Synthesis and Evaluation of New Ligands for Gallium Radiolabelling

A series of N3O3 triaza-tricarboxylate hexadentate ligands, based on the 6-amino-1,4-diazepine scaffold, has been designed and synthesised. An investigation of the suitability of these ligands towards application in 68Ga-PET has been conducted, with particular focus on the efficiency and efficacy of radiolabelling. Subsequently, selectivity for Ga(III) over other relevant cations has been studied, along with exploration of the kinetics of radiolabelling, stability and in vivo behaviour of the radiolabelled complexes in healthy rats. The four best candidates quantitatively radiolabel within three minutes at room temperature over the pH range 4 – 7, to give a single 68Ga-radiolabelled species which is sufficiently stable for in vivo application. As a result, these compounds are very promising candidates for use as ligands in 68Ga-PET. Decoration of the AMPED scaffold amine functionalities yielded a series of chelators, which allowed the 68Ga-radiolabelling properties of this family of ligands to be investigated. The ligands have a mixture of acyclic and cyclic properties, which facilitated rapid binding of the metal and formation of a stable complex. Synthetic details and 1H NMR solution state properties are described. With respect to radiolabelling, the best ligands were those with the least sterically demanding exocyclic amine substituents. However, ligands featuring a mono-alkylated exocyclic amine were prone to internal lactamisation under acidic conditions, which rendered these compounds ineffectual as ligands for 68Ga. The synthesis and radiochemical evaluation of an additional series of ligands, featuring a modified core structure, designed to inhibit the lactamisation reaction and promote ‘pre-organisation’ of the ligand donors were undertaken. The synthetic methodology developed allows for selective functionalisation of the different amine groups of the ring. Modification of the AMPED core by substitution of the tertiary methyl group for a phenyl moiety increased the steric bulk close to exocyclic amine, which inhibited internal lactamisation. Critically, the methyl-for-phenyl substitution does not have a detrimental effect on the complexation properties. Finally a study was undertaken of the radiolabelled complex speciation, using NMR spectroscopy and X-ray crystallography. The presence of multiple radiolabelled complex species was attributed to the formation of kinetically trapped complexes of differing stability. The relative population of the two major ligand conformations is controlled by the relative steric demand of the substituents at the quaternary site. The exocyclic amine is subject to protonation (pKa 5.7), and therefore the relative population of the ligand conformers is pH dependent over the range 3 – 7. By substituting the methyl group for a more sterically demanding phenyl group, the population of the ligand conformation favouring fast and stable gallium binding was increased

Isothiocyanate ligand derivatives of platinum(II) terpyridines.

Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.The novel compounds [Pt(trpy)(NCS)]SbF6 (1) and [Pt{4'-(Ph)trpy}(NCS)]SbF6 (2) where trpy = 2,2':6',2''-terpyridine, have been synthesised and characterised by means of elemental analysis, infrared and 1H NMR spectroscopy, and mass spectroscopy. Compounds 1 and 2 were also prepared with the labelled S13C15N¯ ion as co-ligand; their 13C and 15N NMR spectra recorded at room temperature in CD3CN show that the ambidentate ion is coordinated to the Pt atom mainly (~ 95%) through the N atom, but that a small amount of the S-bound isomer also co-exists in an acetonitrile solution. The synthesis of 1 is preceded by the isolation of yellow 1·CH3CN?Y (Y = yellow) for which the crystal structure has been determined by single crystal X-ray diffraction; this shows that the SCN¯ ion is linearly bound to the Pt atom through the N atom in the solid state, and that the cation is planar. The solvate rapidly loses acetonitrile to form maroon 1-M (M = maroon). The maroon compound exhibits 3MMLCT (metal-metal-to-ligand charge transfer) emission in the solid state as evidenced by a red-shift in the emission maximum from 653 nm at 473 K to 770 nm at 80 K. However, there are anomalous changes in the emission intensity below 200 K; this phenomenon is explained in terms of competitive emission by defect sites in the material. Interestingly, 1-M displays thermochromic behaviour (accompanied by phase changes at Ts > 473 K) that have been documented over the temperature range 80-548 K by means of photography, emission spectral and powder X-ray diffraction measurements. Compound 1-M also exhibits selective and reversible vapochromic behaviour with acetonitrile, DMF and pyridine – the solvates are yellow. We also report solvent specific changes in the emission spectra between 1-M and its acetonitrile, DMF and pyridine solvates. The thermo- and vapochromism of 1-M are linked to the making and breaking of metallophilic Pt...Pt interactions that occur when the planar cations slide in and out of different positions with respect to each other in a π-stack. Single crystals of compound 2 are isolated by desolvation of single crystals of 2·CH3CN. The single-crystal to single-crystal transformation is easily reversed by exposing 2 to vapours of acetonitrile, as confirmed by X-ray structure determinations of 2 and 2·CH3CN performed on the same single crystal. These show that the SCN¯ ion is linearly bound to the Pt atom through the N atom and that the cation is nearly planar. Significantly, there are only very small changes in the cation and anion atom positions between 2 and 2·CH3CN; thus, single crystals of 2 have a porous metal-organic structure with solvent accessible voids/channels. As such, 2 also sorbs methanol and acetone molecules from the vapour phase, the former without loss of single crystallinity, as confirmed by an X-ray crystal structure determination of 2·CH3OH. Single crystals of 2·(CH3)2CO were obtained by direct crystallization from acetone and an X-ray structure determination performed. Interestingly, a single crystal 2·(CH3)2CO desolvates under ambient conditions to give a single crystal of 2 with the original porous metal-organic crystal structure; on the other hand 2·CH3OH does not readily desolvate because of O─H◦◦◦S hydrogen-bonding. Compound 2 and its solvates are yellow, as expected, since the planar cations hardly move on solvent uptake – in marked contrast to the easily moved cations in 1─M – suggestions as to why are given. Finally, we report the solid state photoluminescence (measured at 77 K) of 2, 2·CH3CN, 2·CH3OH, 2·(CH3)2CO and 2·CH3OH_DS where DS denotes desolvation of the methanol solvate. Emission from 2 is characterised by dual emission from 3MLCT (metal-to-ligand charge transfer) and excimeric 3(π-π*) excited states; with the latter being the predominant origin of emission at 77 K. On the other hand, the 2·CH3CN and 2·(CH3)2CO solvates give well defined monomeric 3MLCT emission exclusively. The excimeric emission is representative of the cation packing arrangement in the crystal lattice, and the fact that it is not observed for 2·CH3CN and 2·(CH3)2CO is probably a result of an increase in the potential energy barrier to the formation of excimers when free space is occupied by CH3CN or (CH3)2CO included in the crystal lattice. Emission by 2·CH3OH and 2·CH3OH_DS is further complicated by 3MMLCT emission that arises because of dz2(Pt)-dz2(Pt) orbital interactions present in the solid. As a result multiple emission from 3MLCT, excimeric and 3MMLCT excited states is observed for 2·CH3OH and 2·CH3OH_DS

X-Atlas: An Online Archive of Chandra's Stellar High Energy Transmission Gratings Observations

The high-resolution X-ray spectroscopy made possible by the 1999 deployment of the Chandra X-ray Observatory has revolutionized our understanding of stellar X-ray emission. Many puzzles remain, though, particularly regarding the mechanisms of X-ray emission from OB stars. Although numerous individual stars have been observed in high-resolution, realizing the full scientific potential of these observations will necessitate studying the high-resolution Chandra dataset as a whole. To facilitate the rapid comparison and characterization of stellar spectra, we have compiled a uniformly processed database of all stars observed with the Chandra High Energy Transmission Grating (HETG). This database, known as X-Atlas, is accessible through a web interface with searching, data retrieval, and interactive plotting capabilities. For each target, X-Atlas also features predictions of the low-resolution ACIS spectra convolved from the HETG data for comparison with stellar sources in archival ACIS images. Preliminary analyses of the hardness ratios, quantiles, and spectral fits derived from the predicted ACIS spectra reveal systematic differences between the high-mass and low-mass stars in the atlas and offer evidence for at least two distinct classes of high-mass stars. A high degree of X-ray variability is also seen in both high and low-mass stars, including Capella, long thought to exhibit minimal variability. X-Atlas contains over 130 observations of approximately 25 high-mass stars and 40 low-mass stars and will be updated as additional stellar HETG observations become public. The atlas has recently expanded to non-stellar point sources, and Low Energy Transmission Grating (LETG) observations are currently being added as well

Misinformation as Immigration Control

It is wrong to force refugees to return to the countries they fled from. It is similarly wrong, many argue, to force migrants back to countries with life-threatening conditions. I argue that it is additionally wrong to help such refugees and migrants voluntarily return whilst failing to inform them of the risks. Drawing on existing data, and original data from East Africa, I describe distinct types of cases where such a wrong arises. In ‘Misinformation Cases’ officials tell refugees that it is safe to return, when it is not, and refugees return who would have otherwise stayed. In ‘Omission Cases’ officials do not provide any information on countries of origin, and this omission causes refugees to repatriate. In ‘Relevancy Cases’ refugees are misinformed or uninformed, but would have returned even if better informed. In all of these cases, at least some state officials are blameworthy for their failure to inform refugees, and are engaging in a form of wrongful immigration control

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead