier function, pharmaceutical delivery and wound dressings

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure

From llama to nanobody: a streamlined workflow for the generation of functionalised VHHs

Nanobodies are recombinant antigen-specific single domain antibodies (VHHs) derived from the heavy chain–only subset of camelid immunoglobulins. Their small molecular size, facile expression, high affinity, and stability have combined to make them unique targeting reagents with numerous applications in the biomedical sciences. From our work in producing nanobodies to over sixty different proteins, we present a standardised workflow for nanobody discovery from llama immunisation, library building, panning, and small-scale expression for prioritisation of binding clones. In addition, we introduce our suites of mammalian and bacterial vectors, which can be used to functionalise selected nanobodies for various applications such as in imaging and purification

The spin dependence of high energy proton scattering

Motivated by the need for an absolute polarimeter to determine the beam polarization for the forthcoming RHIC spin program, we study the spin dependence of the proton-proton elastic scattering amplitudes at high energy and small momentum transfer.We examine experimental evidence for the existence of an asymptotic part of the helicity-flip amplitude phi_5 which is not negligible relative to the largely imaginary average non-flip amplitude phi_+. We discuss theoretical estimates of r_5, essentially the ratio of phi_5 to phi_+, based upon extrapolation of low and medium energy Regge phenomenological results to high energies, models based on a hybrid of perturbative QCD and non-relativistic quark models, and models based on eikonalization techniques. We also apply the model-independent methods of analyticity and unitarity.The preponderence of evidence at available energy indicates that r_5 is small, probably less than 10%. The best available experimental limit comes from Fermilab E704:those data indicate that |r_5|<15%. These bounds are important because rigorous methods allow much larger values. In contradiction to a widely-held prejudice that r_5 decreases with energy, general principles allow it to grow as fast as ln(s) asymptotically, and some models show an even faster growth in the RHIC range. One needs a more precise measurement of r_5 or to bound it to be smaller than 5% in order to use the classical Coulomb-nuclear interference technique for RHIC polarimetry. As part of this study, we demonstrate the surprising result that proton-proton elastic scattering is self-analysing, in the sense that all the helicity amplitudes can, in principle, be determined experimentally at small momentum transfer without a knowledge of the magnitude of the beam and target polarization

Crystal Structure of Outer Membrane Protein NMB0315 from Neisseria meningitidis

NMB0315 is an outer membrane protein of Neisseria meningitidis serogroup B (NMB) and a potential candidate for a broad-spectrum vaccine against meningococcal disease. The crystal structure of NMB0315 was solved by single-wavelength anomalous dispersion (SAD) at a resolution of 2.4 Å and revealed to be a lysostaphin-type peptidase of the M23 metallopeptidase family. The overall structure consists of three well-separated domains and has no similarity to any previously published structure. However, only the topology of the carboxyl-terminal domain is highly conserved among members of this family, and this domain is a zinc-dependent catalytic unit. The amino-terminal domain of the structure blocks the substrate binding pocket in the carboxyl-terminal domain, indicating that the wild-type full-length protein is in an inactive conformational state. Our studies improve the understanding of the catalytic mechanism of M23 metallopeptidases

CdTe Quantum Dot/Dye Hybrid System as Photosensitizer for Photodynamic Therapy

We have studied the photodynamic properties of novel CdTe quantum dots—methylene blue hybrid photosensitizer. Absorption spectroscopy, photoluminescence spectroscopy, and fluorescence lifetime imaging of this system reveal efficient charge transfer between nanocrystals and the methylene blue dye. Near-infrared photoluminescence measurements provide evidence for an increased efficiency of singlet oxygen production by the methylene blue dye. In vitro studies on the growth of HepG2 and HeLa cancerous cells were also performed, they point toward an improvement in the cell kill efficiency for the methylene blue-semiconductor nanocrystals hybrid system

Modulating Activity of Vancomycin and Daptomycin on the Expression of Autolysis Cell-Wall Turnover and Membrane Charge Genes in hVISA and VISA Strains

Glycopeptides are still the gold standard to treat MRSA (Methicillin Resistant Staphylococcus aureus) infections, but their widespread use has led to vancomycin-reduced susceptibility [heterogeneous Vancomycin-Intermediate-Staphylococcus aureus (hVISA) and Vancomycin-Intermediate-Staphylococcus aureus (VISA)], in which different genetic loci (regulatory, autolytic, cell-wall turnover and cell-envelope positive charge genes) are involved. In addition, reduced susceptibility to vancomycin can influence the development of resistance to daptomycin. Although the phenotypic and molecular changes of hVISA/VISA have been the focus of different papers, the molecular mechanisms responsible for these different phenotypes and for the vancomycin and daptomycin cross-resistance are not clearly understood. The aim of our study was to investigate, by real time RT-PCR, the relative quantitative expression of genes involved in autolysis (atl-lytM), cell-wall turnover (sceD), membrane charges (mprF-dltA) and regulatory mechanisms (agr-locus-graRS-walKR), in hVISA and VISA cultured with or without vancomycin and daptomycin, in order to better understand the molecular basis of vancomycin-reduced susceptibility and the modulating activity of vancomycin and daptomycin on the expression of genes implicated in their reduced susceptibility mechanisms. Our results show that hVISA and VISA present common features that distinguish them from Vancomycin-Susceptible Staphylococcus aureus (VSSA), responsible for the intermediate glycopeptide resistance i.e. an increased cell-wall turnover, an increased positive cell-wall charge responsible for a repulsion mechanism towards vancomycin and daptomycin, and reduced agr-functionality. Indeed, VISA emerges from hVISA when VISA acquires a reduced autolysis caused by a down-regulation of autolysin genes, atl/lytM, and a reduction of the net negative cell-envelope charge via dltA over-expression. Vancomycin and daptomycin, acting in a similar manner in hVISA and VISA, can influence their cross-resistance mechanisms promoting VISA behavior in hVISA and enhancing the cell-wall pathways responsible for the intermediate vancomycin resistance in VISA. Daptomycin can also induce a charge repulsion mechanism both in hVISA and VISA increasing the activity of the mprF