Some studies on chlorocuprates

The work in this thesis is concerned with alkylammonium chlorocuprates and their solid solutions. The stoichiometries and structures of various chlorocuprate anions are considered in terms of the influence of the size and shape of the cation on the compounds formed. The determination of the structure of (Me3NH)3 Cu2 C17 by X-ray crystallography is described; it is unusual because it contains two distinct chlorocuprate anions, CUC14 2-tetrahedra and (CUC13-)n chains. The symmetry of the CuC142- tetrahedron is approximately C3v, and this is attributed to the effect of the packing of (CuC13-)n chains, together with interactions between CuC142- and the cations. The CuC12- 2- 2- 4 ion in this compound is replaceable by CoC14 and ZnC14 ' while the (CuC13-)n chains are not disturbed. This led to a consideration of the possible effects of replacing the Jahn-Teller distorted ion in simple tetrachlorocuprates by ions not affected by this distortion, and hence to the preparation of solid 'solutions A2 (M,M' )C14. The formation of solid solutions from a system of two salts having a common ion and a solvent is discussed, with particular emphasis on systems which deviate from ideal behaviour. The preparations of solid solutions (Me4N)2(Cu,Co)C14, (Me4N)2(Cu,Zn)C14 and Me4N)2(Co,Zn)Cl4 from ethanol and water are described, and related to the general conditions for solid solution formation. Solid solutions (Me3NH)3Cu(Cu,Co)C17 are also given. Differential scanning calorimetry has been used in an attempt to elucidate the nature of the thermal transitions in (Me4N)2MC14 and in the solid solutions. The crystal structures of (Me4N)2CuC14, and (Me4N)2(Cu,Co)C14 (Cu:Co = 1:1) have been determined, and compared with that of (Me4N)2CoC14' It has been . 2- 2- shown that CuC14 and CoC14 each retain their characteristic configuration in the solid solution, so that CuC142- is the more distorted, because of the Jahn-Teller effect

Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation

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

Discovery of inhibitors of the pentein superfamily protein dimethylarginine dimethylaminohydrolase (DDAH), by virtual screening and hit analysis

Original article can be found at: http://www.sciencedirect.com/science/journal/0960894X--Copyright Elsevier Ltd. DOI : 10.1016/j.bmcl.2007.04.095Peer reviewe