A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

Funder: Allergan Incorporated (now AbbVie)INTRODUCTION: This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day. METHODS: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition. RESULTS: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7-21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post-dose, HTL0018318-related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up-titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints. DISCUSSION: HTL0018318 was well tolerated in mild-to-moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil

The Anatomy of Memory Politics: A Formalist Analysis of Tate Britain’s ‘Artist and Empire’ and the Struggle over Britain’s Imperial Past

In this paper, I propose a new approach for understanding the meaning of memory politics, which draws upon the archetypal literary criticism of Northrop Frye. I suggest that the four archetypes elaborated by Frye—comedy, romance, tragedy, and satire—can be used as a heuristic device for interpreting the contested historical narratives that are associated with the politics of memory. I illustrate this approach through a case-study of Artists and Empire: Facing Britain’s Imperial Past, an exhibition held at Tate Britain in 2016, amidst increasing contestation over the meaning of the British Empire. In sum, I find that the exhibit narrated Britain’s imperial past as a comedy, in which a key theme was the progressive cultural mixing of the British and the people they colonized. To conclude, I discuss the implications of such a narrative for constructing an inclusive, postcolonial British identity. As an alternative, I draw on Aristotle to suggest that a tragic narrative would have been more propitious

Disease: A Hitherto Unexplored Constraint on the Spread of Dogs (Canis lupus familiaris) in Pre-Columbian South America

Although debate continues, there is agreement that dogs (Canis lupus familiaris) were first domesticated in Eurasia, spreading from there to other parts of the world. However, while that expansion already extended as far as Europe, China, and North America by the early Holocene, dogs spread into (and south of) the tropics only much later. In South America, for example, the earliest well attested instances of their presence do not reach back much beyond 3000 cal. BC, and dogs were still absent from large parts of the continent – Amazonia, the Gran Chaco, and much of the Southern Cone – at European contact. Previous explanations for these patterns have focused on cultural choice, the unsuitability of dogs for hunting certain kinds of tropical forest prey, and otherwise unspecified environmental hazards, while acknowledging that Neotropical lowland forests witness high rates of canine mortality. Building on previous work in Sub-Saharan Africa (Mitchell 2015) and noting that the dog’s closest relatives, the grey wolf (C. lupus) and the coyote (C. latrans), were likewise absent from South and most of Central America in Pre- Columbian times, this paper explores instead the possibility that infectious disease constrained the spread of dogs into Neotropical environments. Four diseases are considered, all likely to be native and/or endemic to South America: canine distemper, canine trypanosomiasis, canine rangeliosis, and canine visceral leishmaniasis caused by infection with Leishmania amazonensis and L. colombiensis. The paper concludes by suggesting ways in which the hypothesis that disease constrained the expansion of dogs into South America can be developed further

The biotransformation of t-butylacetonitrile and its boron-containing analogue trimethylamine-cyanoborane by Brevibacterium R312

The ability of the nitrile hydratase/amidase system from Brevibacterium R312 to biotransform tert-butylacetonitrile was studied with a view to their utilisation in the production of novel amino acids from isostructural compounds. Brevibacterium R312 was able to transform nitriles with this structure; however, the wide spectrum amidase from this organism was unable to biotransform the corresponding amide to the carboxlic acid