Probing Unexpected Reactivity in Radiometal Chemistry: Indium-111-Mediated Hydrolysis of Hybrid Cyclen-Hydroxypyridinone Ligands

Chelators based on hydroxypyridinones have utility in incorporating radioactive metal ions into diagnostic and therapeutic agents used in nuclear medicine. Over the course of our hydroxypyridinone studies, we have prepared two novel chelators, consisting of a cyclen (1,4,7,10-tetraazacyclododecane) ring bearing two pendant hydroxypyridinone groups, appended via methylene acetamide motifs at either the 1,4-positions (L1) or 1,7-positions (L2) of the cyclen ring. In radiolabeling reactions of L1 or L2 with the γ-emitting radioisotope, [111In]In3+, we have observed radiometal-mediated hydrolysis of a single amide group of either L1 or L2. The reaction of either [111In]In3+ or [natIn]In3+ with either L1 or L2, in aqueous alkaline solutions at 80 °C, initially results in formation of [In(L1)]+ or [In(L2)]+, respectively. Over time, each of these species undergoes In3+-mediated hydrolysis of a single amide group to yield species in which In3+ remains coordinated to the resultant chelator, which consists of a cyclen ring bearing a single hydroxypyridinone group and a single carboxylate group. The reactivity toward hydrolysis is higher for the L1 complex compared to that for the L2 complex. Density functional theory calculations corroborate these experimental findings and importantly indicate that the activation energy required for the hydrolysis of L1 is significantly lower than that required for L2. This is the first reported example of a chelator undergoing radiometal-mediated hydrolysis to form a radiometalated complex. It is possible that metal-mediated amide bond cleavage is a source of instability in other radiotracers, particularly those in which radiometal complexation occurs in aqueous, basic solutions at high temperatures. This study highlights the importance of appropriate characterization of radiolabeled products

Parenting behavior and the risk of becoming a victim and a bully/victim : a meta-analysis study

Objective: Being bullied has adverse effects on children's health. Children's family experiences and parenting behavior before entering school help shape their capacity to adapt and cope at school and have an impact on children's peer relationship, hence it is important to identify how parenting styles and parent–child relationship are related to victimization in order to develop intervention programs to prevent or mitigate victimization in childhood and adolescence. Methods: We conducted a systematic review of the published literature on parenting behavior and peer victimization using MEDLINE, PsychINFO, Eric and EMBASE from 1970 through the end of December 2012. We included prospective cohort studies and cross-sectional studies that investigated the association between parenting behavior and peer victimization. Results: Both victims and those who both bully and are victims (bully/victims) were more likely to be exposed to negative parenting behavior including abuse and neglect and maladaptive parenting. The effects were generally small to moderate for victims (Hedge's g range: 0.10–0.31) but moderate for bully/victims (0.13–0.68). Positive parenting behavior including good communication of parents with the child, warm and affectionate relationship, parental involvement and support, and parental supervision were protective against peer victimization. The protective effects were generally small to moderate for both victims (Hedge's g: range: −0.12 to −0.22) and bully/victims (−0.17 to −0.42). Conclusions: Negative parenting behavior is related to a moderate increase of risk for becoming a bully/victim and small to moderate effects on victim status at school. Intervention programs against bullying should extend their focus beyond schools to include families and start before children enter school

Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

Genetic diversity of Brazilian isolates of feline immunodeficiency virus

We isolated Feline immunodeficiency virus (FIV) from three adult domestic cats, originating from two open shelters in Brazil. Viruses were isolated from PBMC following co-cultivation with the feline T-lymphoblastoid cell line MYA-1. All amplified env gene products were cloned directly into pGL8MYA. The nucleic acid sequences of seven clones were determined and then compared with those of previously described isolates. The sequences of all of the Brazilian virus clones were distinct and phylogenetic analysis revealed that all belong to subtype B. Three variants isolated from one cat and two variants were isolated from each of the two other cats, indicating that intrahost diversity has the potential to pose problems for the treatment and diagnosis of FIV infection

ATLASGAL - star forming efficiencies and the Galactic star formation rate

The ATLASGAL survey has characterized the properties of approximately 1000 embedded H ii regions and found an empirical relationship between the clump mass and bolometric luminosity that covers 3-4 orders of magnitude. Comparing this relation with simulated clusters drawn from an initial mass function and using different star formation efficiencies we find that a single value is unable to fit the observed luminosity to mass (L/M) relation. We have used a Monte Carlo simulation to generate 200 000 clusters using the L/M-ratio as a constraint to investigate how the star formation efficiency changes as a function of clump mass. This has revealed that the star formation efficiency decreases with increasing clump mass with a value of 0.2 for clumps with masses of a few hundred solar masses and dropping to 0.08 for clumps with masses of a few thousand solar masses. We find good agreement between our results and star formation efficiencies determined from counts of embedded objects in nearby molecular clouds. Using the star formation efficiency relationship and the infrared excess time for embedded star formation of 2 ± 1 Myr we estimate the Galactic star formation rate to be approximately 0.9 ± 0.45 M· yr-1, which is in good agreement with previously reported values. This model has the advantage of providing a direct means of determining the star formation rate and avoids the difficulties encountered in converting infrared luminosities to stellar mass that affect previous galactic and extragalactic studies

CHIMPS: Physical properties of molecular clumps across the inner Galaxy

The latest generation of high-angular-resolution unbiased Galactic plane surveys in molecular-gas tracers are enabling the interiors of molecular clouds to be studied across a range of environments. The CO Heterodyne Inner MilkyWay Plane Survey (CHIMPS) simultaneously mapped a sector of the inner Galactic plane, within 27:8 . 46:2 and jbj 0: 5, in 13CO (3-2) and C18O (3-2) at an angular resolution of 15 arcsec. The combination of the CHIMPS data with 12CO (3-2) data from the CO High Resolution Survey (COHRS) has enabled us to perform a voxel-by-voxel local-thermodynamic-equilibrium (LTE) analysis, determining the excitation temperature, optical depth, and column density of 13CO at each; b; v position. Distances to discrete sources identified by FELLWALKER in the 13CO (3-2) emission maps were determined, allowing the calculation of numerous physical properties of the sources, and we present the first source catalogues in this paper.We find that, in terms of size and density, the CHIMPS sources represent an intermediate population between large-scale molecular clouds identified by CO and dense clumps seen in thermal dust continuum emission, and therefore represent the bulk transition from the diffuse to the dense phase of molecular gas.We do not find any significant systematic variations in the masses, column densities, virial parameters, mean excitation temperature, or the turbulent pressure over the range of Galactocentric distance probed, but we do find a shallow increase in the mean volume density with increasing Galactocentric distance. We find that inter-arm clumps have significantly narrower linewidths, and lower virial parameters and excitation temperatures than clumps located in spiral arms. When considering the most reliable distance-limited subsamples, the largest variations occur on the clump-to-clump scale, echoing similar recent studies that suggest that the star-forming process is largely insensitive to the Galactic-scale environment, at least within the inner disc

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics

CHIMPS: the 13^{13}CO/C18^{18}O (J=3-2) Heterodyne Inner Milky Way Plane Survey

We present the $^{13}$CO/C$^{18}$O (J=3-2) Heterodyne Inner Milky Way Plane Survey (CHIMPS) which has been carried out using the Heterodyne Array Receiver Program on the 15 m James Clerk Maxwell Telescope (JCMT) in Hawaii. The high-resolution spectral survey currently covers |b| < 0.5 deg and 28 < l < 46 deg, with an angular resolution of 15 arcsec in 0.5 km/s velocity channels. The spectra have a median rms of $\sim$ 0.6 K at this resolution, and for optically thin gas at an excitation temperature of 10 K, this sensitivity corresponds to column densities of $N_{\mathrm{H}_{2}} \sim 3 \times 10^{20}\,$cm$^{-2}$ and $N_{\mathrm{H}_{2}} \sim 4 \times 10^{21}\,$cm$^{-2}$ for $^{13}$CO and C$^{18}$O, respectively. The molecular gas that CHIMPS traces is at higher column densities and is also more optically thin than in other publicly available CO surveys due to its rarer isotopologues, and thus more representative of the three-dimensional structure of the clouds. The critical density of the J=3-2 transition of CO is $\gtrsim 10^{4}$ cm$^{-3}$ at temperatures of $\leq 20$ K, and so the higher density gas associated with star formation is well traced. These data complement other existing Galactic plane surveys, especially the JCMT Galactic Plane Survey which has similar spatial resolution and column density sensitivity, and the Herschel infrared Galactic Plane Survey. In this paper, we discuss the observations, data reduction and characteristics of the survey, presenting integrated emission maps for the region covered. Position-velocity diagrams allow comparison with Galactic structure models of the Milky Way, and while we find good agreement with a particular four arm model, there are some significant deviations

Surface-enhanced Raman scattering measurement from a lipid bilayer encapsulating a single decahedral nanoparticle mediated by an optical trap

We present a new technique for the study of model membranes on the length-scale of a single nanosized liposome. Silver decahedral nanoparticles have been encapsulated by a model unilamellar lipid bilayer creating nano-sized lipid vesicles. The metal core has two roles (i) increasing the polarizability of vesicles, enabling a single vesicle to be isolated and confined in an optical trap, and (ii) enhancing Raman scattering from the bilayer, via the high surface-plasmon field at the sharp vertices of the decahedral particles. Combined this has allowed us to measure a Raman fingerprint from a single vesicle of 50 nmdiameter, containing just ∼104 lipid molecules in a bilayer membrane over a surface area of <0.01 µm2, equivalent to a volume of approximately 1 zepto-litre. Raman scattering is a weak and inefficient process and previous studies have required either a substantially larger bilayer area in order to obtain a detectable signal, or the tagging of lipid molecules with a chromophore to provide an indirect probe of the bilayer. Our approach is fully label-free and bio-compatible and, in the future, it will enable much more localized studies of the heterogeneous structure of lipid bilayers and of membrane-bound components than is currently possible