Context-dependent costs and benefits of tuberculosis resistance traits in a wild mammalian host

Disease acts as a powerful driver of evolution in natural host populations, yet individuals in a population often vary in their susceptibility to infection. Energetic trade-offs between immune and reproductive investment lead to the evolution of distinct life history strategies, driven by the relative fitness costs and benefits of resisting infection. However, examples quantifying the cost of resistance outside of the laboratory are rare. Here, we observe two distinct forms of resistance to bovine tuberculosis (bTB), an important zoonotic pathogen, in a free-ranging African buffalo (Syncerus caffer) population. We characterize these phenotypes as “infection resistance,” in which hosts delay or prevent infection, and “proliferation resistance,” in which the host limits the spread of lesions caused by the pathogen after infection has occurred. We found weak evidence that infection resistance to bTB may be heritable in this buffalo population (h2 = 0.10) and comes at the cost of reduced body condition and marginally reduced survival once infected, but also associates with an overall higher reproductive rate. Infection-resistant animals thus appear to follow a “fast” pace-of-life syndrome, in that they reproduce more quickly but die upon infection. In contrast, proliferation resistance had no apparent costs and was associated with measures of positive host health—such as having a higher body condition and reproductive rate. This study quantifies striking phenotypic variation in pathogen resistance and provides evidence for a link between life history variation and a disease resistance trait in a wild mammalian host population

Bovine tuberculosis disturbs parasite functional trait composition in African buffalo

Novel parasites can have wide-ranging impacts, not only on host populations, but also on the resident parasite community. Historically, impacts of novel parasites have been assessed by examining pairwise interactions between parasite species. However, parasite communities are complex networks of interacting species. Here we used multivariate taxonomic and trait-based approaches to determine how parasite community composition changed when African buffalo (Syncerus caffer) acquired an emerging disease, bovine tuberculosis (BTB). Both taxonomic and functional parasite richness increased significantly in animals that acquired BTB than in those that did not. Thus, the presence of BTB seems to catalyze extraordinary shifts in community composition. There were no differences in overall parasite taxonomic composition between infected and uninfected individuals, however. The trait-based analysis revealed an increase in direct-transmitted, quickly replicating parasites following BTB infection. This study demonstrates that trait-based approaches provide insight into parasite community dynamics in the context of emerging infections

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Intrinsically determined cell death of developing cortical interneurons

Cortical inhibitory circuits are formed by GABAergic interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis1-5, is that cortical interneurons are overproduced, and then following their migration into cortex, excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we have characterized the developmental cell death of mouse cortical interneurons in vivo, in vitro, and following transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax- (Bcl-2 associated X-) dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Remarkably, over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by central nervous system (CNS) neurons6-8. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Together, our findings indicate that interneuron cell death is intrinsically determined, either cell-autonomously, or through a population-autonomous competition for survival signals derived from other interneurons

Testing predictions on body mass and gut contents: dissection of an African elephant Loxodonta africana Blumenbach 1797

The values reported in the literature for the total gastrointestinal tract (GIT) content mass of elephants are lower than expected from interspecific mammalian regression. This finding agrees with theoretical considerations that elephants should have less capacious GITs than other herbivorous mammals, resulting in short ingesta retention times. However, the data on elephants was so far derived from either diseased zoo specimens or free-ranging animals subjected to an unknown hunting stress. In this study, we weighed the wet contents of the GIT segments of a captive African elephant that was euthanased because of a positive serological tuberculosis test, but that was clinically healthy, did not show a reduced appetite, and ingested food up to the time of euthanasia. The animal weighed 3,140 kg and its total gut contents were 542 kg or 17% of body mass. This is in close accord with the published mammalian herbivore regression equation of Parra (Comparison of foregut and hindgut fermentation in herbivores. In: Montgomery GG (ed) The ecology of arboreal folivores. Smithsonian Institution Press, Washington DC, pp205-230, 1978) and contradicts the notion that elephants have comparatively less capacious gastrointestinal tracts. Data on the individual gut segments, however, do support earlier suspicions that elephants have a comparatively less capacious caecum and a disproportionally capacious colon

Diversity Partitioning of Stony Corals Across Multiple Spatial Scales Around Zanzibar Island, Tanzania

The coral reefs of Zanzibar Island (Unguja, Tanzania) encompass a considerable proportion of the global coral-reef diversity and are representative of the western Indian Ocean region. Unfortunately, these reefs have been recently subjected to local and regional disturbances. The objectives of this study were to determine whether there are potentially non-random processes forcing the observed coral diversity patterns, and highlight where and at which spatial scales these processes might be most influential.A hierarchical (nested) sampling design was employed across three spatial scales, ranging from transects (<or=20 m), stations (<100 m), to sites (<1000 m), to examine coral diversity patterns. Two of the four sites, Chumbe and Mnemba, were located within Marine Protected Areas (MPAs), while the other two sites, Changuu and Bawe, were not protected. Additive partitioning of coral diversity was used to separate regional (total) diversity (gamma) into local alpha diversity and among-sample beta diversity components. Individual-based null models were used to identify deviations from random distribution across the three spatial scales. We found that Chumbe and Mnemba had similar diversity components to those predicted by the null models. However, the diversity at Changuu and Bawe was lower than expected at all three spatial scales tested. Consequently, the relative contribution of the among-site diversity component was significantly greater than expected. Applying partitioning analysis for each site separately revealed that the within-transect diversity component in Changuu was significantly lower than the null expectation.The non-random outcome of the partitioning analyses helped to identify the among-sites scale (i.e., 10's of kilometers) and the within-transects scale (i.e., a few meters; especially at Changuu) as spatial boundaries within which to examine the processes that may interact and disproportionately differentiate coral diversity. In light of coral community compositions and diversity patterns we strongly recommend that Bawe be declared a MPA

Settling into an Increasingly Hostile World: The Rapidly Closing “Recruitment Window” for Corals

Free space is necessary for larval recruitment in all marine benthic communities. Settling corals, with limited energy to invest in competitive interactions, are particularly vulnerable during settlement into well-developed coral reef communities. This situation may be exacerbated for corals settling into coral-depauperate reefs where succession in nursery microhabitats moves rapidly toward heterotrophic organisms inhospitable to settling corals. To study effects of benthic organisms (at millimeter to centimeter scales) on newly settled corals and their survivorship we deployed terra-cotta coral settlement plates at 10 m depth on the Mesoamerican Barrier Reef in Belize and monitored them for 38 mo. During the second and third years, annual recruitment rates declined by over 50% from the previous year. Invertebrate crusts (primarily sponges) were absent at the start of the experiment but increased in abundance annually from 39, 60, to 73% of the plate undersides by year three. Subsequently, substrates hospitable to coral recruitment, including crustose coralline algae, biofilmed terra-cotta and polychaete tubes, declined. With succession, substrates upon which spat settled shifted toward organisms inimical to survivorship. Over 50% of spat mortality was due to overgrowth by sponges alone. This result suggests that when a disturbance creates primary substrate a “recruitment window” for settling corals exists from approximately 9 to 14 mo following the disturbance. During the window, early-succession, facilitating species are most abundant. The window closes as organisms hostile to coral settlement and survivorship overgrow nursery microhabitats