Marker-dependent associations among oxidative stress, growth and survival during early life in a wild mammal

Oxidative stress (OS) is hypothesized to be a key physiological mechanism mediating life-history trade-offs, but evidence from wild populations experiencing natural environmental variation is limited. We tested the hypotheses that increased early life growth rate increases OS, and that increased OS reduces first-winter survival, in wild Soay sheep (Ovis aries) lambs. We measured growth rate and first-winter survival for four consecutive cohorts, and measured two markers of oxidative damage (malondialdehyde (MDA), protein carbonyls (PC)) and two markers of antioxidant (AOX) protection (total AOX capacity (TAC), superoxide dismutase (SOD)) from blood samples. Faster lamb growth was weakly associated with increased MDA, but not associated with variation in the other three markers. Lambs with higher SOD activity were more likely to survive their first winter, as were male but not female lambs with lower PC concentrations. Survival did not vary with MDA or total TAC. Key predictions relating OS to growth and survival were therefore supported in some OS markers, but not others. This suggests that different markers capture different aspects of the complex relationships between individual oxidative state, physiology and fitness, and that overarching hypotheses relating OS to life-history variation cannot be supported or refuted by studying individual markers

Semi-annual, annual and Universal Time variations in the magnetosphere and in geomagnetic activity: 3. Modelling

This is the third in a series of papers that investigate the semi-annual, annual and Universal Time variations in the magnetosphere. In this paper, we use the Lin et al. (2010) empirical model of magnetopause locations, along with the assumption of pressure equilibrium and the Newtonian approximation of magnetosheath pressure. We show that the equinoctial pattern arises in both the cross-tail current at the tail hinge point and in the total energy stored in the tail. The model allows us to study the effects of both dipole tilt and hemispheric asymmetries. As a test of the necessary assumptions made to enable this analysis, we also study simulations by the BATSRUS global MHD magnetosphere model. These also show that the reconnection voltage in the tail is greatest when the dipole tilt is small but this only applies at low solar wind dynamic pressure pSW and does not, on its own, explain why the equinoctial effect increases in amplitude with increased pSW, as demonstrated by Paper 2. Instead, the effect is consistent with the dipole tilt effect on the energy stored in the tail around the reconnection X line. A key factor is that a smaller/larger fraction of the open polar cap flux threads the tail lobe in the hemisphere that is pointed toward/away from the Sun. The analysis using the empirical model uses approximations and so is not definitive; however, because the magnetopause locations in the two hemispheres were fitted separately in generating the model, it gives a unique insight into the effect of the very different offsets of the magnetic pole from the rotational pole in the two hemispheres. It is therefore significant that our analysis using the empirical model does predict a UT variation that is highly consistent with that found in both transpolar voltage data and in geomagnetic activity

Semi-annual, annual and Universal Time variations in the magnetosphere and in geomagnetic activity: 2. Response to solar wind power input and relationships with solar wind dynamic pressure and magnetospheric flux transport

This is the second in a series of papers that investigate the semi-annual, annual and Universal Time (UT) variations in the magnetosphere. We present a varied collection of empirical results that can be used to constrain theories and modelling of these variations. An initial study of two years’ data on transpolar voltage shows that there is a semi-annual variation in magnetospheric flux circulation; however, it is not as large in amplitude as that in geomagnetic activity, consistent with the latter showing a non-linear (quadratic) variation with transpolar voltage. We find that during the persistent minimum of the UT variation in geomagnetic activity, between about 2 and 10 UT, there is also a persistent decrease in observed transpolar voltage, which may be, in part, caused by a decrease in reconnection voltage in the nightside cross-tail current sheet. We study the response of geomagnetic activity to estimated power input into the magnetosphere using interplanetary data from 1995 onwards, an interval for which the data are relatively free of data gaps. We find no consistent variation in the response delay with time-of-year F and, using the optimum lag, we show that the patterns of variation in F-year spectrograms are very similar for geomagnetic activity and power input into the magnetosphere, both for average values and for the occurrence of large events. The Russell-McPherron (R-M) mechanism is shown to be the central driver of this behaviour. However, the (R-M) effect on power input into the magnetosphere is small and there is a non-linear amplification of the semi-annual variation in the geomagnetic response, such that a very small asymmetry in power input into the magnetosphere P_ between the “favourable” and “unfavourable” polarities of the IMF BY component generates a greatly amplified geomagnetic response. The analysis strongly indicates that this amplification is associated with solar wind dynamic pressure and its role in squeezing the near-Earth tail and so modulating the storage and release of energy extracted from the solar wind. In this paper, we show that the equinoctial pattern is found in the residuals of fits of P_ to the am index and that the amplitude of these equinoctial patterns in the am fit residuals increases linearly with solar wind dynamic pressure. Similarly, the UT variation in am is also found in these fit residuals and also increases in amplitude with solar wind dynamic pressure

Heritable, heterogeneous, and costly resistance of sheep against nematodes and potential feedbacks to epidemiological dynamics

Infected hosts may preserve fitness by resisting parasites (reducing parasite burden) and/or tolerating them (preventing or repairing infection-induced damage). Theory predicts that these individual-level defense strategies generate divergent population-level feedbacks that would maintain genetic heterogeneity for resistance but purge heterogeneity for tolerance. Because resistance reduces parasite abundance, selection for costly resistance traits will weaken as resistance becomes common. Such negative frequency-dependent selection contrasts with predictions for tolerance, which maintains parasite abundance and so is expected to generate positive frequencydependent selection, unless, for example, tolerance trades off with resistance. Thus far, there have been few tests of this theory in natural systems. Here, we begin testing the predictions in a mammalian field system, using data on individual gastrointestinal nematode burdens, nematode-specific antibody titers (as a resistance metric), the slope of body weight on parasite burden (as a tolerance metric), and fitness from an unmanaged population of Soay sheep. We find that nematode resistance is costly to fitness and underpinned by genetic heterogeneity, and that resistance is independent of tolerance. Drawing upon empirical metrics such as developed here, future work will elucidate how resistance and tolerance feedbacks interact to generate population-scale patterns in the Soay sheep and other field systems

Cellular and humoral immunity in a wild mammal: Variation with age & sex and association with overwinter survival

Immune defenses are expected to be crucial for survival under the considerable parasite pressures experienced by wild animals. However, our understanding of the association between immunity and fitness in nature remains limited due to both the complexity of the vertebrate immune system and the often‐limited availability of immune reagents in nonmodel organisms. Here, we use methods and reagents developed by veterinary researchers for domestic ungulates on blood samples collected from a wild Soay sheep population, to evaluate an unusually broad panel of immune parameters. Our evaluation included different innate and acquired immune cell types as well as nematode parasite‐specific antibodies of different isotypes. We test how these markers correlate with one another, how they vary with age‐group and sex, and, crucially, whether they predict overwinter survival either within or among demographic groups. We found anticipated patterns of variation in markers with age, associated with immune development, and once these age trends were accounted for, correlations among our 11 immune markers were generally weak. We found that females had higher proportions of naïve T cells and gamma–delta T cells than males, independent of age, while our other markers did not differ between sexes. Only one of our 11 markers predicted overwinter survival: sheep with higher plasma levels of anti‐nematode IgG antibodies were significantly more likely to survive the subsequent high mortality winter, independent of age, sex, or weight. This supports a previous finding from this study system using a different set of samples and shows that circulating antibody levels against ecologically relevant parasites in natural systems represent an important parameter of immune function and may be under strong natural selection. Our data provide rare insights into patterns of variation among age‐ and sex groups in different T‐cell subsets and antibody levels in the wild, and suggest that certain types of immune response—notably those likely to be repeatable within individuals and linked to resistance to ecologically relevant parasites—may be most informative for research into the links between immunity and fitness under natural conditions

Earliest rock fabric formed in the Solar System preserved in a chondrule rim

Rock fabrics – the preferred orientation of grains – provide a window into the history of rock formation, deformation and compaction. Chondritic meteorites are among the oldest materials in the Solar System1 and their fabrics should record a range of processes occurring in the nebula and in asteroids, but due to abundant fine-grained material these samples have largely resisted traditional in situ fabric analysis. Here we use high resolution electron backscatter diffraction to map the orientation of sub-micrometre grains in the Allende CV carbonaceous chondrite: the matrix material that is interstitial to the mm-sized spherical chondrules that give chondrites their name, and fine-grained rims which surround those chondrules. Although Allende matrix exhibits a bulk uniaxial fabric relating to a significant compressive event in the parent asteroid, we find that fine-grained rims preserve a spherically symmetric fabric centred on the chondrule. We define a method that quantitatively relates fabric intensity to net compression, and reconstruct an initial porosity for the rims of 70-80% - a value very close to model estimates for the earliest uncompacted aggregates2,3. We conclude that the chondrule rim textures formed in a nebula setting and may therefore be the first rock fabric to have formed in the Solar System

The Retinoic Acid Receptor Agonist Am80 Increases Mucosal Inflammation in an IL-6 Dependent Manner During Trichuris muris Infection

PURPOSE: Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. METHODS: Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human Trichuriasis and IBD, treat with an RARα/β agonist (Am80) and quantify the ensuing pathological changes in the gut. RESULTS: Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. CONCLUSIONS: This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-013-9936-8) contains supplementary material, which is available to authorized users

A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis:a protocol for the CLEAR clinical trial

Background: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. Methods: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care-the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: Adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. Discussion: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. Trial registration: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). Sponsor: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: V3.0 Final_14052018