Structure and properties of DOTA-chelated radiopharmaceuticals within the 225Ac decay pathway

The successful delivery of toxic cargo directly to tumor cells is of primary importance in targeted (α) particle therapy. Complexes of radioactive atoms with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent are considered as effective materials for such delivery processes. The DOTA chelator displays high affinity to radioactive metal isotopes and retains this capability after conjugation to tumor targeting moieties. Although the α-decay chains are well defined for many isotopes, the stability of chelations during the decay process and the impact of released energy on their structures remain unknown. The radioactive isotope 225Ac is an α-particle emitter that can be easily chelated by DOTA. However, 225Ac has a complex decay chain with four α-particle emissions during decay of each radionuclide. To advance our fundamental understanding of the consequences of α-decay on the stability of tumor-targeted 225Ac–DOTA conjugate radiopharmaceuticals, we performed first principles calculations of the structure, stability, and electronic properties of the DOTA chelator to the 225Ac radioactive isotope, and the initial daughters in the decay chain, 225Ac, 221Fr, 217At and 213Bi. Our calculations show that the atomic positions, binding energies, and electron localization functions are affected by the interplay between spin–orbit coupling, weak dispersive interactions, and environmental factors. Future empirical measurements may be guided and interpreted in light of these results

Biological and chemical assessment of zinc ageing in field soils

As zinc (Zn) is both an essential trace element and potential toxicant, the effects of Zn fixation in soil are of practical significance. Soil samples from four field sites amended with ZnSO4 were used to investigate ageing of soluble Zn under field conditions over a 2-year period. Lability of Zn measured using 65Zn radioisotope dilution showed a significant decrease over time and hence evidence of Zn fixation in three of the four soils. However, 0.01 M CaCl2 extractions and toxicity measurements using a genetically modified lux-marked bacterial biosensor did not indicate a decrease in soluble/bioavailable Zn over time. This was attributed to the strong regulatory effect of abiotic properties such as pH on these latter measurements. These results also showed that Zn ageing occurred immediately after Zn spiking, emphasising the need to incubate freshly spiked soils before ecotoxicity assessments. Ageing effects were detected in Zn-amended field soils using 65Zn isotopic dilution as a measure of lability, but not with either CaCl2 extractions or a lux-marked bacterial biosensor

Alkaline phosphatase in nasal secretion of cattle: biochemical and molecular characterisation

BACKGROUND: Nasal secretion (NS) was investigated as a source of information regarding the mucosal and systemic immune status of cattle challenged by respiratory disease. A method for the collection of substantial volumes (~12 ml) of NS from cattle was developed to establish a reference range of analytes that are present in the NS of healthy cattle. Biochemical profiles of NS from a group of 38 healthy Holstein-Friesian cows revealed high alkaline phosphatase (AP) activity of up to 2392 IU/L. The character and source of the high activity of AP in bovine NS was investigated. RESULTS: Histochemical analysis confirmed the localization of the AP enzyme activity to epithelial cells and serous glands of the nasal respiratory mucosa. Analysis of mRNA levels from nasal mucosa by end point RT-PCR and PCR product sequencing confirmed that the AP was locally produced and is identical at the nucleotide level to the non-specific AP splice variant found in bovine liver, bone and kidney. Analysis by isoelectric focussing confirmed that AP was produced locally at a high level in nasal epithelium demonstrating that AP from nasal secretion and nasal mucosa had similar pI bands, though differing from those of the liver, kidney, bone and intestine, suggesting different post-translational modification (PTM) of AP in these tissues. CONCLUSIONS: A nasal isozyme of AP has been identified that is present at a high activity in NS, resulting from local production and showing distinctive PTM and may be active in NS as an anti-endotoxin mediator

On the mass-radius relation of hot stellar systems

Most globular clusters have half-mass radii of a few pc with no apparent correlation with their masses. This is different from elliptical galaxies, for which the Faber-Jackson relation suggests a strong positive correlation between mass and radius. Objects that are somewhat in between globular clusters and low-mass galaxies, such as ultra-compact dwarf galaxies, have a mass-radius relation consistent with the extension of the relation for bright ellipticals. Here we show that at an age of 10 Gyr a break in the mass-radius relation at ~10^6 Msun is established because objects below this mass, i.e. globular clusters, have undergone expansion driven by stellar evolution and hard binaries. From numerical simulations we find that the combined energy production of these two effects in the core comes into balance with the flux of energy that is conducted across the half-mass radius by relaxation. An important property of this `balanced' evolution is that the cluster half-mass radius is independent of its initial value and is a function of the number of bound stars and the age only. It is therefore not possible to infer the initial mass-radius relation of globular clusters and we can only conclude that the present day properties are consistent with the hypothesis that all hot stellar systems formed with the same mass-radius relation and that globular clusters have moved away from this relation because of a Hubble time of stellar and dynamical evolution.Comment: 5 pages, 3 figures, MNRAS Letters (accepted

Parametrically forced sine-Gordon equation and domain walls dynamics in ferromagnets

A parametrically forced sine-Gordon equation with a fast periodic {\em mean-zero} forcing is considered. It is shown that $\pi$-kinks represent a class of solitary-wave solutions of the equation. This result is applied to quasi-one-dimensional ferromagnets with an easy plane anisotropy, in a rapidly oscillating magnetic field. In this case the $\pi$-kink solution we have introduced corresponds to the uniform ``true'' domain wall motion, since the magnetization directions on opposite sides of the wall are anti-parallel. In contrast to previous work, no additional anisotropy is required to obtain a true domain wall. Numerical simulations showed good qualitative agreement with the theory.Comment: 3 pages, 1 figure, revte

Total synthesis 2-epi-alpha-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Herein we target the total synthesis of 2-epi-alpha-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and delivers the complex tricyclic structure in just 10 minutes. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target

Assessment of hemodynamic indices of conjunctival microvascular function in patients with coronary microvascular dysfunction

Objective: Coronary microvascular dysfunction (CMD) is a cause of ischaemia with non-obstructive coronary arteries (INOCA). It is notoriously underdiagnosed due to the need for invasive microvascular function testing. We hypothesized that systemic microvascular dysfunction could be demonstrated non-invasively in the microcirculation of the bulbar conjunctiva in patients with CMD. Methods: Patients undergoing coronary angiography for the investigation of chest pain or dyspnoea, with physiologically insignificant epicardial disease (fractional flow reserve ≥0.80) were recruited. All patients underwent invasive coronary microvascular function testing. We compared a cohort of patients with evidence of CMD (IMR ≥25 or CFR &lt;2.0); to a group of controls (IMR &lt;25 and CFR ≥2.0). Conjunctival imaging was performed using a previously validated combination of a smartphone and slit-lamp biomicroscope. This technique allows measurement of vessel diameter and other indices of microvascular function by tracking erythrocyte motion. Results: A total of 111 patients were included (43 CMD and 68 controls). There were no differences in baseline demographics, co-morbidities or epicardial coronary disease severity. The mean number of vessel segments analysed per patient was 21.0 ± 12.8 (3.2 ± 3.5 arterioles and 14.8 ± 10.8 venules). In the CMD cohort, significant reductions were observed in axial/cross-sectional velocity, blood flow, wall shear rate and stress. Conclusion: The changes in microvascular function linked to CMD can be observed non-invasively in the bulbar conjunctiva. Conjunctival vascular imaging may have utility as a non-invasive tool to both diagnose CMD and augment conventional cardiovascular risk assessment.</p

MUSTANG 3.3 Millimeter Continuum Observations of Class 0 Protostars

We present observations of six Class 0 protostars at 3.3 mm (90 GHz) using the 64-pixel MUSTANG bolometer camera on the 100-m Green Bank Telescope. The 3.3 mm photometry is analyzed along with shorter wavelength observations to derive spectral indices (S_nu ~ nu^alpha) of the measured emission. We utilize previously published dust continuum radiative transfer models to estimate the characteristic dust temperature within the central beam of our observations. We present constraints on the millimeter dust opacity index, beta, between 0.862 mm, 1.25 mm, and 3.3 mm. Beta_mm typically ranges from 1.0 to 2.4 for Class 0 sources. The relative contributions from disk emission and envelope emission are estimated at 3.3 mm. L483 is found to have negligible disk emission at 3.3 mm while L1527 is dominated by disk emission within the central beam. The beta_mm^disk <= 0.8 - 1.4 for L1527 indicates that grain growth is likely occurring in the disk. The photometry presented in this paper may be combined with future interferometric observations of Class 0 envelopes and disks.Comment: 19 pages, 3 figures, AJ accepted, in pres

The National Childrens Study: An Introduction and Historical Overview

The National Children’s Study (NCS) was an ambitious attempt to map children’s health and development in a large representative group of children in the United States. In this introduction, we briefly review the background of the NCS and the history of the multiple strategies that were tested to recruit women and children. Subsequent articles then detail the protocols and outcomes of 4 of the recruitment strategies. It is hoped that lessons learned from these attempts to define a study protocol that could achieve the initial aims of the NCS will inform future efforts to conceptualize and execute strategies to provide generalizable insights on the longitudinal health of our nation’s children