Investigating the conservation genetics small population paradigm using the brook trout (Salvelinus fontinalis): do small populations have less adaptive potential?

The conservation genetics small population paradigm predicts reduced quantitative genetic variation and consequently, adaptive potential, for populations which have become small and isolated due to habitat fragmentation. While these expectations are supported by laboratory studies, their generality in wild populations remain unresolved. In actuality, the evolutionary consequences of fragmentation may depend on whether environmental characteristics– and by extension, selective regimes are (1) shifted in a consistent directional manner as is widely assumed (Directional hypothesis), or (2) become more variable as population and fragment size decrease (Variable hypothesis); this latter possibility has so far received little empirical attention. Implementing field techniques, I explore these two competing hypotheses by relating variability in habitat characteristics to population size in a series of differentially abundant brook trout (Salvelinus fontinalis) populations located at Cape Race, Newfoundland. I furthermore use these hypotheses as a foundation to test the assumptions of the conservation genetic small population paradigm by investigating the relationships of population size at Cape Race to additive genetic variation (VA), trait differentiation (QST), and phenotypic plasticity in common garden analyses, and to the extent of natural selection in a meta-analysis using a large number of natural populations and species. Across two years and in relation to two population size metrics, patterns of habitat characteristics among small versus large Cape Race populations supported the Variable hypothesis. However, small brook trout populations did not significantly differ from large populations in either the magnitude or variability of VA, QST, or phenotypic plasticity. Results of the meta-analysis similarly revealed little support for differences in the strength, direction, and form of selection among wild populations differing in population size. The lack of differences might be explained by long term fluctuating environmental conditions which resulted in fluctuating selective pressures and similar outcomes among small compared to large Cape Race populations, and among the species included in the meta-analysis. Overall, the results of this research contradict the assumption that small populations generally inhabit marginal environments and also dispute the major tenets of the conservation genetics small population paradigm. Taken together, they suggest that even very small populations of some species may retain the adaptive potential necessary to cope with future environmental change

Population density and territory size in juvenile rainbow trout, Oncorhynchus mykiss: implications for population regulation.

We manipulated population density of juvenile rainbow trout ( Oncorhynchus mykiss ) across a range of realistic densities in artificial stream channels, while controlling food abundance in two different ways: in Experiment 1, the total amount of food was held constant over a threefold increase in density, whereas in Experiment 2, the per capita amount of food was held constant over an eightfold increase in density. We tested the contrasting predictions that territory size (i) is not affected by population density; (ii) decreases with population density as 1/n, where n = the local population size; or (iii) decreases with population density but towards an asymptotic minimum size. In Experiment 1, territory size decreased with increasing population density. With the broader range of densities used in Experiment 2, territory size initially decreased with density and then leveled off at a minimum territory radius of 20–30 cm. Our results suggest an asymptotic minimum size of about 0.2 m2 for a 5 cm rainbow trout, similar to what is observed for high-density conditions in the wild. This minimum territory size could potentially set an upper limit on local population density and help regulate the population size of stream salmonids. </jats:p

Concurrent habitat and life history influences on effective/census population size ratios in stream-dwelling trout

Lower effective sizes (Ne) than census sizes (N) are routinely documented in natural populations, but knowledge of how multiple factors interact to lower Ne/N ratios is often limited. We show how combined habitat and life-history influences drive a 2.4- to 6.1-fold difference in Ne/N ratios between two pristine brook trout (Salvelinus fontinalis) populations occupying streams separated by only 750 m. Local habitat features, particularly drainage area and stream depth, govern trout biomass produced in each stream. They also generate higher trout densities in the shallower stream by favoring smaller body size and earlier age-at-maturity. The combination of higher densities and reduced breeding site availability in the shallower stream likely leads to more competition among breeding trout, which results in greater variance in individual reproductive success and a greater reduction in Ne relative to N. A similar disparity between juvenile or adult densities and breeding habitat availability is reported for other species and hence may also result in divergent Ne/N ratios elsewhere. These divergent Ne/N ratios between adjacent populations are also an instructive reminder for species conservation programs that genetic and demographic parameters may differ dramatically within species

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Data from: Population correlates of rapid captive-induced maladaptation in a wild fish

Understanding the extent to which captivity generates maladaptation in wild species can inform species recovery programs and elucidate wild population responses to novel environmental change. Though rarely quantified, effective population size (Ne) and genetic diversity should influence the magnitude of plastic and genetic changes manifested in captivity that reduce wild fitness. Sexually-dimorphic traits might also mediate consequences of captivity. To evaluate these relationships, we generated >600 full- and half-sibling families from nine wild brook trout populations, reared them for one generation under common, captive environmental conditions, and contrasted several fitness-related traits in wild vs. captive lines. We found substantial variation in lifetime success (lifetime survival and reproductive success) and life history traits among wild populations after just one captive generation (fourteen- and three-fold ranges across populations, respectively). Populations with lower heterozygosity showed lower captive lifetime success, suggesting that captivity generates maladaptation within one generation. Greater male-biased mortality in captivity occurred in populations having disproportionately higher growth rates in males than females. Wild population Ne and allelic diversity had little or no influence on captive trait expression and lifetime success. Our results have four conservation implications: (i) Trait values and lifetime success were highly variable across populations following one generation of captivity. (ii) Maladaptation induced by captive breeding might be particularly intense for the very populations practitioners are most interested in conserving, such as those with low heterozygosity. (iii) Maladaptive sex differences in captivity might be associated with population-dependent growth costs of reproduction. (iv) Heterozygosity can be a good indicator of short-term, intraspecific responses to novel environmental change

Appendix G. Means and CVs for early-life history traits for small vs. large CR populations.

Means and CVs for early-life history traits for small vs. large CR populations