Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility

Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r ² = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.     

An estimation of Canadian population exposure to cosmic rays from air travel

Based on air travel statistics in 1984, it was estimated that less than 4 % of the population dose from cosmic ray exposure would result from air travel. In the present study, cosmic ray doses were calculated for more than 3,000 flights departing from more than 200 Canadian airports using actual flight profiles. Based on currently available air travel statistics, the annual per capita effective dose from air transportation is estimated to be 32 μSv for Canadians, about 10 % of the average cosmic ray dose received at ground level (310 μSv per year).     

Relatedness affects the density,distribution and phenotype of colonisers in four sessile marine invertebrates

Genetic diversity has emerged as an important source of variation in the ecological properties of populations, but there are few studies of genetic diversity effects on colonisation processes. This relative scarcity of studies is surprising given the influence of colonisation on species coexistence, invasion, and population persistence. Here, we manipulated relatedness in experimental populations of colonising larvae in four sessile marine invertebrates. We then examined the influence of coloniser relatedness on the number, spatial arrangement and phenotype of colonisers following permanent settlement. Overall, relatedness influenced colonisation in all four species, but the effects of relatedness on colonisation differed among species. The variable responses of species to manipulations of relatedness likely reflect differences in intensity of inter‐ and intra‐specific competition among adults, as well as the differential consequences of larval behaviours for each species. Relatedness appears to play an underappreciated role in the colonisation process, and we recommend that future studies of genetic diversity effects consider not only adult stages – the focus of most work to date – but also the importance of genetic diversity in early life history stages.     

EVOLUTIONARY CONSTRAINTS AND THE MAINTENANCE OF INDIVIDUAL SPECIALIZATION THROUGHOUT SUCCESSION

Constraints on life‐history traits, with their close links to fitness, are widely invoked as limits to niche expansion at most organizational levels. Theoretically, such constraints can maintain individual specialization by preventing adaptation to all niches available, but empirical evidence of them remains elusive for natural populations. This problem may be compounded by a tendency to seek constraints involving multiple traits, neglecting their added potential to manifest in trait expression across environments (i.e., within reaction norms). By replicating genotypes of a colonial marine invertebrate across successional stages in its local community, and taking a holistic approach to the analysis of ensuing reaction norms for fitness, we show the potential for individual specialization to be maintained by genetic constraints associated with these norms, which limit the potential for fitness at one successional stage to improve without loss of fitness at others. Our study provides new insight into the evolutionary maintenance of individual specialization in natural populations and reinforces the importance of reaction norms for studying this phenomenon.     

The Snakelike Chain Character of Unstructured RNA

In the absence of base-pairing and tertiary structure, ribonucleic acid (RNA) assumes a random-walk conformation, modulated by the electrostatic self-repulsion of the charged, flexible backbone. This behavior is often modeled as a Kratky-Porod “wormlike chain” (WLC) with a Barrat-Joanny scale-dependent persistence length. In this study we report measurements of the end-to-end extension of poly(U) RNA under 0.1 to 10 pN applied force and observe two distinct elastic-response regimes: a low-force, power-law regime characteristic of a chain of swollen blobs on long length scales and a high-force, salt-valence-dependent regime consistent with ion-stabilized crumpling on short length scales. This short-scale structure is additionally supported by force- and salt-dependent quantification of the RNA ion atmosphere composition, which shows that ions are liberated under stretching; the number of ions liberated increases with increasing bulk salt concentration. Both this result and the observation of two elastic-response regimes directly contradict the WLC model, which predicts a single elastic regime across all forces and, when accounting for scale-dependent persistence length, the opposite trend in ion release with salt concentration. We conclude that RNA is better described as a “snakelike chain,” characterized by smooth bending on long length scales and ion-stabilized crumpling on short length scales. In monovalent salt, these two regimes are separated by a characteristic length that scales with the Debye screening length, highlighting the determining importance of electrostatics in RNA conformation.     

Avidity‐mediated virus separation using a hyperthermophilic affinity ligand

Immunoaffinity separation of large multivalent species such as viruses is limited by the stringent elution conditions necessary to overcome their strong and highly avid interaction with immobilized affinity ligands on the capture surface. Here we present an alternate strategy that harnesses the avidity effect to overcome this limitation. Red clover necrotic mosaic virus (RCNMV), a plant virus relevant to drug delivery applications, was chosen as a model target for this study. An RCNMV binding protein (RBP) with modest binding affinity (K_D ～100 nM) was generated through mutagenesis of the Sso7d protein from Sulfolobus solfataricus and used as the affinity ligand. In our separation scheme, RCNMV is captured by a highly avid interaction with RBP immobilized on a nickel surface through a hexahistidine (6xHis) tag. Subsequently, disruption of the multivalent interaction and release of RCNMV is achieved by elution of RBP from the nickel surface. Finally, RCNMV is separated from RBP by exploiting the large difference in their molecular weights (～8 MDa vs. ～10 kDa). Our strategy not only eliminates the need for harsh elution conditions, but also bypasses chemical conjugation of the affinity ligand to the capture surface. Stable non‐antibody affinity ligands to a wide spectrum of targets can be generated through mutagenesis of Sso7d and other hyperthermophilic proteins. Therefore, our approach may be broadly relevant to cases where capture of large multivalent species from complex mixtures and subsequent release without the use of harsh elution conditions is necessary. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2013     

Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds

In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds’ mechanisms of action—i.e., the specific molecular targets by which they kill the parasite—would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children’s Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC₅₀ < 1 μM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible.     

Feasibility and Acceptability of Global Positioning System (GPS) Methods to Study the Spatial Contexts of Substance Use and Sexual Risk Behaviors among Young Men Who Have Sex with Men in New York City: A P18 Cohort Sub-Study

Background

No global positioning system (GPS) technology study has been conducted among a sample of young gay, bisexual, and other men who have sex with men (YMSM). As such, the purpose of this study was to evaluate the feasibility and acceptability of using GPS methods to understand the spatial context of substance use and sexual risk behaviors among a sample of YMSM in New York City, a high-risk population.

Methods

Data came from a subsample of the ongoing P18 Cohort Study (n = 75). GPS feasibility and acceptability among participants was measured with: 1) a pre- and post-survey and 2) adherence to the GPS protocol which included returning the GPS device, self-report of charging and carrying the GPS device as well as objective data analyzed from the GPS devices. Analyses of the feasibility surveys were treated as repeated measures as each participant had a pre- and post-feasibility survey. When comparing the similar GPS survey items asked at baseline and at follow-up, we present percentages and associated p-values based on chi-square statistics.

Results

Participants reported high ratings of pre-GPS acceptability, ease of use, and low levels of wear-related concerns in addition to few concerns related to safety, loss, or appearance, which were maintained after baseline GPS feasibility data collection. The GPS return rate was 100%. Most participants charged and carried the GPS device on most days. Of the total of 75 participants with GPS data, 75 (100%) have at least one hour of GPS data for one day and 63 (84%) had at least one hour on all 7 days.

Conclusions

Results from this pilot study demonstrate that utilizing GPS methods among YMSM is feasible and acceptable. GPS devices may be used in spatial epidemiology research in YMSM populations to understand place-based determinants of health such as substance use and sexual risk behaviors.