Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning

Some , And Possibly All, Scalar Inferences Are Not Delayed: Evidence For Immediate Pragmatic Enrichment

Scalar inferences are commonly generated when a speaker uses a weaker expression rather than a stronger alternative, e.g., John ate some of the apples implies that he did not eat them all. This article describes a visual-world study investigating how and when perceivers compute these inferences. Participants followed spoken instructions containing the scalar quantifier some directing them to interact with one of several referential targets (e.g., Click on the girl who has some of the balloons). Participants fixated on the target compatible with the implicated meaning of some and avoided a competitor compatible with the literal meaning prior to a disambiguating noun. Further, convergence on the target was as fast for some as for the non-scalar quantifiers none and all. These findings indicate that the scalar inference is computed immediately and is not delayed relative to the literal interpretation of some. It is argued that previous demonstrations that scalar inferences increase processing time are not necessarily due to delays in generating the inference itself, but rather arise because integrating the interpretation of the inference with relevant information in the context may require additional time. With sufficient contextual support, processing delays disappear

Mars analysis correction data assimilation: a multi-annual reanalysis of atmospheric observations for the red planet

Ever-increasing numbers of atmospheric observations from orbiting spacecraft, and increasingly sophisticated numerical atmospheric models, have recently permitted data assimilation techniques to be applied to planets beyond the Earth. Mars is the first extra-terrestrial planet for which reanalyses of the atmospheric state are now available. The Thermal Emission Spectrometer (TES) on board NASA’s Mars Global Surveyor (MGS) has produced an extensive atmospheric data set during its scientific mapping phase between 1999 and 2004. Nadir thermal profiles for the atmosphere below about 40 km altitude, and total dust and water ice opacities, have been retrieved from TES spectra, covering almost three complete Martian seasonal cycles (each seasonal cycle on Mars corresponds to 668.6 mean solar days, and the Martian mean solar day is about 24 hours and 40 minutes). Note that dust on Mars plays a key role in the weather and climate, mainly through its strong absorption of short wave radiation with a short radiative relaxation timescale of 1-2 days. Assimilating dust opacities correctly is, therefore, particularly important for atmospheric data assimilation on the Red Planet. TES retrieved observations have been analysed by assimilation into a Mars general circulation model (MGCM), making use of a sequential procedure known as the Analysis Correction scheme, a form of successive corrections method which has proved simple and robust under Martian conditions, even during the less-than-ideal MGS aerobraking period. The MGCM used at the University of Oxford and at The Open University consists of a spectral dynamical solver and a tracer transport scheme developed in the UK. Its package of state-of-the-art physical parameterization routines is shared with the LMD-MarsGCM, developed by the Laboratoire de Météorologie Dynamique in Paris (France). One limitation of TES is that relatively few limb profiles are available, compared to nadir soundings. Our MGS/TES reanalysis, therefore, does not include observations of temperature above about 40 km altitude, nor 3D information on dust opacity (the vertical distribution of dust opacity is prescribed assuming a well mixed dust layer with a rapid transition to a clear upper atmosphere at a height which depends on latitude and season. In September 2006 NASA’s Mars Reconnaissance Orbiter (MRO) started its mapping phase. The Mars Climate Sounder (MCS) on board MRO is a radiometer with eight mid- and far-infrared channels and one visible channel, which takes measurements in limb and off-nadir geometries. Retrieved vertical profiles of temperature, dust and water ice opacities from MCS observations can now be assimilated using the same scheme we used for TES, with the advantage of the extension in altitude (thermal profiles can extend to above 80 km altitude, although errors become larger at greater altitudes), the increased vertical resolution (~ 5km compared to > 10km for TES nadir retrievals), and the direct information on the vertical distribution of dust and water ice. Overall, the application of our data assimilation scheme to retrieved observations from TES and MCS spans almost six complete Martian seasonal cycles. This represents a multi-annual climatology for Mars, which has the advantage of being a complete, dynamically-balanced, four-dimensional best-fit to observations for all the atmospheric variables, including those for which no direct measurements are available (e.g. wind and surface pressure) and with regions of no observations filled-in in a physically-consistent way. The reanalysis represents, therefore, a unique opportunity to study the inter-annual variability of the Martian weather and climate with respect to all its components, such as the dust cycle, the water cycle, the CO2 cycle, the atmospheric tides and other prominent waves, such as high latitude baroclinic waves. In this contribution we present the first results of a complete assimilation of both datasets, using a consistent model and data assimilation scheme, and highlight the challenges of combining TES and MCS data assimilation to produce a multi-annual climatology. Particular attention will be devoted to the inter-annual variability of the atmospheric thermal field in response to dust storm activity. We will also provide an insight into the dynamics, looking in particular at the high latitude winds, waves and polar vortices. Our data assimilation products are freely available to the community for both science- and engineering-oriented purposes. The British Atmospheric Data Centre (BADC, http://badc.nerc.ac.uk) hosts our datasets, which, for the time being, are limited to the MGS/TES reanalysis. People may contact the corresponding author in order to register their interest and be updated about the status of the project. New versions of the MGS/TES reanalysis as well as the MRO/MCS reanalysis will be made available through the BADC in future. Interested people can download the current TES reanalysis dataset by registering at the BADC and searching for the MACDA (“Mars Analysis Correction Data Assimilation”) project. The direct link to the project is provided by the following URL: http://badc.nerc.ac.uk/view/badc.nerc.ac.uk__ATOM__DE_095e8da2-cf02-11e0-8b7a-00e08147026

The UN in the lab

We consider two alternatives to inaction for governments combating terrorism, which we term Defense and Prevention. Defense consists of investing in resources that reduce the impact of an attack, and generates a negative externality to other governments, making their countries a more attractive objective for terrorists. In contrast, Prevention, which consists of investing in resources that reduce the ability of the terrorist organization to mount an attack, creates a positive externality by reducing the overall threat of terrorism for all. This interaction is captured using a simple 3×3 “Nested Prisoner’s Dilemma” game, with a single Nash equilibrium where both countries choose Defense. Due to the structure of this interaction, countries can benefit from coordination of policy choices, and international institutions (such as the UN) can be utilized to facilitate coordination by implementing agreements to share the burden of Prevention. We introduce an institution that implements a burden-sharing policy for Prevention, and investigate experimentally whether subjects coordinate on a cooperative strategy more frequently under different levels of cost sharing. In all treatments, burden sharing leaves the Prisoner’s Dilemma structure and Nash equilibrium of the game unchanged. We compare three levels of burden sharing to a baseline in a between-subjects design, and find that burden sharing generates a non-linear effect on the choice of the efficient Prevention strategy and overall performance. Only an institution supporting a high level of mandatory burden sharing generates a significant improvement in the use of the Prevention strategy

Bayesian Methods for Exoplanet Science

Exoplanet research is carried out at the limits of the capabilities of current telescopes and instruments. The studied signals are weak, and often embedded in complex systematics from instrumental, telluric, and astrophysical sources. Combining repeated observations of periodic events, simultaneous observations with multiple telescopes, different observation techniques, and existing information from theory and prior research can help to disentangle the systematics from the planetary signals, and offers synergistic advantages over analysing observations separately. Bayesian inference provides a self-consistent statistical framework that addresses both the necessity for complex systematics models, and the need to combine prior information and heterogeneous observations. This chapter offers a brief introduction to Bayesian inference in the context of exoplanet research, with focus on time series analysis, and finishes with an overview of a set of freely available programming libraries.Comment: Invited revie

Mosaic DNA imports with interspersions of recipient sequence after natural transformation of Helicobacter pylori

Helicobacter pylori colonizes the gastric mucosa of half of the human population, causing gastritis, ulcers, and cancer. H. pylori is naturally competent for transformation by exogenous DNA, and recombination during mixed infections of one stomach with multiple H. pylori strains generates extensive allelic diversity. We developed an in vitro transformation protocol to study genomic imports after natural transformation of H. pylori. The mean length of imported fragments was dependent on the combination of donor and recipient strain and varied between 1294 bp and 3853 bp. In about 10% of recombinant clones, the imported fragments of donor DNA were interrupted by short interspersed sequences of the recipient (ISR) with a mean length of 82 bp. 18 candidate genes were inactivated in order to identify genes involved in the control of import length and generation of ISR. Inactivation of the antimutator glycosylase MutY increased the length of imports, but did not have a significant effect on ISR frequency. Overexpression of mutY strongly increased the frequency of ISR, indicating that MutY, while not indispensable for ISR formation, is part of at least one ISR-generating pathway. The formation of ISR in H. pylori increases allelic diversity, and contributes to the uniquely low linkage disequilibrium characteristic of this pathogen

Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers

Rationale: Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. Objectives: To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. Methods: Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. Measurements and Main Results Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively). Conclusions: Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders

miR-155 in the progression of lung fibrosis in systemic sclerosis

Background\ud MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used.\ud \ud Methods\ud RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2–3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin.\ud \ud Results\ud Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice.\ud \ud Conclusions\ud miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD