Merchants of Doubt. How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming

Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.

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Advances in oligonucleotide drug delivery

Worldwide, there is a need to enhance our understanding of vulnerability and to develop methodologies and tools to assess vulnerability. One of the most important goals of assessing coastal flood vulnerability, in particular, is to create a readily understandable link between the theoretical concepts of flood vulnerability and the day-to-day decision-making process and to encapsulate this link in an easily accessible tool. This article focuses on developing a Coastal City Flood Vulnerability Index (CCFVI) based on exposure, susceptibility and resilience to coastal flooding. It is applied to nine cities around the world, each with different kinds of exposure. With the aid of this index, it is demonstrated which cities are most vulnerable to coastal flooding with regard to the system’s components, that is, hydro-geological, socio-economic and politico-administrative. The index gives a number from 0 to 1, indicating comparatively low or high coastal flood vulnerability, which shows which cities are most in need of further, more detailed investigation for decision-makers. Once its use to compare the vulnerability of a range of cities under current conditions has been demonstrated, it is used to study the impact of climate change on the vulnerability of these cities over a longer timescale. The results show that CCFVI provides a means of obtaining a broad overview of flood vulnerability and the effect of possible adaptation options. This, in turn, will allow for the direction of resources to more in-depth investigation of the most promising strategies.

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A flood vulnerability index for coastal cities and its use in assessing climate change impacts

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.

Genetics of diabetes mellitus and diabetes complications.

There is growing demand among stakeholders across public and private institutions for spatially-explicit information regarding vulnerability to climate change at the local scale. However, the challenges associated with mapping the geography of climate change vulnerability are non-trivial, both conceptually and technically, suggesting the need for more critical evaluation of this practice. Here, we review climate change vulnerability mapping in the context of four key questions that are fundamental to assessment design. First, what are the goals of the assessment? A review of published assessments yields a range of objective statements that emphasize problem orientation or decision-making about adaptation actions. Second, how is the assessment of vulnerability framed? Assessments vary with respect to what values are assessed (vulnerability of what) and the underlying determinants of vulnerability that are considered (vulnerability to what). The selected frame ultimately influences perceptions of the primary driving forces of vulnerability as well as preferences regarding management alternatives. Third, what are the technical methods by which an assessment is conducted? The integration of vulnerability determinants into a common map remains an emergent and subjective practice associated with a number of methodological challenges. Fourth, who participates in the assessment and how will it be used to facilitate change? Assessments are often conducted under the auspices of benefiting stakeholders, yet many lack direct engagement with stakeholders. Each of these questions is reviewed in turn by drawing on an illustrative set of 45 vulnerability mapping studies appearing in the literature. A number of pathways for placing vulnerability mapping on a more robust footing are also identified.

Putting vulnerability to climate change on the map: a review of approaches, benefits, and risks

Rising sea levels and changing wind climates are widely expected to be associated with receding coastlines, creating a planning need for coastal change prediction, especially for soft shores like those associated with saltmarsh. We ask whether it is possible use a simple cartographic wind-wave fetch method to estimate the spatial pattern of progradation and recession of soft shores in swell-sheltered situations in which there is little or no input of new sediment from terrestrial sources. For points on an extensive embayment shoreline of this type we mapped change over 54 years from aerial photographs, recorded current shoreline morphology and calculated a wave fetch index (WFI). Morphological indication of strong progradation was associated with low WFI, but there was no statistically significant effect of variation in WFI on the degree of shoreline retreat. Saltmarsh shorelines averaged 14 cm per annum retreat between 1952 and 2006, a rate that did not vary significantly between air photo periods. We conclude that our geographic information system approach utilising WFI is likely to be useful as a planning tool in identifying those parts of sediment-poor saltmarsh shores where erosion is most likely or least likely to occur, but not particularly useful for predicting finer-scale variation in rates of shoreline recession within the particular substrate types in our study area. In the context of relative sea-level rise and increasing wind speeds, such modelling can help identify coastlines which are likely to support saltmarshes into the future.

Is wind-wave fetch exposure related to soft shoreline change in swell-sheltered situations with low terrestrial sediment input?

There is a profound change in sedimentary environment and in fauna going from
the Middle-Upper Ordovician of Ida Bay to Surprise Bay over a present distance
of only 25 km. The transition is from peritidal carbonates at Ida Bay, to subtidal
carbonates at Precipitous Bluff to deep subtidal calcareous shales at Pt. Cecil to
deep water micrites, graptolitic shales and carbonate turbidites at Surprise Bay.
The blind (Nanshanaspis, Bulbaspis) or large eyed (Telephina) trilobites at Surprise
Bay suggest sub-photic or twilight depositional conditions and a phosphatic,
ironstone hardground enriched in metals and with imploded nautiloids suggests
a zone of nutrient-rich upwelling currents at about 300 ± 50 m water
depth. Macrofauna from Ida Bay is mainly endemic and is associated with Midcontinent
province type or endemic conodonts. The shelf edge sections at Precipitous
Bluff and Pt. Cecil contain more widespread macrofossils and Midcontinent
conodonts whereas the macrofauna from the deep-water deposits is
widespread or cosmopolitan and is associated with North Atlantic province
conodonts.

Middle-Upper Ordovician Shallow Platform to Deep Basin Transect, Southern Tasmania.

Potential Climate Change Impacts on Geodiversity in the Tasmanian Wilderness World Heritage Area: A Management Response Position Paper

A thermal demagnetization study of 48 limestone samples from the Ordovician Gordon Subgroup of Ida Bay (Tasmania), indicated complete remagnetization (D = 9 .4° , I= - 81 . 4°,k = 137.5, a95 = l . 3o, N = 92 South pole position 59.8°5 1 41.1°E, dp = 2 . 4°, dm = 2 . 5°)during Late Cretaceous or less likely Early Tertiary time . This finding further supports a recently recognized Late Cretaceous remagnetization event in southeastern Au stral ia ,which is attributed to r ift forming processes preceding the opening of t he Tasman Sea.
Conodont colour indicates that the limestones studied have not been subjected to temperatures in e xcess of l00°c . This suggests a possible widespread occurrence of this magnetic overprint.

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C Sharples

Papers

Is wind-wave fetch exposure related to soft shoreline change in swell-sheltered situations with low terrestrial sediment input?

Middle-Upper Ordovician Shallow Platform to Deep Basin Transect, Southern Tasmania.

Potential Climate Change Impacts on Geodiversity in the Tasmanian Wilderness World Heritage Area: A Management Response Position Paper

Palaeomagnetic results from the Gordon Subgroup of Tasmania: Further evidence for a late Cretaceous magnetic overprint in Southeastern Australia

Middle- Upper Ordovician shallow platform to deep basin transect, southern Tasmania, Australia