Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

A flexible mathematical model platform for studying branching networks : experimentally validated using the model actinomycete, Streptomyces coelicolor

Branching networks are ubiquitous in nature and their growth often responds to environmental cues dynamically. Using the antibiotic-producing soil bacterium Streptomyces as a model we have developed a flexible mathematical model platform for the study of branched biological networks. Streptomyces form large aggregates in liquid culture that can impair industrial antibiotic fermentations. Understanding the features of these could aid improvement of such processes. The model requires relatively few experimental values for parameterisation, yet delivers realistic simulations of Streptomyces pellet and is able to predict features, such as the density of hyphae, the number of growing tips and the location of antibiotic production within a pellet in response to pellet size and external nutrient supply. The model is scalable and will find utility in a range of branched biological networks such as angiogenesis, plant root growth and fungal hyphal networks

The babel of drugs: On the consequences of evidential pluralism in pharmaceutical regulation and regulatory data journeys

This is the final version. Available on open access from Springer via the DOI in this recordThroughout the last century, pharmaceutical regulators all over the world have used various methods to test medical treatments. From 1962 until 2016, the Randomized Clinical Trial (RCT) was the reference test for most regulatory agencies. Today, the standards are about to change, and in this chapter we draw on the idea of the data journey to illuminate the trade-offs involved. The 21st Century Cures Act (21CCA) allows for the use of Electronic Health Records (EHRs) for the assessment of different treatment indications for already approved drugs. This might arguably shorten the testing period, bringing treatments to patients faster. Yet, EHR are not generated for testing purposes and no amount of standardization and curation can fully make up for their potential flaws as evidence of safety and efficacy. The more noise in the data, the more mistakes regulators are likely to make in granting market access to new drugs. In this paper we will discuss the different dimensions of this journey: the different sources and levels of curation involved, the speed at which they can travel, and the level of risk of regulatory error involved as compared with the RCT standard. We are going to defend that what counts as evidence, at the end of the journey, depends on the risk definition and threshold regulators work with.European Research Council (ERC)Engineering and Physical Sciences Research Council (EPSRC

Isomeric iodo-N-(nitrobenzyl)anilines: interplay of hard and soft hydrogen bonds, iodo...nitro interactions and aromatic π...π stacking interactions

Molecules of 2-iodo-N-(4-nitrobenzyl) aniline, 4-O2NC6H4CH2NHC6H4I- 2' (1) are linked into chains by C-H...O hydrogen bonds. In the isomeric compound 3-iodo-N( 4-nitrobenzyl) aniline (2) a combination of N - H...O and C - H...O hydrogen bonds and iodo ... nitro and aromatic pi...pi stacking interactions links the molecules into a three-dimensional framework structure. The two-dimensional supramolecular structure of 4-iodo-N-(4-nitrobenzyl) aniline ( 6) is built from a combination of C - H ... O and N-H...pi(arene) hydrogen bonds and aromatic pi...pi stacking interactions. 2-Iodo-N-(2-nitrobenzyl) aniline (7) crystallizes with two molecules in the asymmetric unit and these molecules are linked into ladders by a combination of N H H...O and C - H ... O hydrogen bonds and iodo ... nitro and aromatic pi...pi stacking interactions. Comparisons are made between the supramolecular structures of these compounds and those of other isomers, in terms both of the types of direction-specific intermolecular interactions exhibited and the dimensionality of the resulting supramolecular structures.</p

2-Iodobenzylidene-3'-nitroaniline: sheets formed by a combination of C-H...O hydrogen bonds and two aromatic m stacking interactions

Molecules of the title compound, C13H9IN2O2, are linked into [010] chains by a single C-H...O hydrogen bond and these chains are linked into (100) sheets by two independent aromatic pi-pi-stacking interactions, each involving one of the two substituted arene rings.</p

Hydrogen-bonded Molecular Ladders in trans-1,2-Bis-(2-nitroanilino)cyclohexane

Crystals of the title compound, C18H20N4O4, contain equal numbers of (R,R) and(S,S) molecules, but these are not precise enantiomorphs, neither are they related by crystallographic symmetry; in addition, each molecule exhibits approximate, but not exact, twofold rotational symmetry. There are intramolecular N-H ... O hydrogen bonds [N ... O 2.609 (4)-2.638 (5) Angstrom; N-H ... O 125-132 degrees] and the molecules are linked into molecular ladders by C-H ... O hydrogen bonds [C ... O 3.306 (6)-3.386 (6) Angstrom; C-H ... O 146-160 degrees].</p