Triton's surface age and impactor population revisited in light of Kuiper Belt fluxes: Evidence for small Kuiper Belt objects and recent geological activity

Neptune's largest satellite, Triton, is one of the most fascinating and enigmatic bodies in the solar system. Among its numerous interesting traits, Triton appears to have far fewer craters than would be expected if its surface was primordial. Here we combine the best available crater count data for Triton with improved estimates of impact rates by including the Kuiper Belt as a source of impactors. We find that the population of impactors creating the smallest observed craters on Triton must be sub-km in scale, and that this small-impactor population can be best fit by a differential power-law size index near -3. Such results provide interesting, indirect probes of the unseen small body population of the Kuiper Belt. Based on the modern, Kuiper Belt and Oort Cloud impactor flux estimates, we also recalculate estimated ages for several regions of Triton's surface imaged by Voyager 2, and find that Triton was probably active on a time scale no greater than 0.1-0.3 Gyr ago (indicating Triton was still active after some 90% to 98% of the age of the solar system), and perhaps even more recently. The time-averaged volumetric resurfacing rate on Triton implied by these results, 0.01 km$^3$ yr$^{-1}$ or more, is likely second only to Io and Europa in the outer solar system, and is within an order of magnitude of estimates for Venus and for the Earth's intraplate zones. This finding indicates that Triton likely remains a highly geologically active world at present, some 4.5 Gyr after its formation. We briefly speculate on how such a situation might obtain.Comment: 14 pages (TeX), plus 2 postscript figures Stern & McKinnon, 2000, AJ, in pres

Translational Epidemiology In Psychiatry: Linking Population To Clinical And Basic Sciences

Translational research generally refers to the application of knowledge generated by advances in basic sciences research translated into new approaches for diagnosis, prevention, and treatment of disease. This direction is called bench-to-bedside. Psychiatry has similarly emphasized the basic sciences as the starting point of translational research. This article introduces the term translational epidemiology for psychiatry research as a bidirectional concept in which the knowledge generated from the bedside or the population can also be translated to the benches of laboratory science. Epidemiologic studies are primarily observational but can generate representative samples, novel designs, and hypotheses that can be translated into more tractable experimental approaches in the clinical and basic sciences. This bedside-to-bench concept has not been explicated in psychiatry, although there are an increasing number of examples in the research literature. This article describes selected epidemiologic designs, providing examples and opportunities for translational research from community surveys and prospective, birth cohort, and family-based designs. Rapid developments in informatics, emphases on large sample collection for genetic and biomarker studies, and interest in personalized medicine—which requires information on relative and absolute risk factors—make this topic timely. The approach described has implications for providing fresh metaphors to communicate complex issues in interdisciplinary collaborations and for training in epidemiology and other sciences in psychiatry. Translational research generally refers to the application of knowledge generated by advances in basic sciences research translated into new approaches for prevention, diagnosis, and treatment of disease, followed by the introduction of innovations into clinical practice and health policy. This direction is called bench-to-bedside. Translational research has received increasing priority in recent years, by means of the National Institutes of Health's Road Map Plan, newly launched scientific journals (eg, http:// www.sciencetranslationalmedicine.org), new career programs, and the Clinical and Translational Science Award program. This emphasis is not just within the United States: the British Medical Research Council in 2007 established new translational medicine centers, one of which is devoted to translational epidemiology, and translational research has served as a centerpiece of the European Commission health budget. Psychiatry has similarly emphasized the basic sciences as the starting point of translational research. Wang et al, in an explicit application of translation research to psychiatry, applied the Institute of Medicine's recommendations for translational research to schizophrenia and other psychotic disorders. They describe the application of 2 translational blocks. The first block, called T1, translates discoveries from the basic sciences into new diagnostic and preventive interventions, including early identification of high-risk individuals and new methods for testing interventions. In the second block, called T2, resulting clinical developments are received in clinical practice in comparative effectiveness studies, bridging the gap between diagnosis and actual treatment, providing health education, and changing prescribing practices. Within this bench-to-bedside framework, Wang et al argue, clinical epidemiology has played an important role in the design of clinical trials, prevention, health education, and service delivery. The purpose of this article is to expand the term translational epidemiology into psychiatric research as a bidirectional concept in which the bedside, ie, the population, can also be translated into the benches of laboratory science. This approach uses epidemiologic designs and findings to facilitate or to partner with basic science research. We will apply this concept of translational epidemiology to psychiatry and demonstrate that the representative samples, novel designs, and hypotheses offered by epidemiology can be translated into more tractable experimental approaches in the clinical and basic sciences. Because the validity, interpretation, and generalizability of findings vary by design, we provide a brief overview of core epidemiologic designs and provide illustrations of translational applications with each design. The discussion of design is not intended as a substitute for an exhaustive review of epidemiologic design, for which we direct the reader to one of many excellent textbooks. We also do not intend to appropriate bedside-to-bench as a novel direction. There are a number of classic examples in medicine, such as the epidemiologic observation of the relationship between smoking and lung cancer, which led to animal studies demonstrating the carcinogenic effect of nicotine and other cigarette toxins. This approach does not contradict the literature on bench-to-bedside translation; rather, it is complementary and iterative. The use of epidemiology in bedside-to-bench translational research in psychiatry has not been fully explicated, even though a number of studies appearing in the psychiatric literature have indirectly used epidemiologic designs. It is useful to make this idea explicit because epidemiology can provide hypotheses, designs, and samples for basic research, and the failure to avail oneself of these resources can lead to lost opportunities. Furthermore, different epidemiologic designs answer different questions, and inappropriate designs or inferences, particularly generalization of findings across designs, can confound results

Clonal Tracking of Rhesus Macaque Hematopoiesis Highlights a Distinct Lineage Origin for Natural Killer Cells

SummaryAnalysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16+/CD56− peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Innovation in health economic modelling of service improvements for longer-term depression: demonstration in a local health community

Background The purpose of the analysis was to develop a health economic model to estimate the costs and health benefits of alternative National Health Service (NHS) service configurations for people with longer-term depression. Method Modelling methods were used to develop a conceptual and health economic model of the current configuration of services in Sheffield, England for people with longer-term depression. Data and assumptions were synthesised to estimate cost per Quality Adjusted Life Years (QALYs). Results Three service changes were developed and resulted in increased QALYs at increased cost. Versus current care, the incremental cost-effectiveness ratio (ICER) for a self-referral service was £11,378 per QALY. The ICER was £2,227 per QALY for the dropout reduction service and £223 per QALY for an increase in non-therapy services. These results were robust when compared to current cost-effectiveness thresholds and accounting for uncertainty. Conclusions Cost-effective service improvements for longer-term depression have been identified. Also identified were limitations of the current evidence for the long term impact of services

Neural correlates of attention-executive dysfunction in lewy body dementia and Alzheimer's disease.

Attentional and executive dysfunction contribute to cognitive impairment in both Lewy body dementia and Alzheimer's disease. Using functional MRI, we examined the neural correlates of three components of attention (alerting, orienting, and executive/conflict function) in 23 patients with Alzheimer's disease, 32 patients with Lewy body dementia (19 with dementia with Lewy bodies and 13 with Parkinson's disease with dementia), and 23 healthy controls using a modified Attention Network Test. Although the functional MRI demonstrated a similar fronto-parieto-occipital network activation in all groups, Alzheimer's disease and Lewy body dementia patients had greater activation of this network for incongruent and more difficult trials, which were also accompanied by slower reaction times. There was no recruitment of additional brain regions or, conversely, regional deficits in brain activation. The default mode network, however, displayed diverging activity patterns in the dementia groups. The Alzheimer's disease group had limited task related deactivations of the default mode network, whereas patients with Lewy body dementia showed heightened deactivation to all trials, which might be an attempt to allocate neural resources to impaired attentional networks. We posit that, despite a common endpoint of attention-executive disturbances in both dementias, the pathophysiological basis of these is very different between these diseases.This work was supported by an Intermediate Clinical Fellowship . Grant Number: (WT088441MA) to John‐Paul Taylor the National Institute for Health Research (NIHR), and Newcastle Biomedical Research Unit (BRU) based at Newcastle upon Tyne Hospitals NHS Trust, Newcastle University