Population variation in the thermal response to climate change reveals differing sensitivity in a benthic shark

Many species with broad distributions are exposed to different thermal regimes which often select for varied phenotypes. This intraspecific variation is often overlooked but may be critical in dictating the vulnerability of different populations to environmental change. We reared Port Jackson shark (Heterodontus portusjacksoni) eggs from two thermally discrete populations (i.e. Jervis Bay and Adelaide) under each location's present‐day mean temperatures, predicted end‐of‐century temperatures and under reciprocal‐cross conditions to establish intraspecific thermal sensitivity. Rearing temperatures strongly influenced ?O_2Max and critical thermal limits, regardless of population, indicative of acclimation processes. However, there were significant population‐level effects, such that Jervis Bay sharks, regardless of rearing temperature, did not exhibit differences in ?O_2Rest, but under elevated temperatures exhibited reduced maximum swimming activity with step‐wise increases in temperature. In contrast, Adelaide sharks reared under elevated temperatures doubled their ?O_2Rest, relative to their present‐day temperature counterparts; however, maximum swimming activity was not influenced. With respect to reciprocal‐cross comparisons, few differences were detected between Jervis Bay and Adelaide sharks reared under ambient Jervis Bay temperatures. Similarly, juveniles (from both populations) reared under Adelaide conditions had similar thermal limits and swimming activity (maximum volitional velocity and distance) to each other, indicative of conserved acclimation capacity. However, under Adelaide temperatures, the ?O_2Rest of Jervis Bay sharks was greater than that of Adelaide sharks. This indicates that the energetics of cooler water population (Adelaide) is likely more thermally sensitive than that of the warmer population (Jervis Bay). While unique to elasmobranchs, these data provide further support that by treating species as static, homogeneous populations, we ignore the impacts of thermal history and intraspecific variation on thermal sensitivity. With climate change, intraspecific variation will manifest as populations move, demographics change or extirpations occur, starting with the most sensitive populations.     

Phase locking, the Moran effect and distance decay of synchrony: experimental tests in a model system

Spatially separated populations of many species fluctuate synchronously. Synchrony typically decays with increasing interpopulation distance. Spatial synchrony, and its distance decay, might reflect distance decay of environmental synchrony (the Moran effect), and/or short-distance dispersal. However, short-distance dispersal can synchronize entire metapopulations if within-patch dynamics are cyclic, a phenomenon known as phase locking. We manipulated the presence/absence of short-distance dispersal and spatially decaying environmental synchrony and examined their separate and interactive effects on the synchrony of the protist prey species Tetrahymena pyriformis growing in spatial arrays of patches (laboratory microcosms). The protist predator Euplotes patella consumed Tetrahymena and generated predator-prey cycles. Dispersal increased prey synchrony uniformly over both short and long distances, and did so by entraining the phases of the predator-prey cycles. The Moran effect also increased prey synchrony, but only over short distances where environmental synchrony was strongest, and did so by increasing the synchrony of stochastic fluctuations superimposed on the predator-prey cycle. Our results provide the first experimental demonstration of distance decay of synchrony due to distance decay of the Moran effect. Distance decay of the Moran effect likely explains distance decay of synchrony in many natural systems. Our results also provide an experimental demonstration of long-distance phase locking, and explain why cyclic populations provide many of the most dramatic examples of long-distance spatial synchrony in nature.     

A mathematical framework for estimating pathogen transmission fitness and inoculum size using data from a competitive mixtures animal model

We present a method to measure the relative transmissibility ("transmission fitness") of one strain of a pathogen compared to another. The model is applied to data from "competitive mixtures" experiments in which animals are co-infected with a mixture of two strains. We observe the mixture in each animal over time and over multiple generations of transmission. We use data from influenza experiments in ferrets to demonstrate the approach. Assessment of the relative transmissibility between two strains of influenza is important in at least three contexts: 1) Within the human population antigenically novel strains of influenza arise and compete for susceptible hosts. 2) During a pandemic event, a novel sub-type of influenza competes with the existing seasonal strain(s). The unfolding epidemiological dynamics are dependent upon both the population's susceptibility profile and the inherent transmissibility of the novel strain compared to the existing strain(s). 3) Neuraminidase inhibitors (NAIs), while providing significant potential to reduce transmission of influenza, exert selective pressure on the virus and so promote the emergence of drug-resistant strains. Any adverse outcome due to selection and subsequent spread of an NAI-resistant strain is exquisitely dependent upon the transmission fitness of that strain. Measurement of the transmission fitness of two competing strains of influenza is thus of critical importance in determining the likely time-course and epidemiology of an influenza outbreak, or the potential impact of an intervention measure such as NAI distribution. The mathematical framework introduced here also provides an estimate for the size of the transmitted inoculum. We demonstrate the framework's behaviour using data from ferret transmission studies, and through simulation suggest how to optimise experimental design for assessment of transmissibility. The method introduced here for assessment of mixed transmission events has applicability beyond influenza, to other viral and bacterial pathogens.     

Expression of cancer testis antigens in human BRCA-associated breast cancers: potential targets for immunoprevention?

Introduction

Novel breast cancer risk-reducing strategies for individuals with germline mutations of the BRCA1 and/or BRCA2 genes are urgently needed. Identification of antigenic targets that are expressed in early cancers, but absent in normal breast epithelium of these high-risk individuals, could provide the basis for the development of effective immunoprophylactic strategies. Cancer testis (CT) antigens are potential candidates because their expression is restricted to tumors, and accumulating data suggest that they play important roles in cellular proliferation, stem cell function, and carcinogenesis. The objective of this study was to examine the expression of CT antigens and their frequency in BRCA-associated breast cancers.

Methods

Archived breast cancer tissues (n?=?26) as well as morphologically normal breast tissues (n?=?7) from women carrying deleterious BRCA 1 and/or 2 mutations were obtained for antigen expression analysis by immunohistochemistry. Expression of the following CT antigens was examined: MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1.CT7, NY-ESO-1, MAGE-C2/CT10, and GAGE.

Results

CT antigens were expressed in 16/26 (61.5%, 95% CI 43?C80%) of BRCA-associated cancers, including in situ tumors. Thirteen of twenty-six (50%) breast cancers expressed two or more CT antigens; three cancers expressed all seven CT antigens. MAGE-A was expressed in 13/26 (50%) of cancers, NY-ESO-1 was expressed in 10/26 (38%) of tumors. In contrast, none of the CT antigens were expressed in adjacent or contralateral normal breast epithelium (P?=?0.003).

Conclusions

We report a high CT antigen expression rate in BRCA-associated breast cancer as well as the lack of expression of these antigens in benign breast tissue of carriers, identifying CT antigens as potential vaccine targets for breast cancer prevention in these high-risk individuals.     

Influence of contact definitions in assessment of the relative importance of social settings in disease transmission risk

Background

Realistic models of disease transmission incorporating complex population heterogeneities require input from quantitative population mixing studies. We use contact diaries to assess the relative importance of social settings in respiratory pathogen spread using three measures of person contact hours (PCH) as proxies for transmission risk with an aim to inform bipartite network models of respiratory pathogen transmission.

Methods and Findings

Our survey examines the contact behaviour for a convenience sample of 65 adults, with each encounter classified as occurring in a work, retail, home, social, travel or “other” setting. The diary design allows for extraction of PCH-interaction (cumulative time in face-face conversational or touch interaction with contacts) – analogous to the contact measure used in several existing surveys – as well as PCH-setting (product of time spent in setting and number of people present) and PCH-reach (product of time spent in setting and number of people in close proximity). Heterogeneities in day-dependent distribution of risk across settings are analysed using partitioning and cluster analyses and compared between days and contact measures. Although home is typically the highest-risk setting when PCH measures isolate two-way interactions, its relative importance compared to social and work settings may reduce when adopting a more inclusive contact measure that considers the number and duration of potential exposure events.

Conclusions

Heterogeneities in location-dependent contact behaviour as measured by contact diary studies depend on the adopted contact definition. We find that contact measures isolating face-face conversational or touch interactions suggest that contact in the home dominates, whereas more inclusive contact measures indicate that home and work settings may be of higher importance. In the absence of definitive knowledge of the contact required to facilitate transmission of various respiratory pathogens, it is important for surveys to consider alternative contact measures.     

2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists

High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.     

The crystal structure of the ivy Delta4-16:0-ACP desaturase reveals structural details of the oxidized active site and potential determinants of regioselectivity

The multifunctional acyl-acyl carrier protein (ACP) desaturase from Hedera helix (English ivy) catalyzes the Delta(4) desaturation of 16:0-ACP and the Delta(9) desaturation of 18:0-ACP and further desaturates Delta(9)-16:1 or Delta(9)-18:1 to the corresponding Delta(4,9) dienes. The crystal structure of the enzyme has been solved to 1.95 A resolution, and both the iron-iron distance of approximately 3.2A and the presence of a mu-oxo bridge reveal this to be the only reported structure of a desaturase in the oxidized FeIII-FeIII form. Significant differences are seen between the oxidized active site and the reduced active site of the Ricinus communis (castor) desaturase; His(227) coordination to Fe2 is lost, and the side chain of Glu(224), which bridges the two iron ions in the reduced structure, does not interact with either iron. Although carboxylate shifts have been observed on oxidation of other diiron proteins, this is the first example of the residue moving beyond the coordination range of both iron ions. Comparison of the ivy and castor structures reveal surface amino acids close to the annulus of the substrate-binding cavity and others lining the lower portion of the cavity that are potential determinants of their distinct substrate specificities. We propose a hypothesis that differences in side chain packing explains the apparent paradox that several residues lining the lower portion of the cavity in the ivy desaturase are bulkier than their equivalents in the castor enzyme despite the necessity for the ivy enzyme to accommodate three more carbons beyond the diiron site.