Arthur Lindo Patterson, his function and element preferences in early crystal structures

In 1934, Arthur Lindo Patterson showed that a map of interatomic vectors is obtainable from measured X-ray diffraction data without phase information. Such maps were interpretable for simple crystal structures, but proliferation and overlapping of peaks caused confusion as the number of atoms increased. Since the peak height of a vector between two particular atoms is related to the product of their atomic numbers, a complicated structure could effectively be reduced to a simple one by including just a few heavy atoms (of high atomic number) since their interatomic vectors would stand out from the general clutter. Once located, these atoms provide approximate phases for Fourier syntheses that reveal the locations of additional atoms. Surveys of small-molecule structures in the Cambridge Structural Database during the periods 1936-1969, when Patterson methods were commonly used, and 1980-2013, dominated by direct methods, demonstrate large differences in the abundance of certain elements. The moderately heavy elements K, Rb, As and Br are the heaviest elements in the structure more than 3 times as often in the early period than in the recent period. Examples are given of three triumphs of the heavy atom method and two initial failures that had to be overcome

Molecular subclassification of medulloblastoma and its utility for disease prognostication

Medulloblastoma is the most common malignant brain tumour of childhood. Transcriptomic classification of the disease has indicated the existence of discrete molecular subgroups of medulloblastoma, although the precise number, nature and clinical significance of these subgroups remains unclear. Two groups, characterised by activation of the WNT and SHH signalling pathways, are common to all published studies. An assay for the rapid diagnosis of medulloblastoma subgroups was therefore designed, using transcriptomic gene signatures of pathway activation for the WNT and SHH signalling pathways. The successful validation of these gene signatures in vitro and in silico enabled a meta-analysis of 173 new and published cases to be performed, which defined the molecular and clinico-pathological correlates of the disease subgroups more precisely. WNT subgroup cases were associated with CTNNB1 mutation, chromosome 6 loss and classic histology and were diagnosed > 5 years of age. SHH cases predominated in infants and showed an age-dependent relationship to desmoplastic / nodular histology. WNT / SHH independent tumours showed all histologies, peaked at 3 to 6 years and were associated with chromosome 17p loss. A novel DNA methylation array-based approach was next applied to disease subclassification. Using consensus clustering, based on non-negative matrix factorisation, four methylomic subgroups were identified in a training cohort (n = 100), which were robustly validated in a test cohort (n = 130). The subgroups were characterised by significant relationships to specific clinico-pathological and molecular markers. Two subgroups were characterised by activation of the WNT and SHH signalling pathways and showed equivalent clinico-pathological and molecular characteristics to the previously defined transcriptomic subgroups. For the WNT / SHH independent subgroups, group I was associated with a loss of chromosome 17p, whereas group II was enriched for large cell / anaplastic (LCA) histology. The WNT subgroup was associated with a favourable prognosis, while no survival differences were apparent between the remaining subgroups (SHH, group I, group II). Specific methylation biomarkers were identified for the discrimination of all subgroups. Assays of DNA methylation status were robust in derivatives of FFPE tissues, enabling testing in routinely-collected clinical material. Finally, the prognostic potential of methylomic biomarkers was investigated in a large clinical trials-based cohort (n = 191), with particular focus on the non-WNT subgroups (n = 163), where subgroup membership was not prognostic. Using the Cox Boost algorithm, which adds high dimensional data to mandatory clinical covariates to form cross-validated prognostic Cox survival models, the methylation status of MXI1 and IL8 were each identified as independent prognostic markers. These were incorporated into a novel risk stratification scheme, based on the cumulative assessment of disease risk using clinical (metastatic disease; poor prognosis), pathological (LCA pathology, poor prognosis) and methylomic variables (WNT subgroup, favourable prognosis; MXI1 and IL8 status). Importantly, this scheme assigns 46% of cases to a low risk group of patients (>90% survival) who could potentially be treated less intensively, with the aim of reducing therapy-associated late effects. This model out-performed the current clinical and other state-of-the-art medulloblastoma risk classification schemes. These data provide clear precedent for the utility of DNA methylation biomarkers for disease subclassification and prognostication in medulloblastoma, and their clinical application in diagnostic tumour biopsies.EThOS - Electronic Theses Online ServiceKatie TrustGBUnited Kingdo

Zur Kenntnis der Hydro- und Hydratcellulosen

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Spritgewinnung aus den Ablaugen der Zellstoffabrikation

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Fe III in a low-spin state in caesium bis[3-ethoxysalicylaldehyde 4-methylthiosemicarbazonato(2–)-κ3O2,N1,S]ferrate(III) methanol monosolvate

The synthesis and crystal structure (at 100K) of the title compound, Cs[Fe(C11H13N3O2S2) 2] CH3OH, is reported. The asymmetric unit consists of an octahedral [FeIII(L)2]- fragment, where L 2- is 3-ethoxysalicylaldehyde 4-methylthiosemicarbazonate(2-) {systematic name: [2-(3-ethoxy-2-oxidobenzylidene)hydrazin-1-ylidene] (methylamino)methanethiolate}, a caesium cation and a methanol solvent molecule. Each L2- ligand binds through the thiolate S, the imine N and the phenolate O atoms as donors, resulting in an FeIIIS2N 2O2 chromophore. The O,N,S-coordinating ligands are orientated in two perpendicular planes, with the O and S atoms in cis positions and the N atoms in trans positions. The FeIII cation is in the low-spin state at 100K

Analysis of Listeria using exogenous volatile organic compound metabolites and their detection by static headspace–multi-capillary column–gas chromatography–ion mobility spectrometry (SHS–MCC–GC–IMS)

Listeria monocytogenes is a Gram-positive bacterium and an opportunistic food-borne pathogen which poses significant risk to the immune-compromised and pregnant due to the increased likelihood of acquiring infection and potential transmission of infection to the unborn child. Conventional methods of analysis suffer from either long turn-around times or lack the ability to discriminate between Listeria spp. reliably. This paper investigates an alternative method of detecting Listeria spp. using two novel enzyme substrates that liberate exogenous volatile organic compounds in the presence of α-mannosidase and d-alanyl aminopeptidase. The discriminating capabilities of this approach for identifying L. monocytogenes from other species of Listeria are investigated. The liberated volatile organic compounds (VOCs) are detected using an automated analytical technique based on static headspace–multi-capillary column–gas chromatography–ion mobility spectrometry (SHS–MCC–GC–IMS). The results obtained by SHS–MCC–GC–IMS are compared with those obtained by the more conventional analytical technique of headspace–solid phase microextraction–gas chromatography–mass spectrometry (HS–SPME–GC–MS). The results found that it was possible to differentiate between L. monocytogenes and L. ivanovii, based on their VOC response from α-mannosidase activity

Caesium bis­(5-bromo­salicyl­aldehyde thio­semicarbazonato-κ3O,N,S)ferrate(III): supramolecular arrangement of low-spin FeIII complex anions mediated by Cs+ cations

The synthesis and crystal structure determination (at 293 K) of the title complex, Cs[Fe(C8H6BrN3OS)2], are reported. The compound is composed of two dianionic O,N,S-tridentate 5-bromo­salicyl­aldehyde thio­semicarbazonate(2-) ligands coord­inated to an FeIII cation, displaying a distorted octa­hedral geometry. The ligands are orientated in two perpendicular planes, with the O- and S-donor atoms in cis positions and the N-donor atoms in trans positions. The complex displays inter­molecular N-H...O and N-H...Br hydrogen bonds, creating R44(18) rings, which link the FeIII units in the a and b directions. The FeIII cation is in the low-spin state at 293 K

A concise synthesis of isoguanine 2’-deoxyriboside and its adenine-like triplex formation when incorporated into DNA

A concise synthesis of 2’-deoxyisoguanosine is achieved whereby 2,6-dichloropurine is glycosylated using the Hoffer sugar to give a pair of beta-configured nucleoside N9/N7 regioisomers that are aminated using methanolic ammonia with concomitant deprotection of the sugar. Following chromatographic separation, pure 2-chloro-2’-deoxyadenosine was isolated as a single isomer. Displacement of the C2 chlorine atom using sodium benzyloxide, followed by hydrogenolysis of the benzyl group, gives 2’-deoxyisoguanosine. Isoguanine was incorporated into DNA by solid supported synthesis using the suitably protected 2-allyloxy-2’-deoxyadenosine phosphoramidite with the allyl group being removed post-oligomerisation under Noyori conditions. DNA melting studies showed isoguanine to exhibit adenine-like triplex formation

Lars Vegard:key communicator and pioneer crystallographer

The Norwegian physicist Lars Vegard studied with William H. Bragg in Leeds and then with Wilhelm Wien in Würzburg. There, in 1912, he heard a lecture by Max Laue describing the first X-ray diffraction experiments and took accurate notes which he promptly sent to Bragg. Although now remembered mainly for his work on the physics of the aurora borealis, Vegard also did important pioneering work in three areas of crystallography. He derived chemical insight from a series of related crystal structures that he determined, Vegard's Law relates the unit-cell dimensions of mixed crystals to those of the pure components, and he determined some of the first crystal structures of gases solidified at cryogenic temperatures

Evaluation of analogues of furan-amidines as inhibitors of NQO2

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 μM