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

Methylation of the imprinted GNAS1 gene in cell-free plasma DNA : equal steady-state quantities of methylated and unmethylated DNA in plasma

Background Genomic DNA sequences in cell-free plasma are biomarkers of cancer prognosis, where characteristic changes in methylation of tumour suppressor or oncogene DNA regions are indicative of changes in gene activity. Also, cell-free fetal DNA can be distinguished, by its methylation status, from the maternal DNA in the plasma of pregnant women, hence providing DNA biomarkers for the proposed minimally-invasive diagnosis of fetal aneuploidies, including Down's syndrome. However, the production and clearance of cell-free DNA from plasma in relation to its methylation status, are poorly understood processes. Methods We studied the methylation status of DNA derived from the imprinted GNAS1 locus, in cell-free plasma DNA of healthy adults. Heterozygotes were identified that carried the SNP rs1800905 in the imprinted region. The parent-of-origin-dependent DNA methylation was analysed by bisulfite conversion, followed by cloning and sequencing. Results Genomic DNA molecules derived from both the methylated, maternal, allele and the unmethylated, paternal, allele were found in plasma. Methylated and unmethylated DNA molecules were present in equal numbers. Conclusions Our data indicate that the methylation status of a DNA sequence has no effect on its steady state concentration in the cell-free DNA component of plasma, in healthy adults

Further Flattening of a Degraded, Turbid Reef System Following a Severe Coral Bleaching Event

Increasing incidence of severe coral bleaching events caused by climate change is contributing to extensive coral losses, shifts in species composition and widespread declines in the physical structure of coral reef ecosystems. With these ongoing changes to coral communities and the concomitant flattening of reef structural complexity, understanding the links between coral composition and structural complexity in maintaining ecosystem functions and processes is of critical importance. Here, we document the impacts of the 2016 global-scale coral bleaching event on seven coral reefs in Singapore; a heavily degraded, turbid reef system. Using a combination of field-based surveys, we examined changes in coral cover, composition and structural complexity before, during and after the 2016 bleaching event. We also quantified differential bleaching responses and mortality among coral taxa and growth forms using a bleaching response index. Elevated SSTs induced moderate to severe coral bleaching across reefs in Singapore in July 2016, but low overall coral mortality (~12% of colonies). However, we observed high bleaching prevalence and post-bleaching mortality of the three most abundant coral genera (Merulina, Pachyseris and Pectinia), all generalists, declined significantly across reefs between March and November 2016. Four months post-bleaching (November 2016), small-scale structural complexity declined across all Singaporean reefs and no moderately complex reefs remained. Importantly, reductions in structural complexity occurred across reefs with a large range of live coral cover (19–62%) and was linked to the loss of dominant coral genera with low-profile foliose-laminar growth forms which resulted in flatter, less structurally complex reefs. And while generalist coral taxa remain highly competitive within Singapore’s reef environment, they may not have the capacity to maintain structural complexity or ensure the persistence of other reef functions, even within communities with high coral cover. The widespread loss of structurally complexity on Singapore’s degraded coral reefs may further impair ecosystem functioning, potentially compromising the long-term stability of reef biodiversity and productivity

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

Freshwater species and their habitats, and transportation networks are at heightened risk from changing climate and are priorities for adaptation, with the sheer abundance and individuality of road-river structures complicating mitigation efforts. We present a new spatial dataset of road-river structures attributed as culverts, bridges, or fords, and use this along with data on gradient and stream order to estimate structure sensitivity and exposure in and out of special areas of conservation (SAC) and built-up areas to determine vulnerability to damage across river catchments in Wales, UK. We then assess hazard of flooding likelihood at the most vulnerable structures to determine those posing high risk of impact on roads and river-obligate species (fishes and mussels) whose persistence depends on aquatic habitat connectivity. Over 5% (624/11,680) of structures are high vulnerability and located where flooding hazard is highest, posing high risk of impact to roads and river-obligate species. We assess reliability of our approach through an on-ground survey in a river catchment supporting an SAC and more than 40% (n = 255) of high-risk structures, and show that of the subset surveyed >50% had obvious physical degradation, streambank erosion, and scouring. Our findings help us to better understand which structures pose high-risk of impact to river-obligate species and humans with increased flooding likelihood

Macroalgae exhibit diverse responses to human disturbances on coral reefs

Scientists and managers rely on indicator taxa such as coral and macroalgal cover to evaluate the effects of human disturbance on coral reefs, often assuming a universally positive relationship between local human disturbance and macroalgae. Despite evidence that macroalgae respond to local stressors in diverse ways, there have been few efforts to evaluate relationships between specific macroalgae taxa and local human-driven disturbance. Using genus-level monitoring data from 1205 sites in the Indian and Pacific Oceans, we assess whether macroalgae percent cover correlates with local human disturbance while accounting for factors that could obscure or confound relationships. Assessing macroalgae at genus level revealed that no genera were positively correlated with all human disturbance metrics. Instead, we found relationships between the division or genera of algae and specific human disturbances that were not detectable when pooling taxa into a single functional category, which is common to many analyses. The convention to use percent cover of macroalgae as an indication of local human disturbance therefore likely obscures signatures of local anthropogenic threats to reefs. Our limited understanding of relationships between human disturbance, macroalgae taxa, and their responses to human disturbances impedes the ability to diagnose and respond appropriately to these threats

Playing in the water: an exquisite corpse and found river and underwater poems

This article shares and reflects on Underwater Haiku Exquisite Corpse – a playful approach to writing and enquiry about rivers and their underwater environments. The Underwater Haiku Exquisite Corpse was an adaptation of the Surrealist exquisite corpse concept – a collaborative game in which each participant wrote or drew in response to a prompt and kept their contribution concealed until the end, when the full corpse was revealed to all contributors. We consider how our approach to exquisite corpse fostered playful co-creation and community and contributed to better understanding people’s experiences with and intuitive responses to river environments. This article blends academic writing and found poems (existing words or phrases reframed into a poem) from Underwater Haiku Exquisite Corpse, in response to calls for more creative and entangled ways to write about the world. We applied this technique, using lines of text by different Underwater Haiku Exquisite Corpse contributors and reordering lines into poems that illustrated how contributors intertwined notions of humans, rivers, and what lies below the surface. We hope that by sharing our experiences with the Underwater Haiku Exquisite Corpse, we encourage more playful approaches to geopoetics, to foster conversations across disciplines, as well as within and outside the academy

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

Collaging to find river connections and stimulate new meanings

This article contributes to work in creative geographies through the lens of river spaces and a multimodal practice among an ensemble of artists/poets/scientists. The collaboration created two collage series with both planned and unplanned visual, textual, and audio-visual media. Orchestrated in a time of global pandemic, learnings from the ensemble’s online creative practice are shared and discussed, including: the methodological possibilities of online collaboration and the Internet’s ability to facilitate distanced and sustained co-creation, as well as the potential of collage and poetry to reimagine relationships with rivers