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Quantifying the marine radiocarbon reservoir effect, offsets (ΔR), and ΔR variability over time is critical to improving dating estimates of marine samples while also providing a proxy of water mass dynamics. In the northeastern Pacific, where no high-resolution time series of ΔR has yet been established, we sampled radiocarbon (14C) from exactly dated growth increments in a multicentennial chronology of the long-lived bivalve, Pacific geoduck (Paneopea generosa) at the Tree Nob site, coastal British Columbia, Canada. Samples were taken at approximately decadal time intervals from 1725 CE to 1920 CE and indicate average ΔR values of 256 ± 22 years (1σ) consistent with existing discrete estimates. Temporal variability in ΔR is small relative to analogous Atlantic records except for an unusually old-water event, 1802–1812. The correlation between ΔR and sea surface temperature (SST) reconstructed from geoduck increment width is weakly significant (r2 = .29, p = .03), indicating warm water is generally old, when the 1802–1812 interval is excluded. This interval contains the oldest (–2.1σ) anomaly, and that is coincident with the coldest (–2.7σ) anomalies of the temperature reconstruction. An additional 32 14C values spanning 1952–1980 were detrended using a northeastern Pacific bomb pulse curve. Significant positive correlations were identified between the detrended 14C data and annual El Niño Southern Oscillation (ENSO) and summer SST such that cooler conditions are associated with older water. Thus, 14C is generally relatively stable with weak, potentially inconsistent associations to climate variables, but capable of infrequent excursions as illustrated by the unusually cold, old-water 1802–1812 interval.

Deep oceanic overturning circulation in the Atlantic (Atlantic Meridional Overturning Circulation, AMOC) is projected to decrease in the future in response to anthropogenic warming. Caesar et al. 1 argue that an AMOC slowdown started in the 19 th century and intensified during the mid-20th century. Although the argument and selected evidence proposed have some merits, we find that their conclusions might be different if a more complete array of data available in the North Atlantic region had been considered. We argue that the strength of AMOC over recent centuries is still poorly constrained and the expected slowdown may not have started yet. K.H.K. acknowledges funding from NOAA grant NA20OAR4310481. D.E.A. and B.L.O.-B. acknowledge support from the National Center for Atmospheric Research, which is a major facility sponsored by the National Science Foundation under cooperative agreement no. 1852977. N.M.W. acknowledges support from a NOAA Climate and Global Change Postdoctoral Fellowship. M.F.J. acknowledges support from NSF award OCE-1846821 and C.M.L. acknowledges support from NSF award OCE-1805029. This is UMCES contribution 6062. Peer Reviewed Article signat per 17 autors/es: University of Maryland Center for Environmental Science, Chesapeake Biological Laboratory, Solomons, MD, USA: K. Halimeda Kilbourne / Department of Geological and Atmospheric Sciences, Iowa State University, Ames, IA, USA: Alan D. Wanamaker / Geography Department, Durham University, Durham, UK: Paola Moffa-Sanchez / Centre for Geography and Environmental Sciences, University of Exeter, Penryn, UK: David J. Reynolds, Paul G. Butler & James Scourse / Climate and Global Dynamics Laboratory, National Center for Atmospheric Research, Boulder, CO, USA: Daniel E. Amrhein & Bette L. Otto-Bliesner / Woods Hole Oceanographic Institution, Falmouth, MA, USA: Geoffrey Gebbie & Nina M. Whitney / Cooperative Institute for Marine and Atmospheric Studies, University of Miami, Miami, FL, USA: Marlos Goes / Atlantic Oceanographic and Meteorological Laboratory, National Oceanic and Atmospheric Administration, Miami, FL, USA: Marlos Goes / Department of the Geophysical Sciences, The University of Chicago, Chicago, IL, USA: Malte F. Jansen / Oceanography Department, Atmospheric and Environmental Research, Inc., Texas, TX, USA: Christopher M. Little / US Geological Survey, St Petersburg Coastal and Marine Science Center, St Petersburg, FL, USA: Madelyn Mette / Barcelona Supercomputing Center, Barcelona, Spain: Eduardo Moreno-Chamarro & Pablo Ortega / Graduate School of Oceanography, University of Rhode Island, Kingston, RI, USA: Thomas Rossby / University Corporation of Atmospheric Research, Boulder, CO, USA: Nina M. Whitney

SUMMARY Restrictions on the use of antibiotics in broiler chicken production have led to a resurgence in necrotic enteritis (NE) and heightened interest in non-antibiotic alternatives to control the problem. Probiotics, which are beneficial bacteria that improve the enteric microbial balance, and which range from defined single-organism products to complex mixtures of undefined normal gut flora (the latter known as competitive exclusion cultures) have been investigated as alternative control measures for NE, with varying results. In this study, a complex undefined competitive exclusion culture (Aviguard) was compared to bacitracin methylene disalicylate (BMD) in a NE challenge model. Male broiler chickens housed in floor pens were either treated with Aviguard on the day of hatch, fed rations containing 55 ppm of BMD, or untreated, then challenged with coccidiosis and Clostridium perfringens in a NE challenge model. One group was untreated and unchallenged. The challenge successfully induced NE as evidenced by challenge control having NE mortality (12%) and lesion scores (0.367). The Aviguard group had numerically lower lesion scores (0.267) and the Aviguard and BMD groups had significant lower mortality (8%; 9%, respectively). There were no significant treatment effects on adjusted feed conversion or body weight by 42 d. Poultry producers do not adjust feed conversion for mortality, therefore using this standard, the Aviguard treatment was the only treatment for which the feed conversion that was not adjusted for mortality was statistically the same as the unchallenged control group (1.653; 1.636, respectively).

The Geological Orrery is a network of geological records of orbitally paced climate designed to address the inherent limitations of solutions for planetary orbits beyond 60 million years ago due to the chaotic nature of Solar System motion. We use results from two scientific coring experiments in Early Mesozoic continental strata: the Newark Basin Coring Project and the Colorado Plateau Coring Project. We precisely and accurately resolve the secular fundamental frequencies of precession of perihelion of the inner planets and Jupiter for the Late Triassic and Early Jurassic epochs (223–199 million years ago) using the lacustrine record of orbital pacing tuned only to one frequency (1/405,000 years) as a geological interferometer. Excepting Jupiter’s, these frequencies differ significantly from present values as determined using three independent techniques yielding practically the same results. Estimates for the precession of perihelion of the inner planets are robust, reflecting a zircon U–Pb-based age model and internal checks based on the overdetermined origins of the geologically measured frequencies. Furthermore, although not indicative of a correct solution, one numerical solution closely matches the Geological Orrery, with a very low probability of being due to chance. To determine the secular fundamental frequencies of the precession of the nodes of the planets and the important secular resonances with the precession of perihelion, a contemporaneous high-latitude geological archive recording obliquity pacing of climate is needed. These results form a proof of concept of the Geological Orrery and lay out an empirical framework to map the chaotic evolution of the Solar System.

Uncontrollable kicks are the most costly events that occur while drilling for oil and gas. Formation water flow sometimes turns to kicks that lead to life threatening and environmentaly disastrous blowouts. Prediction of the possible abrupt pressure surges that characterize the subsurface geological setting before drilling sheds light on some of the challenges that may be encountered along the bore-hole trajectory. This will also help curtail human error during penetration of certain zones along the well-hole trajectory, and consequently reach the objective depth safely and with less nonproductive time (NPT). Before drilling, pore andfracture pressure predictions from seismic velocity are critical for assessing the economic feasibility and safety for the whole prospective trap. Integrating the seismic velocity drifts and the sequence stratigraphy semblance at the proposed location can point to the possible pressure transgressive intervals that can cause a sudden pressure surge (PS). Moreover, modifying the drilling tolerance window (DTW) to accommodate the expected hydrocarbon column in the prospective reservoirs reduces the potential of unexpected hard kicks at the shale – sand interface. This paper briefly discusses the impact of subsurface geopressure compartmentalization on seismic velocity drift and consequently on PS. It also examines the subsurface geological setting that can cause substantial pressure increase penetrating the lithological interfaces. Therefore, the pressure transgression and expected excess pressure in pay zones should be encompassed within the numerical algorithm of the predictive model before drilling. Monitoring the logging while drilling (LWD) data slopes in shale beds can successfully point to a possible kick ahead of the drill bit. Maneuvering the mud weight and casing program while drilling within the DTW based on the modified numerical pressure profile can achieve safe drilling. Examples from onshore and deep-water wells are shown. This paper covers several geological features that correlate to open bore-hole flows or kicks that sometimes develop to a blowout if the formation flow is not controlled by the right mud weight kill. Detecting these subsurface features and their associated seismic velocities before drilling can lead to safe drilling and avoiding NPT. Moreover, this paper sheds light on the potential to enhance drilling safety in advance, even in cases where managed pressure drilling (MPD) equipment is used.

WOS:000582677500029; International audience; Horizon scanning is an increasingly common strategy to identify key research needs and frame future agendas in science. Here, we present the results of the first such exercise for the field of sclerochronology, thereby providing an overview of persistent and emergent research questions that should be addressed by future studies. Through online correspondence following the 5th International Sclerochronology Conference in 2019, participants submitted and rated questions that addressed either knowledge gaps or promising applications of sclerochronology. An initial list of 130 questions was compiled based on contributions of conference attendees and reviewed by expert panels formed during the conference. Herein, we present and discuss the 50 questions rated to be of the highest priority, determined through an online survey distributed to sclerochronology community members post the conference. The final list (1) includes important questions related to mechanisms of biological control over biomineralization, (2) highlights state of the art applications of sclerochronological methods and data for solving long-standing questions in other fields such as climate science and ecology, and (3) emphasizes the need for common standards for data management and analysis. Although research priorities are continually reassessed, our list provides a roadmap that can be used to motivate research efforts and advance sclerochronology toward new, and more powerful, applications.

Given the rapid increase in atmospheric carbon dioxide concentrations (pCO2) over the industrial era, there is a pressing need to construct long‐term records of natural carbon cycling prior to this perturbation and to develop a more robust understanding of the role the oceans play in the sequestration of atmospheric carbon. Here we reconstruct the past biological and climate controls on the carbon isotopic (δ13Cshell) composition of the North Icelandic shelf waters over the last millennium, derived from the shells of the long‐lived marine bivalve mollusk Arctica islandica. Variability in the annually resolved δ13Cshell record is dominated by multidecadal variability with a negative trend (−0.003 ± 0.002‰ yr−1) over the industrial era (1800–2000 Common Era). This trend is consistent with the marine Suess effect brought about by the sequestration of isotopically light carbon (δ13C of CO2) derived from the burning of fossil fuels. Comparison of the δ13Cshell record with Contemporaneous proxy archives, over the last millennium, and instrumental data over the twentieth century, highlights that both biological (primary production) and physical environmental factors, such as relative shifts in the proportion of Subpolar Mode Waters and Arctic Intermediate Waters entrained onto the North Icelandic shelf, atmospheric circulation patterns associated with the winter North Atlantic Oscillation, and sea surface temperature and salinity of the subpolar gyre, are the likely mechanisms that contribute to natural variations in seawater δ13C variability on the North Icelandic shelf. Contrasting δ13C fractionation processes associated with these biological and physical mechanisms likely cause the attenuated marine Suess effect signal at this locality.

The lack of long-term, highly resolved (annual to sub-annual) and absolutely dated baseline records of marine variability extending beyond the instrumental period (last ~50-100 years) hinders our ability to develop a comprehensive understanding of the role the ocean plays in the climate system. Specifically, without such records, it remains difficult to fully quantify the range of natural climate variability mediated by the ocean, and to robustly attribute recent changes to anthropogenic or natural drivers. Here we present a 211-year (1799-2010 CE; all dates hereafter are common era) seawater temperature (SWT) reconstruction from the northeast Atlantic Ocean derived from absolutely dated, annually resolved, oxygen isotope ratios recorded in the shell carbonate (δ18Oshell) of the long-lived marine bivalve mollusc Glycymeris glycymeris. The annual record was calibrated using sub-annually resolved δ18Oshell values drilled from multiple shells covering the instrumental period. Calibration verification statistics and spatial correlation analyses indicate that the δ18Oshell record contains significant skill at reconstructing Northeast Atlantic Ocean mean summer SWT variability associated with changes in sub-polar gyre (SPG) dynamics and the North Atlantic Current. Reconciling differences between the δ18Oshell data and corresponding growth increment width chronology demonstrates that 68% of the variability in G. glycymeris shell growth can be explained by the combined influence of biological productivity and SWT variability. These data suggest G. glycymeris can provide seasonal to multi-centennial absolutely dated baseline records of past marine variability that will lead to the development of a quantitative understanding of the role the marine environment plays in the global climate system.

The combined influence of temperature and the isotopic composition of the seawater (δ18Ow) often precludes the use of oxygen isotope (δ18O) records, derived from marine carbonates, to reconstruct absolute seawater temperatures, without the application of an independent δ18Ow proxy. Here we investigate the application of carbon isotope records (δ13Cshell), derived from the long-lived marine bivalve Glycymeris glycymeris, as a proxy for δ18Ow variability. Our analyses indicate G. glycymeris δ13Cshell data derived from growth increments >20 years of age contain strong ontogenetic trends (−0.013‰ yr−1, R = 0.98, P

Educational games are potential tools for communicating climate science to the public and thus improving public understanding of climate change. In this article we explore the use of co-design methodologies, a participatory open design process, to communicate climate change to a wider audience. To this end, we hosted Climate Jam 2018, a game jam with the objective of creating games to communicate climate change science and to gain insight into how developers approach educational game design. The inclusive event attracted professional game developers and hobbyists from four continents. Participants received a science pack with scientific information about climate change and completed a pre- and post-game-jam survey containing questions relating to climate change, motivations, and game design principles. We present a description of select games that highlight different approaches to communicating climate change to a general audience. Additional results from the surveys showed that few game developers engaged with the science pack and other resources in depth, that communicating climate science was of medium interest to game developers, and that the games’ potential learning effects relate mostly to memorizing and recalling the information communicated in the games. The results are discussed with respect to improving communication between scientists and game developers in the co-creation process.

The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.

Over the past century, the dendrochronology technique of crossdating has been widely used to generate a global network of tree-ring chronologies that serves as a leading indicator of environmental variability and change. Only recently, however, has this same approach been applied to growth increments in calcified structures of bivalves, fish and corals in the world's oceans. As in trees, these crossdated marine chronologies are well replicated, annually resolved and absolutely dated, providing uninterrupted multi-decadal to millennial histories of ocean palaeoclimatic and palaeoecological processes. Moreover, they span an extensive geographical range, multiple trophic levels, habitats and functional types, and can be readily integrated with observational physical or biological records. Increment width is the most commonly measured parameter and reflects growth or productivity, though isotopic and elemental composition capture complementary aspects of environmental variability. As such, crossdated marine chronologies constitute powerful observational templates to establish climate–biology relationships, test hypotheses of ecosystem functioning, conduct multi-proxy reconstructions, provide constraints for numerical climate models, and evaluate the precise timing and nature of ocean–atmosphere interactions. These ‘present–past–future’ perspectives provide new insights into the mechanisms and feedbacks between the atmosphere and marine systems while providing indicators relevant to ecosystem-based approaches of fisheries management.

Crossdating is the defining technique of dendrochronology, ensuring that all measurements in a dataset are annually resolved and absolutely dated. This level of accuracy allows for the development of high-resolution environmental reconstructions of climate, disturbance, and productivity not only in trees, but also in other ring-forming organisms including fish, corals, and bivalves. However, crossdating is a laborious process and can be a significant bottleneck in the development of new chronologies, especially when attempting to find matches among undated, dead-collected material. Several software packages have been developed to aid in crossdating, yet efficiently identifying matches among large numbers of dead-collected samples of unknown antiquity remains a gap in functionality. To address this issue we present RingdateR, a new stand-alone and web-based application for statistical and graphical crossdating that shares many key features with established crossdating applications, but has been optimised for crossdating large collections of dead-collected material. The workflow allows users to load undated measurement time series in common file types (e.g. pos, lps, csv, and xlsx) to be matched against one another (i.e. pairwise analyses) or against an existing chronology. RingdateR provides graphical tools to help identify false or missed rings remaining in the matched measurement time series and to evaluate the impact of the newly crossdated measurement time series on chronology statistics. Whilst the decision as to whether a sample is correctly crossdated ultimately lies with careful visual inspection and discretion of the investigator, guidance from RingdateR can greatly expedite the process, especially when building chronologies that involve dead-collected samples.

Our understanding of North Atlantic Ocean variability within the coupled climate system is limited by the brevity of instrumental records and a deficiency of absolutely dated marine proxies. Here we demonstrate that a spatial network of marine stable oxygen isotope series derived from molluscan sclerochronologies (δ18Oshell) can provide skillful annually resolved reconstructions of key components of North Atlantic Ocean variability with absolute dating precision. Analyses of the common δ18Oshell variability, using principal component analyses (PCA), highlight strong connections with tropical North Atlantic and subpolar gyre (SPG) sea surface temperatures (SSTs) and sea surface salinity (SSS) in the North Atlantic Current (NAC) region. These analyses suggest that low frequency variability is dominated by the tropical Atlantic signal whilst decadal variability is dominated by variability in the SPG and salinity transport in the NAC. Split calibration and verification statistics indicate that the composite series produced using the PCA can provide skillful quantitative reconstructions of tropical North Atlantic and SPG SSTs and NAC SSSs over the industrial period (1864‐2000). The application of these techniques with extended individual δ18Oshell series provide powerful baseline records of past North Atlantic variability into the unobserved pre‐industrial period. Such records are essential for developing our understanding of natural climate variability in the North Atlantic Ocean and the role it plays in the wider climate system, especially on multi‐decadal to centennial timescales, potentially enabling reduction of uncertainties in future climate predictions.

In order to assess its potential as a sclerochronological archive, we present statistical and geochemical analyses of internal growth increment series in shells of the heart cockle Glossus humanus (L.), a large marine bivalve. The investigated samples were collected from Loch Sunart and the Sound of Mull, Scotland, United Kingdom. High-resolution stable isotope (δ18Ο) analyses and radiocarbon (14C) determinations indicated that G. humanus forms annual growth lines. Examination of the growth increment series revealed that the maximum longevity of G. humanus in this region was 78 years. Radiocarbon dating and crossmatching techniques, derived from dendrochronology, were used to provide an estimation of the temporal distribution of the fossil G. humanus. Of the shells that contained >25 growth increments, seven were found to statistically crossmatch, including shells from two distinct sites 15 km apart. The calibrated 14C determinations independently confirmed the crossmatching of three G. humanus shells from the Sound of Mull with a separately constructed Glycymeris glycymeris chronology and a further three G. humanus shells from site 3, in the main basin of Loch Sunart, but indicate a significant difference (site 1) in the antiquity of the two G. humanus populations. Radiocarbon dating indicated that, despite their fragile nature, G. humanus shells remain preserved in near original condition for at least 700 years. Given the small amount of available shell material, it is unlikely that G. humanus will become a key species for the construction of long absolutely dated sclerochronologies. However, these data do indicate that the\ud annually resolved G. humanus growth series could be used to supplement series from other long-lived bivalves and facilitate the construction of a robust multispecies sclerochronology spanning the last 1000 years.

There is currently a deficiency of annually-resolved temperature series from the marine environment. We present a multiproxy reconstruction of Hebridean shelf sea (Tiree Passage; NW Scotland) spring sea surface temperatures (SSTs) for the period AD 1805–2010. The reconstruction is based on the growth increment series from the first absolutely dated annually-resolved multi-centennial Glycymeris glycymeris bivalve mollusc sclerochronology coupled with previously published stable oxygen isotope data (δ18O) from benthic foraminifera sampled from a dated sediment core from nearby Loch Sunart. The independent series contain significant correlations with SSTs across complementary frequency domains. The low frequency component of the sedimentary archive was combined with the mid and high frequency components of the G. glycymeris chronology indices to create a single multiproxy series. Split calibration-verification statistics (reduction of error, RE, coefficient of efficiency, CE, and R2) indicate that the multiproxy record, calibrated to local instrumental sea surface temperatures, contains significant precision and skill at reconstructing spring SSTs (RE = 0.59, CE = 0.26, R2 = 0.54). These data demonstrate that bivalve sclerochronologies, when combined with low frequency proxies such as sediment archives, can facilitate statistically robust reconstructions of palaeoceanographic variability during the late Holocene for hydrographically-significant regions of the temperate marine system previously void of annually-resolved archives. The reconstructed SSTs contain a general warming trend of 0.60 ± 0.14 °C per century. Only four years in the reconstructed period (1999, 2000, 2002 and 2003) exceed temperatures greater than two standard deviations higher than the reconstructed mean SST (9.03 °C), whilst just three years in the first half of the 19th century (1835, 1838 and 1840) fall more than 2σ below the reconstructed mean (6.80 °C).

Cross-dated chronologies derived from internal growth increments in the shells of the long-lived bivalve, the dog cockle Glycymeris glycymeris (Linnaeus, 1758), live-collected from two different sites off the east (1997) and south (2009) coasts of the Isle of Man respectively, are described. The chronologies, developed from ten individuals from each site, were found to be statistically robust (Expressed Population Signal (EPS)=0.87 and 0.94 respectively) with a significant common growth signal despite their location 27 km apart (R = 0.53; N = 49, P = b 0.0001). The period of common growth between the two chronologies is consistent with the 12- year difference in their dates of collection thus providing evidence of an annual periodicity of growth line formation. Significant positive correlations were identified between the chronology indices from both the southern (R = 0.55, N = 58, P = b 0.0001) and eastern sites (R = 0.64, N = 68, P = b 0.0001) and mean January to September sea surface temperatures. A significant positive correlation was also found between the southern site and the winter North Atlantic Oscillation index (R=0.43; N=49, P=0.0009). These data indicate that annual growth increments in the shells of G. glycymeris have the potential to be used as a scleroclimatological archive.

A multicentennial and absolutely-dated shell-based chronology for the marine environment of the North Icelandic Shelf has been constructed using annual growth increments in the shell of the long-lived bivalve clam Arctica islandica. The region from which the shells were collected is close to the North Atlantic Polar Front and is highly sensitive to the varying influences of Atlantic and Arctic water masses. A strong common environmental signal is apparent in the increment widths, and although the correlations between the growth increment indices and regional sea surface temperatures are significant at the 95% confidence level, they are low (r ~ 0.2), indicating that a more complex combination of environmental forcings is driving growth. Remarkable longevities of individual animals are apparent in the increment-width series used in the chronology, with several animals having lifetimes in excess of 300 years and one, at 507 years, being the longest-lived non-colonial animal so far reported whose age at death can be accurately determined. The sample depth is at least three shells after AD 1175, and the time series has been extended back to AD 649 with a sample depth of one or two by the addition of two further series, thus providing a 1357-year archive of dated shell material. The statistical and spectral characteristics of the chronology are investigated by using two different methods of removing the age-related trend in shell growth. Comparison with other proxy archives from the same region reveals several similarities in variability on multidecadal timescales, particularly during the period surrounding the transition from the Medieval Climate Anomaly to the Little Ice Age.

The stable carbon isotope ratio in bivalve shells (δ13CS) is an enigmatic geochemical archive whose interpretation is often frustrated by the intrusion of variable and unpredictable vital effects which can influence the mix of metabolic and dissolved inorganic carbon (DIC) in the shell material. The impacts of vital effects and rapid changes in calcification rates on the variability and value of δ13CS have been described in a number of studies and in many bivalve species with typical lifespans between a few years and a few decades, δ13CS has been observed to change (usually decreasing) with biological age. Very long-lived animals, by contrast, spend most of their lives in the mature, slow-growing phase, and it might be expected that in these instances the effect of changes in calcification rates on δ13CS would be less marked, or even absent. Analysis of δ13CS in mature (>40years old) Arctica islandica, reported here, indicates that this is the case. δ13CS in shell samples with biological ages between 42 and 391 years from four distinct sites in the North Atlantic shelf seas (Gulf of Maine, north Icelandic shelf, Irish Sea and North Sea) shows no age-related trend. This suggests that metabolic vital effects in mature A. islandica may be reasonably stable at the population level. If the drivers of isotopic disequilibrium between shell and ambient environment can be identified and quantified, it may be feasible to adjust for them and use δ13CS in mature A. islandica to investigate long-term changes in nutrient sources and as a robust proxy for δ13C of environmental DIC.

The spatial distribution, density, growth rate, longevity, mortality and recruitment patterns of the long-lived clamArctica islandicain Belfast Lough, Northern Ireland, UK are described. TheA. islandicapopulation at Belfast Lough appears to be restricted to a small area at the mouth of the Lough. Additional searches for specimens further into the Lough and into deeper waters found no evidence of a larger more widespread population and we report population densities of 4.5 individuals m−2. The ages of the clams were determined from the number of internal annual growth lines in acetate peel replicas of shell sections. The population growth curve was fitted using the Von Bertalanffy growth equation: Lt = 93.7 mm (1−e−0.03(t–1.25)). Based on catch curve analysis, the Belfast Lough population has an estimated longevity of 220 years and a natural mortality rate of 0.02. We compare growth characteristics and life history traits in this population with other analogousA. islandicapopulations. The overall growth performance and the phi-prime index were used to compare growth parameters with data from the literature and we observed no significant relationship between the growth performance indices and longevity or latitude. Analysis of the age-structure and reconstructed dates of settlement indicate that this population has experienced almost continual recruitment over the last century with a gap in successful recruitment into the population 90–100 years ago and another 140–150 years ago. The size-structure revealed a scarcity of small individuals which we believe may be an artefact of the dredge sampling process.

In this article, we explore the use of fluorescence spectroscopy to image growth patterns in the marine bivalve Arctica islandica (L.). The method presented here does not require any chemical treatment of the polished shell section and yields results comparable to acetate peels of acid-etched shell sections and Mutveitreated shell sections. Further, our results indicate that the annual growth lines in A. islandica fluoresce in the blue light spectrum (450–490 nm), thus an ultraviolet source (mercury lamp) is not required. The reflected light entering the digital camera was filtered (510–540 nm) and later enhanced to emphasize the annual growth patterns. The fluorescence of annual growth lines was consistent among the four animals used in this study. Additionally, we measured growth increments in the umbo section of one A. islandica shell using both the traditional acetate method and fluorescence imaging. The two sets of measurements were highly correlated (r = 0.97; P < 0.0001). We suggest that the fluorescence imaging method presented here is a viable option for increment identification and measurement in this key marine archive. It is likely that the methods demonstrated here for A. islandica can easily be used/modified for other bivalve (mollusk) taxa. Fluorescence microscopy permits rapid analysis of shell growth patterns with minimal pretreatment and offers an objective method of determination of annual growth increments and lines.

A novel series of tyrosine-derived HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and two protease inhibitor-resistant viruses. All of the compounds had wild-type antiviral activities that were similar to or greater than several currently marketed HIV protease inhibitors. In addition, a number of compounds in this series were more potent against the drug-resistant mutant viruses than they were against wild-type virus.

A tandem time-of-flight (TOF-TOF) mass spectrometer comprised of two ion mirrors is described. The first ion mirror, which is a linear-field, single-stage mirror (MS1) with an intermediate collision cell, has been designed to provide the temporal focus necessary for the second, quadratic-field ion mirror (MS2) to function effectively. Due to the wide energy-range focusing capabilities of the quadratic field employed in the second ion mirror all the fragment ions can be collected in one spectrum without the need to step the reflecting working voltage of the MS2. The size of the active area of the microchannel plate detector used in the preliminary experiments was the limiting factor governing the collection efficiently of fragment ions. The use of the first ion mirror to provide temporal focusing of the precursor ion packet at the first focal point of the quadratic mirror used as the MS2 requires no alteration of the focusing conditions for different masses, in contrast to delayed extraction or postsource pulsed focusing. Precursor ions formed by matrix-assisted laser desorption/ionization were mass-selected with an ion gate located before the collision cell and the fragment ions were mass analyzed using the quadratic-field ion mirror. Experimental results demonstrating effective high-energy collision-induced dissociation of polymer and fullerene molecule-ions are presented.

This article is a summary of some of the more recent research on the diagnosis, etiology, and treatment of Cluster B personality disorders (antisocial, histrionic, borderline, and narcissistic). Research on psychological, psychosocial, and biological perspectives of these disorders is presented. Individual psychotherapy, group psychotherapy, and other forms of multi-person therapies are also discussed. Finally, perspectives on issues of countertransference when treating these personality-disordered patients are addressed.

A tandem mass spectrometer consisting of a double-focusing magnetic-sector mass analyzer in series with a time-of-flight (TOF) mass analyzer has been designed and constructed. The TOF analyzer was a quadratic-field ion mirror. The method of ionization used was matrix-assisted laser desorption/ionization. Precursor ions were mass selected with the magnetic-sector analyzer, and time focused by ion bunching prior to fragmentation in a collision cell. The fragment ions were mass analyzed with the TOF analyzer, which possessed the property that residence times (i.e., times of flight) in the mirror were independent of ion velocity. The theoretical background to the instrumental design is presented. Experimental results are presented, showing resolutions of 4000 in fragment ion spectra and demonstrating effective high-energy collision-induced decomposition of peptide molecule ions.

Traditionally, many companies have zero‐phased seismic data using operators based on wavelets estimated from well matching. However, in new areas of exploration, other methods must be used. A data example from deep‐water West Africa is discussed in which the use of two independent methods of estimating the wavelet (physical modeling and statistical evaluation) allows for increased confidence in the resulting zero‐phasing. The two methods are complimentary in that they compensate for the inadequacies of each other's assumptions. The combination of the two to reduce uncertainty in wavelet estimation is the main objective. The acquisition and processing of the data are of great importance in ensuring wavelet stability in the section and allowing the wavelet estimation methods to be used reliably. Careful application of gapped deconvolutions in the processing sequence allows for wavelet compression and consistency over large areas of data that can then be zero‐phased using a single operator, even though the data covers diverse geology and water depths.

In oral carcinogenicity bioassays, zidovudine (ZDV) induced vaginal epithelial cell tumors in mice given 30 or 40 mg/kg/day and rats given 300 mg/kg/day. To determine if lifetime exposure to ZDV, beginning perinatally, would alter this pattern of carcinogenicity, two groups of 60 pregnant CD-1 mice were given 20 or 40 mg/kg/day of ZDV in 0.5% methyl cellulose from Gestation Day 10 through Lactation Day 21. At weaning, 2 pups per sex from each of 35 litters in each group were assigned to the study and given 20 or 40 mg/kg/day of ZDV in the drinking water until 17–35 days of age, followed by daily gavage for 24 months. Two additional groups of 60 pregnant CD-1 mice each were given 40 mg/kg/day of ZDV daily from Gestation Day 10 through Lactation Day 21; in one, ZDV treatment was halted at weaning and in the other, treatment was stopped 90 days after weaning. Two other groups of 60 pregnant CD-1 mice were left untreated (environmental control) or were given 0.5% methyl cellulose beginning on Gestation Day 10 (vehicle control). Vehicle control progeny received plain drinking water for 17–35 days postweaning and then 0.5% methyl cellulose daily by gavage for 24 months. ZDV treatment did not affect survival or body weight in either sex. In females given 20 or 40 mg/kg/day of ZDV for 24 months there was mild macrocytic anemia. Similar, non-dose-related changes were seen in males in these groups. ZDV-related tumor findings were limited to the vagina, where there were 2 and 11 vaginal squamous cell carcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively. This incidence was not remarkably different from that seen in previously reported bioassays. It was concluded that lifetime oral treatment of mice with ZDV, beginning perinatally, did not alter the previously reported pattern of carcinogenicity and that under the conditions tested ZDV was not a transplacental carcinogen.

A new charged particle analyzer offering parallel and multichannel detection of a range of emitted energy and angle is described. Simultaneous multiplex detection of both these variables is achieved with the use of a two‐dimensional position sensitive detector. The instrument is so arranged that angular information is recovered from the azimuthal coordinate, and energy from the radial coordinate of each detected particle. The instrument is based upon the original ‘Bessel Box’ design of Allen and co‐workers and shares many of the favorable characteristics of that analyzer. General theoretical principles are considered and assessed, and then the actual performance of a specific device, fabricated for use in an angle resolved UV photoelectron‐photoion coincidence experiment is reported. Simple in situ control of the operational mode of the instrument is described and demonstrated with the prototype, allowing convenient selection of the most effective compromise between resolution and bandwidth.

N,N-dimethyl-n-octadecylamine borane 1¯ at 8 mg/kg/day, tetrakis-u-(trimethylamine boranecarboxylato)-bis(trimethyl-carboxyborane)-dicopper(II) 2¯ at 2.5 mg/kg/day and trimethylamine-carboxyborane 3¯ at 8 mg/kg/day were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent administered orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and compounds 2¯ and 3¯ increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic agent in rats. The three agents did decrease cholesterol absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholsterol-7-α -hydroxylase, sn glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase, were reduced. However, the boron derivatives 1¯ and 3¯ decreased hepatic HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, but the compounds had no effects on small intestinal mucosa HMG-CoA reductase activity. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat.

We report the design, construction and performance of an energy resolved time-of-flight (ER-TOF) mass spectrometer. The system consists of a linear TOF coupled in parallel to the electric sector of a large double-focussing magnetic-sector mass spectrometer. The use of lensing between the TOF and the electric sector is discussed with respect to the required beam conditions. Ion transmission through the electric sector is treated theoretically, especially with respect to time-of-flight. Preliminary experimental results from the instrument using matrix-assisted laser desorption—ionisation are presented and discussed, with particular regard to the fragmentation of large ions.

Arrangements to encode the position of a particle incident on a microchannel plate detector in less than 1 mu s are described. This permits operation in a pulse-counting mode at high count-rates with minimal losses due to paralysis, while maintaining high spatial resolution. Results obtained indicate that a spatial resolution of better than 0.25% of the detector dimension is achievable.

The hyperelasticity condition imposed on a material in which the stress is given as a function of the deformation gradient requires the existence of a strain-energy density function. If the material is incompressible, the indeterminacy of the pressure field is normally an additional postulate on material behavior. However, it is shown that in the case of a material in which the strain is determined as a function of an appropriately chosen stress measure, hyperelasticity demands the existence of a complementary strain-energy density function and the incompressibility condition isequivalent to the indeterminacy of the pressure field. The dependence of the complementary strain-energy density on the pressure, necessary and sufficient for incompressibility, is presented.

6,7-Dihydro-5 H -dibenz(c,e)azepine (azepine) and lovastatin were investigated for their hypolipidemic activity in Sprague–Dawley male rats. Azepine lowered both serum total cholesterol and serum triglyceride levels, whereas lovastatin only lowered serum total cholesterol levels significantly. Lovastatin also elevated lipid levels in tissues, whereas azepine in general did not have a similar effect. High-density lipoprotein cholesterol levels were significantly elevated and low-density lipoprotein cholesterol levels were reduced after treatment with both agents. Concentrations of ApoE and ApoAl of high-density lipoprotein were increased after treatment, a result that should enhance the reverse cholesterol transport process of returning cholesterol to the liver for excretion. Azepine appeared to be safe in its therapeutic range in rodents.

The cyclic imides, o-(N-phthalimido)acetophenone, 2,3-dihydrophthazine-1,4-dione and N(4-methyl phenyl)diphenimide, were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent at 20 mg/kg/day orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic in rats. The three agents did decrease cholesterol and cholic acid absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha hydroxylase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase were reduced. However, the cyclic imides did not accelerate HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, in a manner which would accelerate biliary cholesterol excretion. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat.

2-Furoic acid was shown to be effective in lowering both serum cholesterol and serum triglyceride levels significantly in rats with an elevation of HDL cholesterol level at 20 mg/kg/day orally. LDL receptor activity was reduced in hepatocytes, aorta foam cells, small intestinal epithelium cells and fibroblasts. HDL receptor activity was elevated in the rat hepatocytes and small intestinal cells. These activities were correlated with inhibition of acyl CoA cholesterol acyl transferase activity. Neutral cholesterol ester hydrolase activity was elevated in rat hepatocytes and human fibroblasts. Thus, 2-furoic acid appears to interfere directly with activity of intracellular enzymes rather than affecting high affinity-mediated lipoprotein membrane receptors. In vivo treatment with 2-furoic acid led to reduction in the liver and small intestine ATP dependent citrate lyase, acetyl CoA synthetase, acyl CoA cholesterol acyl transferase, sn-glycerol 3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin induced lipoprotein lipase activities. 2-Furoic acid reduced biliary cholesterol levels but the agent increased bile salts which are lithogenic. Acute toxicity studies in mice suggest that the agent has some hepatic toxicity effects. The LD50 was relatively low at 250 mg/kg IP in mice.

6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid (AMMPCA) was found to be a potent hypolipidemic agent at oral closes of 10 and 20 mg/kg/day in rodents. This agent was observed to affect de novo lipid synthesizing enzyme activities in a manner that resulted in lower lipid levels in tissues including the aorta wall. Very low density lipoprotein and low density lipoprotein cholesterol levels were reduced, whereas high density lipoprotein cholesterol levels were significantly increased. AMMPCA interfered with low density receptor activity, suggesting that the drug blocked lipid uptake by peripheral tissue while stimulating binding of lipid to the high density lipoprotein receptor, which should accelerate lipid clearance from the tissues and blood. A second mode of action of the drug is enhanced biliary excretion of lipids, but there was no evidence of a lithogenic effect. Acute toxicity studies in rodents support the fact that AMMPCA is safe in its therapeutic dose range.

The potent and selective activity of 6-methoxypurine arabinoside (9-[β-D-arabinofuranosyl]-6-methoxy-9H-purine; 1) and its pharmacokinetic limitations have been described previously. In an attempt to circumvent first-pass catabolism following oral administration, a series of 5′-esters (2a-t) was prepared by dicyclohexyl-carbodiimide-promoted condensation with formic acid in the case of 2a, or by direct acylation of the parent nucleoside with the corresponding acyl chloride. These compounds were evaluated in rats for efficacy as oral prodrugs of 1 by measuring the amount of 1 excreted in the urine. Both aliphatic and aromatic esters exhibited a range of systemic availabilities. The substituted benzoate esters showed a correlation between the amount of 1 excreted and the electron-donating properties of the substituent. A similar relationship was observed for the relative stabilities of this series of esters to non-enzymatic hydrolysis at neutral pH. No clear relationship between systemic availability and solubility, partition coefficient, or stability was observed for the remaining esters of 1. Although significant enhancements in systemic availability were observed with some of the 5′-esters of this series, their limited water solubility precluded their use in intravenous formulations.

6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavourable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5'-diesters of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3'-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.

N(4-Methylphenyl)diphenimide proved to be an effective hypolipidemic agent in rats at 10 and 20 mg/kg/day. Both serum cholesterol and triglyceride levels were reduced significantly. Decreases in tissue lipids as well as VLDL cholesterol levels were observed. HDL-cholesterol was elevated even at 10 mg/kg/day. The agent was equally effective in hyperlipidemic diet-induced rats, lowering serum lipids and VLDL- and LDL-cholesterol while elevating HDL-cholesterol levels. The drug interfered with the incorporation of 3H-cholesterol and 3H-palmitic acid into chylomicrons, VLDL, and LDL. The two precursors were incorporated at a higher rate into HDL.3H-Leucine was incorporated into chylomicrons, VLDL, and LDL at a higher rate, but not into HDL. Reduced uptake of the precursor for lipid synthesis was noted in tissues after treatment with the drug.

The first five electronically excited states of PF+3 generated by He i photoionization are found to dissociate exclusively to PF+2 with dynamically distinct mechanisms. A pronounced correlation is observed between the direction of ejection of the photoelectron and the photofragment ion which issue from individual photoionization events, from which it is inferred that both the photoelectron emission and the subsequent unimolecular ion dissociation are highly anisotropic processes. Measurement of the kinetic energy which accompanies PF+2 formation at its experimental onset is used to identify the preferred thermochemical threshold value for this ion.

A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.

A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.

GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl 3 ) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.

GW4511, GW4751, and GW3011 showed IC50 values ≤2 nM against wild type HIV-1 and