The 10,000-year biocultural history of fallow deer and its implications for conservation policy.

Over the last 10,000 y, humans have manipulated fallow deer populations with varying outcomes. Persian fallow deer (Dama mesopotamica) are now endangered. European fallow deer (Dama dama) are globally widespread and are simultaneously considered wild, domestic, endangered, invasive and are even the national animal of Barbuda and Antigua. Despite their close association with people, there is no consensus regarding their natural ranges or the timing and circumstances of their human-mediated translocations and extirpations. Our mitochondrial analyses of modern and archaeological specimens revealed two distinct clades of European fallow deer present in Anatolia and the Balkans. Zooarchaeological evidence suggests these regions were their sole glacial refugia. By combining biomolecular analyses with archaeological and textual evidence, we chart the declining distribution of Persian fallow deer and demonstrate that humans repeatedly translocated European fallow deer, sourced from the most geographically distant populations. Deer taken to Neolithic Chios and Rhodes derived not from nearby Anatolia, but from the Balkans. Though fallow deer were translocated throughout the Mediterranean as part of their association with the Greco-Roman goddesses Artemis and Diana, deer taken to Roman Mallorca were not locally available Dama dama, but Dama mesopotamica. Romans also initially introduced fallow deer to Northern Europe but the species became extinct and was reintroduced in the medieval period, this time from Anatolia. European colonial powers then transported deer populations across the globe. The biocultural histories of fallow deer challenge preconceptions about the divisions between wild and domestic species and provide information that should underpin modern management strategies.

Molecular archaeoparasitology identifies cultural changes in the Medieval Hanseatic trading centre of Lübeck.

Throughout history, humans have been afflicted by parasitic worms, and eggs are readily detected in archaeological deposits. This study integrated parasitological and ancient DNA methods with a large sample set dating between Neolithic and Early Modern periods to explore the utility of molecular archaeoparasitology as a new approach to study the past. Molecular analyses provided unequivocal species-level parasite identification and revealed location-specific epidemiological signatures. Faecal-oral transmitted nematodes (Ascaris lumbricoides and Trichuris trichiura) were ubiquitous across time and space. By contrast, high numbers of food-associated cestodes (Diphyllobothrium latum and Taenia saginata) were restricted to medieval Lübeck. The presence of these cestodes and changes in their prevalence at approximately 1300 CE indicate substantial alterations in diet or parasite availability. Trichuris trichiura ITS-1 sequences grouped into two clades; one ubiquitous and one restricted to medieval Lübeck and Bristol. The high sequence diversity of T.tITS-1 detected in Lübeck is consistent with its importance as a Hanseatic trading centre. Collectively, these results introduce molecular archaeoparasitology as an artefact-independent source of historical evidence.

Design, synthesis and biological evaluation of non-natural modulators of quorum sensing in Pseudomonas aeruginosa.

Many species of bacteria employ a mechanism of intercellular communication known as quorum sensing which is mediated by small diffusible signalling molecules termed autoinducers. The most common class of autoinducer used by Gram-negative bacteria are N-acylated-L-homoserine lactones (AHLs). Pseudomonas aeruginosa is a clinically important bacterium which is known to use AHL-mediated quorum sensing systems to regulate a variety of processes associated with virulence. Thus the selective disruption of AHL-based quorum sensing represents a strategy to attenuate the pathogenicity of this bacterium. Herein we describe the design, synthesis and biological evaluation of a collection of structurally novel AHL mimics. A number of new compounds capable of modulating the LasR-dependent quorum sensing system of P. aeruginosa were identified, which could have value as molecular tools to study and manipulate this signalling pathway. Worthy of particular note, this research has delivered novel potent quorum sensing antagonists, which strongly inhibit the production of virulence factors in a wild type strain of this pathogenic bacterium.

Reconstructing the history of helminth prevalence in the UK.

Intestinal helminth parasites (worms) have afflicted humans throughout history and their eggs are readily detected in archaeological deposits including at locations where intestinal parasites are no longer considered endemic (e.g. the UK). Parasites provide valuable archaeological insights into historical health, sanitation, hygiene, dietary and culinary practices, as well as other factors. Differences in the prevalence of helminths over time may help us understand factors that affected the rate of infection of these parasites in past populations. While communal deposits often contain relatively high numbers of parasite eggs, these cannot be used to calculate prevalence rates, which are a key epidemiological measure of infection. The prevalence of intestinal helminths was investigated through time in England, based on analysis of 464 human burials from 17 sites, dating from the Prehistoric to Industrial periods. Eggs from two faecal-oral transmitted nematodes (Ascaris sp. and Trichuris sp.) and the food-derived cestodes (Taenia spp. and Diphyllobothrium latum syn Dibothriocephalus latus) were identified, although only Ascaris was detected at a high frequency. The changing prevalence of nematode infections can be attributed to changes in effective sanitation or other factors that affect these faecal-oral transmitted parasites and the presence of cestode infections reflect dietary and culinary preferences. These results indicate that the impact of helminth infections on past populations varied over time, and that some locations witnessed a dramatic reduction in parasite prevalence during the industrial era (18th-19th century), whereas other locations continued to experience high prevalence levels. The factors underlying these reductions and the variation in prevalence provide a key historical context for modern anthelmintic programs.

Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening.

The screening of large arrays of drug-like small-molecules was traditionally a time consuming and resource intensive task. New methodology developed within our laboratories provides an attractive low cost, 3D microarray-assisted screening platform that could be used to rapidly assay thousands of compounds. As a proof-of-principle the platform was exploited to screen a number of quorum sensing analogs. Quorum sensing is used by bacterium to initiate and spread infection; in this context its modulation may have significant clinical value. 3D microarray slides were probed with fluorescently labeled ligand-binding domains of the LuxR homolog CarR from Erwinia carotovora subsp. carotovora. The 3D microarray platform was used to discover the biologically active chloro-pyridine pharmacophore, which was validated using a fluorometric ligand binding assay and ITC. Analogs containing the chloro-pyridine pharmacophore were found to be potent inhibitors of N-acyl-homoserine-lactone (AHL) mediated quorum sensing phenotypes in Serratia (IC(50) = ∼5 µM) and Pseudomonas aeruginosa (IC(50) = 10-20 µM).

Epidemiological insights from a large-scale investigation of intestinal helminths in Medieval Europe.

Helminth infections are among the World Health Organization's top neglected diseases with significant impact in many Less Economically Developed Countries. Despite no longer being endemic in Europe, the widespread presence of helminth eggs in archaeological deposits indicates that helminths represented a considerable burden in past European populations. Prevalence of infection is a key epidemiological feature that would influence the elimination of endemic intestinal helminths, for example, low prevalence rates may have made it easier to eliminate these infections in Europe without the use of modern anthelminthic drugs. To determine historical prevalence rates we analysed 589 grave samples from 7 European sites dated between 680 and 1700 CE, identifying two soil transmitted nematodes (Ascaris spp. and Trichuris trichiura) at all locations, and two food derived cestodes (Diphyllobothrium latum and Taenia spp.) at 4 sites. The rates of nematode infection in the medieval populations (1.5 to 25.6% for T. trichiura; 9.3-42.9% for Ascaris spp.) were comparable to those reported within modern endemically infected populations. There was some evidence of higher levels of nematode infection in younger individuals but not at all sites. The genetic diversity of T. trichiura ITS-1 in single graves was variable but much lower than with communal medieval latrine deposits. The prevalence of food derived cestodes was much lower (1.0-9.9%) than the prevalence of nematodes. Interestingly, sites that contained Taenia spp. eggs also contained D. latum which may reflect local culinary practices. These data demonstrate the importance of helminth infections in Medieval Europe and provide a baseline for studies on the epidemiology of infection in historical and modern contexts. Since the prevalence of medieval STH infections mirror those in modern endemic countries the factors affecting STH decline in Europe may also inform modern intervention campaigns.

Doubly diastereoselective [3,3]-sigmatropic aza-Claisen rearrangements.

The doubly diastereoselective [3,3]-sigmatropic aza-Claisen rearrangement of silylketene aminals derived from 5-substituted (3S,4E,alphaR)-1-benzyloxy-3-[N-acyl-N-(alpha-methylbenzyl)amino]pent-4-enes furnishes 2,3-disubstituted (R)-N-alpha-methylbenzyl (2S,3R,4E)-7-benzyloxyhept-4-enamides in >90% de under the "matched" control of both stereogenic centres. Rearrangement of the "mismatched" diastereomeric (3R,4E,alphaR)-substrates proceeds with low diastereoselectivity. The substrate scope of the doubly diastereoselective rearrangement of the "matched" substrates in which two new stereogenic centres are created has been delineated.

Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units.

As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a range of homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding beta-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral alpha,beta-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral alpha,beta-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the beta-amino ester products of conjugate addition gives access to polyoxygenated beta-amino acid derivatives.

Fluorous tagged small molecule microarrays.

The affinity fluorous interaction between fluorous tagged small molecules and a fluoroalkyl modified glass surface was shown to facilitate the detection of protein-ligand binding interactions in the fabrication and screening of small molecule microarrays.

Components of task-set reconfiguration: differential effects of 'switch-to' and 'switch-away' cues.

Preparation for a switch in task was manipulated using two types of switch cues: 'switch-away' from the previous task-set and 'switch-to' a different task-set. Increasing cue-stimulus interval resulted in a reduction in reaction time switch cost for switch-to trials only. Cue-locked difference waveforms for both switch-to and switch-away trials showed a large, broad differential positivity, relative to repeat waveforms. However, the later part of the differential positivity was significantly reduced on switch-away trials. A differential positivity then emerged after stimulus onset for switch-away trials only. This suggests that, with a long cue-stimulus interval, the new task-set was implemented before stimulus onset for switch-to trials, whereas on switch-away trials this process was delayed until after stimulus onset leading to increased switch cost. These results demonstrate dissociable effects of switching away from the current task-set and switching to the upcoming task-set and support the interpretation that the differential positivity observed for switch-to trials reflects processes associated with anticipatory task-set reconfiguration.

ERPs dissociate the effects of switching task sets and task cues.

Recent studies have suggested that reaction time (RT) costs associated with switching tasks do not reflect an endogenous control process of task set reconfiguration [Logan, G. D., Bundesen, C., 2003. Clever Homunculus: Is There an Endogenous Act of Control in the Explicit Task-Cuing Procedure? J. Exp. Psychol. Hum. Percept. Perform. 29 (3), 575-599]. Participants randomly switched between two simple tasks. Task was cued 600 ms prior to stimulus presentation using either a color or shape cue. A significant RT task switch cost was found when controlling for either a repeat or switch in cue category. In comparison, a switch in cue category had no effect on RT, even when examined across a cumulative distribution. Electrophysiological data revealed early cue processing effects within the first 300 ms after cue onset. However, replicating previous findings, an increased parietal positivity was found for task switch relative to task repeat trials that emerged prior to stimulus onset. This suggests that task set reconfiguration processes are activated when switching between tasks and supports the usefulness of task-switching paradigms in investigating cognitive control processes.

Switching between univalent task-sets in schizophrenia: ERP evidence of an anticipatory task-set reconfiguration deficit.

OBJECTIVE: The present study used behavioral and event-related potential (ERP) indices of task-switching to examine whether schizophrenia patients have a specific deficit in anticipatory task-set reconfiguration. METHODS: Participants switched between univalent tasks in an alternating runs paradigms with blocked response-stimulus interval (RSI) manipulation (150, 300, 600, and 1200ms). Nineteen high functioning people with schizophrenia were compared to controls that were matched for age, gender, education and premorbid IQ estimate. RESULTS: Schizophrenia patients had overall increased RT, but no increase in corrected RT switch cost. In the schizophrenia group, ERPs showed reduced activation of the differential positivity in anticipation of switch trial at the optimal 600ms RSI and reduced activation of the frontal post-stimulus switch negativity at both 600 and 1200ms RSI compared to the control group. CONCLUSIONS: Despite no behavioral differences in task switching performance, anticipatory and stimulus-triggered ERP indices of task-switching suggest group differences in processing of switch and repeat trials, especially at longer RSI conditions that for control participants provide opportunity for anticipatory activation of task-set reconfiguration processes. SIGNIFICANCE: These results are compatible with impaired implementation of endogenously driven processes in schizophrenia and greater reliance on external task cues, especially at long preparation intervals.

Double diastereoselective [3,3]-sigmatropic aza-Claisen rearrangements.

Asymmetric [3,3]-sigmatropic aza-Claisen rearrangement of the (Z)-N-allyl-N,O-silylketene aminal of (3S,4E,alphaR)-1-benzyloxy-3-(N-propionyl-N-alpha-methylbenzylamino)hex-4-ene furnishes (2S,3R,4E,alphaR)-N-alpha-methylbenzyl-2,3-dimethyl-7-benzyloxyhept-4-enamide in > 92% d.e.; rearrangement of the diastereomeric (3R,4E,alphaR)-(Z)-N,O-silylketene aminal proceeds with low diastereoselectivity.

Responding to a radiological crisis: experiences of British foreign office staff in Japan after the Fukushima nuclear meltdown.

OBJECTIVES: To identify factors that affected well-being among British embassy staff based in Japan after the 2011 earthquake, tsunami, and nuclear meltdown. METHODS: In-depth qualitative interviews were conducted with 36 members of staff 8 to 9 months after the earthquake. RESULTS: Participants described their crisis work as stressful, exciting, and something of which they were proud. Aside from disaster-specific stressors, factors identified as stressful included unclear roles, handing over work to new personnel, being assigned to office-based work, feeling that work was not immediately beneficial to the public, not taking good-quality breaks, and difficulties with relatives. The radiation risk provoked mixed feelings, with most participants being reassured by contact with senior scientists. CONCLUSIONS: Interventions to safeguard the well-being of personnel during crisis work must consider the impact of a broad range of stressors.(Disaster Med Public Health Preparedness. 2014;0:1-7).

3D small-molecule microarrays.

A PEG based 3D hydrogel slide was developed specifically for small-molecule microarraying purposes, which displayed improved loading capacity, signal sensitivity and spot morphology compared with a commercially available slide and comparative 2D slide.

Asymmetric synthesis of vicinal amino alcohols: xestoaminol C, sphinganine and sphingosine.

The highly diastereoselective anti-aminohydroxylation of alpha,beta-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O-diacetyl xestoaminol C (41% yield over 8 steps), N,O,O-triacetyl sphinganine (30% yield over 8 steps) and N,O,O-triacetyl sphingosine (30% yield over 7 steps).

Highly (E)-selective Wadsworth-Emmons reactions promoted by methylmagnesium bromide.

An experimentally simple protocol for the very highly (E)-selective Wadsworth-Emmons reaction [(E):(Z) selectivities in excess of 180:1 in some cases] of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes via reaction with an alkyl diethylphosphonoacetate and MeMgBr is reported.

2-Methoxycyclopentyl analogues of a Pseudomonas aeruginosa quorum sensing modulator.

Diastereomeric 2-methoxycyclopentyl analogues of a natural quorum sensing signaling molecule from Pseudomonas aeruginosa were synthesized and screened in pigment production assays with P. aeruginosa and Serratia strain ATCC39006.

Asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylline via lithium amide conjugate addition.

The highly diastereoselective anti-aminohydroxylation of (E)-gamma-tri-iso-propylsilyloxy-alpha,beta-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine (20% yield over 7 steps), the anhydrophytosphingosine jaspine B (10% yield over 9 steps), 2-epi-jaspine B (14% yield over 9 steps), and the Prosopis alkaloid deoxoprosophylline (26% yield over 7 steps).

Small-molecule screening: advances in microarraying and cell-imaging technologies.

Cell-permeable small molecules can be used to modulate protein function selectively, rapidly, reversibly, and conditionally with temporal and quantitative control in biological systems. The identification of these chemical probes can require the screening of large numbers of small molecules. With the advent of new technologies, small-molecule high-throughput screening is widely available. This Review focuses on the emerging technologies of microarray screening platforms and high-content screening formats.