A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Addressing road-river infrastructure gaps using a model-based approach

The world's rivers are covered over and fragmented by road infrastructure. Road-river infrastructure result in many socio-environmental questions and documenting where different types occur is challenged by their sheer numbers. Equally, the United Nations has committed the next decade to ecosystem restoration, and decision makers across government, non-government, and private sectors require information about where different types of road-river infrastructure occur to guide management decisions that promote both transport and river system resilience. Field-based efforts alone cannot address data and information needs at relevant scales, such as across river basins, nations, or regions to guide road-river infrastructure remediation. As a first step toward overcoming these data needs in Great Britain, we constructed a georeferenced database of road-river infrastructure, validated a subset of locations, and used a Boosted Regression Tree model-based approach with environmental data to predict which infrastructure are bridges and culverts. We mapped 110,406 possible road-river infrastructure locations and were able to either validate or predict which of 110,194 locations were bridges (n=60,385) or culverts (n=49,809). Upstream drainage area had the greatest contribution to determining infrastructure type: when <10 km2 our model correctly predicted culverts 73% of the time but only 60% of the time for bridges. Road type and stream gradient also influenced model results. Our model-based approach is readily applied to other locations and contexts and can be used to inform decisions about management of smaller infrastructure that are frequently overlooked worldwide

A European eel (Anguilla anguilla) case study using structured elicitation to estimate instream infrastructure passability for freshwater fishes

Conservation efforts are hampered by limited understanding about how different types of instream infrastructure impact migration patterns and fish survival. We used a rapid, fully online IDEA protocol to elicit expert judgments for the passability of seven different in-stream infrastructures to elver European eels (Anguilla anguilla) in Great Britain. Nine experts provided judgments via our online survey, followed by a second elicitation via email for reflection and adjustment of initial estimates. We found that on average, bridges were judged the most passable (95% passability), followed by fords, nonperched culverts, weirs, sluices, dams, and perched culverts (7%). Results showed a high degree of agreement about how passable bridges and perched culverts are for elver eels, but less certainty about other infrastructure. Thirty-four distinct factors were identified that experts believed influence infrastructure passability for elver eels, including: the structure itself, hydraulics, elver characteristics, obstructions (e.g., debris accumulation), and vegetation (e.g., to aid climbing). We discuss how our rapid, online-only variation on the IDEA protocol compares with the more traditional protocol, and how the expert estimates generated in this study can be used in future scenario building and connectivity modeling, with a view to improving conservation to support species persistence

Restricted by borders: trade-offs in transboundary conservation planning for large river systems

Effective conservation of freshwater biodiversity requires accounting for connectivity and the propagation of threats along river networks. With this in mind, the selection of areas to conserve freshwater biodiversity is challenging when rivers cross multiple jurisdictional boundaries. We used systematic conservation planning to identify priority conservation areas for freshwater fish conservation in Hungary (Central Europe). We evaluated the importance of transboundary rivers to achieve conservation goals by systematically deleting some rivers from the prioritization procedure in Marxan and assessing the trade-offs between complexity of conservation recommendations (e.g., conservation areas located exclusively within Hungary vs. transboundary) and cost (area required). We found that including the segments of the largest transboundary rivers (i.e. Danube, Tisza) in the area selection procedure yielded smaller total area compared with the scenarios which considered only smaller national and transboundary rivers. However, analyses which did not consider these large river segments still showed that fish diversity in Hungary can be effectively protected within the country’s borders in a relatively small total area (less than 20 % of the country’s size). Since the protection of large river segments is an unfeasible task, we suggest that transboundary cooperation should focus on the protection of highland riverine habitats (especially Dráva and Ipoly Rivers) and their valuable fish fauna, in addition to the protection of smaller national rivers and streams. Our approach highlights the necessity of examining different options for selecting priority areas for conservation in countries where transboundary river systems form the major part of water resources.Full Tex

Fresh Waters and Fish Diversity: Distribution, Protection and Disturbance in Tropical Australia

Background: Given the globally poor protection of fresh waters for their intrinsic ecological values, assessments are needed to determine how well fresh waters and supported fish species are incidentally protected within existing terrestrial protected-area networks, and to identify their vulnerability to human-induced disturbances. To date, gaps in data have severely constrained any attempt to explore the representation of fresh waters in tropical regions.\ud \ud Methodology and Results: We determined the distribution of fresh waters and fish diversity in the Wet Tropics of Queensland, Australia. We then used distribution data of fresh waters, fish species, human-induced disturbances, and the terrestrial protected-area network to assess the effectiveness of terrestrial protected areas for fresh waters and fish species. We also identified human-induced disturbances likely to influence the effectiveness of freshwater protection and evaluated the vulnerability of fresh waters to these disturbances within and outside protected areas. The representation of fresh waters and fish species in the protected areas of the Wet Tropics is poor: 83% of stream types defined by order, 75% of wetland types, and 89% of fish species have less than 20% of their total Wet Tropics length, area or distribution completely within IUCN category II protected areas. Numerous disturbances affect fresh waters both within and outside of protected areas despite the high level of protection afforded to terrestrial areas in the Wet Tropics (>60% of the region). High-order streams and associated wetlands are influenced by the greatest number of human-induced disturbances and are also the least protected. Thirty-two percent of stream length upstream of protected areas has at least one human-induced disturbance present.\ud \ud Conclusions/Significance: We demonstrate the need for greater consideration of explicit protection and off-reserve management for fresh waters and supported biodiversity by showing that, even in a region where terrestrial protection is high, it does not adequately capture fresh waters

Supporting proactive planning for climate change adaptation and conservation using an attributed road-river structure dataset

Welsh European Funding Office; European Regional Development Fund [80761-SU-140]; Engineering and Physical Sciences Research Council (ESPRC) [EP/R00742X/2]; Ser Cymru ERDF Cofund Fellowship [80761-SU-135

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods: SLC3A2 was assessed at the genomic level, using METABRIC data (n=1,980), and proteomic level, using immunohistochemistry on TMA sections constructed from a large well-characterised primary BC cohort (n=2,500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results: SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple negative (TN), HER2+, and ER+ high proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p<0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p<0.001)), but only in the ER+ high proliferation (p=0.01) and triple negative (p=0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter breast cancer specific survival (p<0.001). Conclusions: SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes

Perceptions of a curriculum vitae clinic for conservation science students

We led a curriculum vitae (CV) clinic aimed at student participants attending the 28th International Congress for Conservation Biology (ICCB 2017) in Cartagena, Colombia. The CV Clinic was a pilot program consisting of resources to assist with developing an effective CV and involving preconference and at-conference reviews of student attendees' CVs. Here, we explore our experiences in organizing the CV Clinic as well as nonparticipant and participant perceptions of the clinic. We used an online standardized interview form to gather qualitative data on nonparticipant and participant perceptions of the CV Clinic, and to explore how such a CV Clinic program could best align with student needs. Most respondents who submitted their CV for review ahead of ICCB 2017 (n = 9) found the template and guidance useful. Half of the respondents who did not participate in the CV Clinic perceived the clinic as duplicating services provided by their academic institutions. Both par- ticipant and nonparticipant respondents perceived value in such a CV Clinic, but also believed that adjustments could be made to make the CV review part of a broader professional development program lead by Society for Conservation Biol- ogy (SCB). Key lessons learned from the CV Clinic include the need to: (a) document and evaluate professional development initiatives within SCB; (b) better understand and account for the diversity of student needs before program creation; and (c) pilot and evaluate appropriateness of different locations, fre- quency, and duration of professional development programs.John Wiley & Son

Sixteen years of social and ecological dynamics reveal challenges and opportunities for adaptive management in sustaining the commons

Efforts to confront the challenges of environmental change and uncertainty include attempts to adaptively manage social–ecological systems. However, critical questions remain about whether adaptive management can lead to sustainable outcomes for both ecosystems and society. Here, we make a contribution to these efforts by presenting a 16-y analysis of ecological outcomes and perceived livelihood impacts from adaptive coral reef management in Papua New Guinea. The adaptive management system we studied was a customary rotational fisheries closure system (akin to fallow agriculture), which helped to increase the biomass of reef fish and make fish less wary (more catchable) relative to openly fished areas. However, over time the amount of fish in openly fished reefs slowly declined. We found that, overall, resource users tended to have positive perceptions about this system, but there were negative perceptions when fishing was being prohibited. We also highlight some of the key traits of this adaptive management system, including 1) strong social cohesion, whereby leaders played a critical role in knowledge exchange; 2) high levels of compliance, which was facilitated via a “carrot-and-stick” approach that publicly rewarded good behavior and punished deviant behavior; and 3) high levels of participation by community actors