The Future of Drug Development: The Economics of Pharmacogenomics

This paper models how the evolving field of pharmacogenomics (PG), which is the science of using genomic markers to predict drug response, may impact drug development times, attrition rates, costs, and the future returns to research and development (R&D). While there still remains an abundance of uncertainty around how PG will impact the future landscape of pharmaceutical and biological R&D, we identify several likely outcomes. We conclude PG has the potential to significantly reduce both expected drug development costs (via higher probabilities of technical success, shorter clinical development times, and smaller clinical trials) and returns. The impact PG has on expected returns is partially mitigated by higher equilibrium prices, expedited product launches, and longer effective patent lives. Our conclusions are, of course, accompanied by numerous caveats.

Updated Cariaco Basin C-14 calibration dataset from 0-60 cal kyr BP

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hughen, K. A., & Heaton, T. J. Updated Cariaco Basin C-14 calibration dataset from 0-60 cal kyr BP. Radiocarbon, 62(4), (2020): 1001-1043, doi:10.1017/RDC.2020.53.We present new updates to the calendar and radiocarbon (14C) chronologies for the Cariaco Basin, Venezuela. Calendar ages were generated by tuning abrupt climate shifts in Cariaco Basin sediments to those in speleothems from Hulu Cave. After the original Cariaco-Hulu calendar age model was published, Hulu Cave δ18O records have been augmented with increased temporal resolution and a greater number of U/Th dates. These updated Hulu Cave records provide increased accuracy as well as precision in the final Cariaco calendar age model. The depth scale for the Ocean Drilling Program Site 1002D sediment core, the primary source of samples for 14C dating, has been corrected to account for missing sediment from a core break, eliminating age-depth anomalies that afflicted the earlier calendar age models. Individual 14C dates for the Cariaco Basin remain unchanged from previous papers, although detailed comparisons of the Cariaco calibration dataset to those from Hulu Cave and Lake Suigetsu suggest that the Cariaco marine reservoir age may have shifted systematically during the past. We describe these recent changes to the Cariaco datasets and provide the data in a comprehensive format that will facilitate use by the community.K.A. Hughen was supported by funds from U.S. NSF grant #OCE-1657191, and by the Investment in Science Fund at WHOI. T.J. Heaton is supported by a Leverhulme Trust Fellowship RF-2019-140\9, “Improving the Measurement of Time Using Radiocarbon”

Geochemistry of surface sediments from the fjords of Northern Chilean Patagonia (44–47°S) : spatial variability and implications for paleoclimate reconstructions

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 76 (2012): 125-146, doi:10.1016/j.gca.2011.10.028.The Patagonian fjords have a clear potential to provide high-resolution sedimentary and geochemical records of past climate and environmental change in the Southern Andes. To improve our ability to interpret these proxy records, we investigated the processes that control fjord sediment inorganic geochemistry through a geochemical, mineralogical and sedimentological analysis of surface sediment samples from the fjords of Northern Chilean Patagonia. A simple terrestrial index based on measurements of salinity and fraction of terrestrial carbon was used to estimate the terrestrial input/river discharge at each site. Our results demonstrate that, under the cold climate conditions of Patagonia, chemical weathering is weak and the inorganic geochemical composition of the fjord sediments is primarily controlled by hydrodynamic mineralogical sorting, i.e., the intensity of river discharge. Our results suggest that the distribution of Fe, Ti and Zr in surface sediments is controlled by their association with heavy and/or coarse minerals, whereas Al is independent of hydrodynamic processes. The elemental ratios Fe/Al, Ti/Al and Zr/Al are therefore well suited for estimating changes in the energy of terrestrial sediment supply into the fjords through time. Zr/Al is particularly sensitive in proximal environments, while Fe/Al is most useful in the outer fjords and on the continental margin. In the most proximal environments, however, Fe/Al is inversely related to hydrodynamic conditions. Caution should therefore be exercised when interpreting Fe/Al ratios in terms of past river discharge. The application of these proxies to long sediment cores from Quitralco fjord and Golfo Elefantes validates our interpretations. Our results also emphasize the need to measure Al-based elemental ratios at high precision, which can be achieved using simultaneous acquisition ICP-AES technology. This study therefore constitutes a strong basis for the interpretation of sedimentary records from the Chilean Fjords.This research was supported by a BAEF fellowship (Belgian American Educational Foundation) and an EU FP6 Marie Curie Outgoing Fellowship to S. Bertrand. J. Sepúlveda was supported by Fundación Andes through the WHOI/University of Concepción agreement, and by a scholarship from the Graduate School of the University of Concepción

Effects of Nitrogen and Clipping Termination Dates on Forage Production, Grain Yield, and Yield Components of Tam W101 Wheat

Agronom

Mauyen Keane, Love Without Border in War-Torn Europe : An Irishwoman’s Story

Love Without Borders is a memoir of multiple stories. It is a war-time romance between an Irish nurse and a German Soldier that crossed borders and transgressed societal norms. It is also a story of emigration and a personal recollection of the Second World War. Mauyen Keane begins her story with her departure from home. There are some hints about what was being left behind. Her family could afford to keep a ‘favourite’ horse, unwittingly revealing th..

Record of Little Ice Age sea surface temperatures at Bermuda using a growth-dependent calibration of coral Sr/Ca

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 20 (2005): PA4016, doi:10.1029/2005PA001140.Strontium to calcium ratios (Sr/Ca) are reported for a massive brain coral Diploria labyrinthiformis collected from the south shore of Bermuda and are strongly correlated with both sea surface temperature (SST) and mean annual skeletal growth rate. High Sr/Ca ratios correspond with cold SSTs and slow skeletal growth rate and vice versa. We provide a quantitative calibration of Sr/Ca to extension rate and SST along the axis of maximum growth and derive a growth-dependent Sr/Ca–SST calibration equation to reconstruct western subtropical North Atlantic SSTs for the past 223 years. When the influence of growth rate is excluded from the calibration, Sr/Ca ratios yield SSTs that are too cold during cool anomalies and too warm during warm anomalies. Toward the end of the Little Ice Age (∼1850), SST changes derived using a calibration that is not growth-dependent are exaggerated by a factor of 2 relative to those from the growth-corrected model that yields SSTs ∼1.5°C cooler than today. Our results indicate that incorporation of growth rate effects into coral Sr/Ca calibrations may improve the accuracy of SSTs derived from living and fossil corals.A Stanley Watson Foundation Fellowship (N.F.G.), and grants from NSF (OCE-0402728) and WHOI (K.A.H., A.L.C., and M.S.M.) supported this work

Century-scale records of land-based activities recorded in Mesoamerican coral cores

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Marine Pollution Bulletin 58 (2009): 1835-1842, doi:10.1016/j.marpolbul.2009.07.024.The Mesoamerican Reef, the second-largest barrier reef in the world, is located in the western Caribbean Sea off the coasts of Mexico, Belize, Guatemala, and Honduras. Particularly in the south, the surrounding watersheds are steep and the climate is extremely wet. With development and agricultural expansion, the potential for negative impacts to the reef from land-based runoff becomes high. We constructed annually resolved century-scale records of metal/calcium ratios in coral skeletons collected from four sites experiencing a gradient of land-based runoff. Our proxy data indicate that runoff onto the reef has increased relatively steadily over time at all sites, consistent with land use trends from historical records. Sediment supply to the reef is greater in the south, and these more exposed reefs will probably benefit most immediately from management that targets runoff reduction. However, because runoff at all sites is steadily increasing, even distal sites will benefit from watershed management.This research was supported by funds from the PADI Foundation, B. Katz, two anonymous donors and the Edna Bailey Sussman Foundation to J.C

Two hundred fifty years of reconstructed South Asian summer monsoon intensity and decadal-scale variability

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 46(7) (2019): 3927-3935, doi: 10.1029/2018GL081593.Climate model simulations of the summer South Asian monsoon predict increased rainfall in response to anthropogenic warming. However, instrumental data show a decline in Indian rainfall in recent decades, underscoring the critical need for additional, independent records of past monsoon variability. Here, we present new reconstructions of annual summer South Asian Monsoon circulation over the past 250 years, based on the geochemical barium‐calcium signature of dust present in Red Sea corals. These records reveal how monsoon circulation has evolved with warming climate and indicate a significant multi‐century long monsoon intensification, with decreased multidecadal variance. Stronger monsoon circulation would have increased the moisture transport from the Arabian Sea and Bay of Bengal over the Indian subcontinent. If these trends continue, the monsoon circulation and associated moisture transport and precipitation will remain strong and stable for several decades.We thank Editor Valerie Trouet and two anonymous reviewers for their constructive comments. We gratefully acknowledge Justin Ossolinski for assistance during core drilling; Maureen Auro, Laura Robinson, and Tom Marchitto for use of lab space and for technical advice; Margaret Sulanowska for providing XRD analysis of dust samples; and Sujata Murty and Ryan Davis for assistance in the lab. We thank Falmouth Hospital for use of X‐ray equipment. We acknowledge the use of the NSF‐supported WHOI ICP‐MS facility and thank Scot Birdwhistell for his assistance. This research was supported by grants to K. A. H. from NSF award OCE‐1031288 and KAUST award USA00002, and by a WHOI Postdoctoral Fellowship awarded to S. P. B. All data presented in this manuscript will be made publicly available online through the NOAA NCDC Paleoclimatology data archive (https://www.ncdc.noaa.gov/data‐access/paleoclimatology‐data/).2019-09-2

Two centuries of limited variability in subtropical North Atlantic thermocline ventilation

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 3 (2012): 803, doi:10.1038/ncomms1811.Ventilation and mixing of oceanic gyres is important to ocean-atmosphere heat and gas transfer, and to mid-latitude nutrient supply. The rates of mode water formation are believed to impact climate and carbon exchange between the surface and mid-depth water over decadal periods. Here, a record of 14C/12C (1780–1940), which is a proxy for vertical ocean mixing, from an annually banded coral from Bermuda, shows limited inter-annual variability and a substantial Suess Effect (the decrease in 14C/12C since 1900). The Sargasso Sea mixing rates between the surface and thermocline varied minimally over the past two centuries, despite changes to mean-hemispheric climate, including the Little Ice Age and variability in the North Atlantic Oscillation. This result indicates that regional formation rates of sub-tropical mode water are stable over decades, and that anthropogenic carbon absorbed by the ocean does not return to the surface at a variable rate.Funding provided by NSF’s Chemical Oceanography Program OCE - 0526463 and 0961980 and the Stephen Hui Trust Fund

Radiocarbon dating of alkenones from marine sediments : III. Influence of solvent extraction procedures on 14C measurements of foraminifera

Author Posting. © Arizona Board of Regents on behalf of the University of Arizona, 2005. This article is posted here by permission of Dept. of Geosciences, University of Arizona for personal use, not for redistribution. The definitive version was published in Radiocarbon 47 (2005): 425-432.As a result of the growing use of multiple geochemical proxies to reconstruct ocean and climate changes in the past, there is an increasing need to establish temporal relationships between proxies derived from the same marine sediment record and ideally from the same core sections. Coupled proxy records of surface ocean properties, such as those based on lipid biomarkers (e.g. alkenone-derived sea surface temperature) and planktonic foraminiferal carbonate (oxygen isotopes), are a key example. Here, we assess whether 2 different solvent extraction procedures used for isolation of molecular biomarkers influence the radiocarbon contents of planktonic foraminiferal carbonate recovered from the corresponding residues of Bermuda Rise and Cariaco Basin sediments. Although minor Δ14C differences were observed between solvent-extracted and unextracted samples, no substantial or systematic offsets were evident. Overall, these data suggest that, in a practical sense, foraminiferal shells from a solvent-extracted residue can be reliably used for 14C dating to determine the age of sediment deposition and to examine age relationships with other sedimentary constituents (e.g. alkenones).This work was financially supported by NSF grant 9809624. N Ohkouchi was supported by a fellowship from Japan Society for the Promotion of Science