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Computing phenotypic similarity has been shown to be useful in identification of new disease genes and for rare disease diagnostic support. Genotype–phenotype data from orthologous genes in model organisms can compensate for lack of human data to greatly increase genome coverage. Work over the past decade has demonstrated the power of cross-species phenotype comparisons, and several cross-species phenotype ontologies have been developed for this purpose. The relative contribution of different model organisms to computational identification of disease-associated genes is not yet fully explored. We use methods based on phenotype ontologies to semantically relate phenotypes resulting from loss-of-function mutations in different model organisms to disease-associated phenotypes in humans. Semantic machine learning methods are used to measure how much different model organisms contribute to the identification of known human gene–disease associations. We find that mouse genotype-phenotype data is the most important dataset in the identification of human disease genes by semantic similarity and machine learning over phenotype ontologies. Data from other model organisms does not improve identification over that obtained by using the mouse alone, and therefore does not contribute significantly to this task. Our work has implications for the future development of integrated phenotype ontologies, as well as for the use of model organism phenotypes in human genetic variant interpretation., King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under Award No.URF/1/3790-01-01, URF/1/4355-01-01, and FCC/1/1976-34-01.

It is often argued that, because she would always be in the position to waive it, a person cannot owe a duty to herself. In a recent AJP article, Janis David Schaab argues that a person can owe a d...

Here we report for the first time a laboratory challenge model for Enterocytozoon hepatopenaei (EHP) to determine the difference of two Specific Pathogen Free (SPF) lines of Penaeus vannamei shrimp. These lines were experimentally challenged using EHP-infected fecal strings as inoculum. Real-time PCR and histopathology assays were performed to confirm EHP infection and evaluate differences in EHP susceptibility in the two genetic lines screened. Although the histopathology of the hepatopancreas tissue showed EHP lesions in both challenged groups, the histological lesions were more pronounced in one of the SPF lines. Quantitative PCR results revealed that animals displaying less hepatocellular damage have lower EHP load compared to animals displaying more pronounced pathological changes. There was no significant difference in final survival at 36 days post-infection in these lines with survival ranging between 80 and 100%. The data showed that mortality as an endpoint metric is not a suitable parameter to determine genetic susceptibility to EHP. Instead, histopathological changes in hepatopancreas, EHP load of the same tissue, and growth retardation would be better metrics to screen EHP susceptibility in P. vannamei. The results show the feasibility of screening genetic lines of P. vannamei for EHP resistance/tolerance using fecal string as an inoculum and, assessing histopathological changes, EHP load, and weight as indicators of resistance.

This chapter is concerned with Michael Haneke’s Funny Games and the role of imagination in cinematic engagement. Drawing upon the work of Richard Moran, the chapter shows how Funny Games makes the case that a film’s audience is, through its imaginative engagement, morally implicated in the events depicted on screen. I demonstrate that Funny Games develops certain themes found in Moran’s “The Expression of Feeling in Imagination.” While the bulk of Moran’s article is devoted to attacking a particular trend in the philosophical aesthetics literature, wherein film viewing is understood as an exercise in make-believe, Moran ends on a constructive note, recommending additional ways that imagination might be deployed for the purpose of appreciating art. My suggestion is that Funny Games uses the resources of its medium to investigate the role of imagination in our engagement with film in ways first suggested by Moran, thereby engaging philosophically with questions about aesthetics, art, and the philosophy of film.

In this paper, I appeal to the notion of practical identity in order to defend the possibility of synchronic duties to the self—that is, self-directed duties focused on one’s present self as opposed to one’s future self. While many dismiss the idea of self-directed duties, I show that a person may be morally required to act in ways that advance her present interests and autonomy by virtue of her occupying multiple practical identities at a single moment.

Background Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations. Objectives We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool. Methods As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability. Results Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95). Conclusions We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.

Duty to self has not been taken seriously by contemporary moral and political philosophers, with many even denying the coherence of the notion. Morality and politics concern treatment of others, according to common understanding, and so the very idea of a duty to oneself is thought to be mistaken. Against this, this book aims to vindicate the idea of duties owed by a person to herself, within both the moral and the political domains. Temporal divisions within a life, as well as between practical identities, enable an individual to relate to herself second-personally as she would to another, and thus to owe herself obligations. This book argues that such duties have implications for ethics, practical reasoning, and moral psychology. It also advances a new justification for paternalistic laws, which appeals to the notion of political self-duty.

This chapter lays out and then develops the “waivability objection,” which has throughout philosophy’s history been the most serious objection to duties to the self. The objection holds that a person who has a duty to herself will always be in a position to waive it, and a duty that a person can simply escape by waiving it is no duty at all. Some attempts to answer this objection, including Kant’s, are considered and rejected. The chapter concludes that this objection is formidable and that any account of duties to the self should be constructed in response to it.

This chapter argues for the existence of political duties owed to the self, which justify state coercion for the sake of the individual coerced. A person can pose a threat to her own freedom, and to her own ability to acquire what she is owed. Thus, a person’s relationship to herself raises concerns about both right and justice, thereby licensing the state to subject her to paternalistic policy, justified on liberal grounds. Paternalistic laws discussed include those outlawing tobacco, those limiting the amount of debt a person can take on, forced savings programs, and prohibitions on slavery contracts.

This chapter argues that a person can owe second-personal duties to herself at a moment, rather than merely across time. At a single moment, a person occupies multiple perspectives, associated with different practical identities. The good associated with one of her practical identities can conflict with the good associated with another practical identity, and her ends adopted from the standpoint of one identity can conflict with her ends adopted by another. Because of this, a person can make demands on herself from the perspective of one practical identity to another, pertaining to the protection of her wellbeing and ends, just as she might make demands on another person. Such demands can generate second-personal duties, which require that a person treat herself a particular way in the present. Since some duties owed to the self cannot be waived due to their relationship to the individual’s identity, the waivability objection is answered.

This chapter argues that a person can owe second-personal duties to herself by virtue of the fact that she occupies multiple temporal perspectives. An individual’s wellbeing at one time can conflict with her wellbeing at another time, and her ends at one moment can conflict with her ends at another moment. Because of this, a person can make demands on herself from one temporal perspective to another, pertaining to the protection of her wellbeing and ends, just as she might make demands on another person. Such demands can generate second-personal duties across time, as they can when they are issued interpersonally, and so a person can owe duties to her past and future selves, just as she owes them to others. Since duties owed to the self at a time other than the present cannot be waived, the waivability objection is answered.

This chapter introduces the concept of duties to the self, situating it within our everyday thought and talk, as well as within the history of moral philosophy. Contemporary dismissals of self-duty are discussed, as are contemporary Kantian attempts to appeal to the notion without vindicating it, and it is concluded that there exists a need for a comprehensive defense of duties to the self. The chapter concludes by noting the lack of discussion of self-duty within political philosophy, and by raising the possibility of paternalistic law justified through appeal to state-enforced duties to the self.

This chapter considers lines of inquiry that emerge from the argument pursued throughout the book. It considers the possibility, raised by Kant, that self-duty is a necessary ground for all duty. It considers a debate between Kant and Fichte about the nature of self-consciousness, discussing ways in which the account in the book might illuminate that debate. Finally, it considers the implication of holding, as this book does, that parts of a unified whole can relate to one another second-personally, and applies this thought to debates in political philosophy about communitarianism and liberalism.

This chapter discusses difficulties with the idea that there exist duties to the self that the state may paternalistically force a person to discharge. The liberal tradition typically prizes freedom, and so views with suspicion any suggestion that a person ought to be coerced for her own sake. State coercion is permissible only to realize right and justice, which are usually thought to regulate relationships between distinct persons. Since a person’s relationship to herself is typically not thought to be one regulated by right or justice, coercion of a person for her own sake has been consistently rejected within the liberal tradition.

This chapter distinguishes between mere self-regarding reasons to treat oneself in particular ways, and more robust moral duties owed to oneself. While the former are a philosophical commonplace, the latter are absent from most contemporary accounts and their addition to our practical philosophy would be significant. Duties owed to the self are second-personal, in the sense of being directed at a specific person. When a person has a duty to herself, her reasons are particularly strict, they pre-empt other reasons, they require a special sort of acknowledgment of their moral quality, and they engage special moral emotions. As such, if a person accepts that she owes duties to herself, it will impact the way in which she treats herself, and the way she relates to herself, beyond the mere acknowledgment that she has self-regarding reasons.

Voluntarists in the early modern period speak of an agent’s following the law because she was ordered to do so or because it’s the law. Contemporary philosophers tend either to ignore or to dismiss...

The International Energy Agency Technology Collaboration Programme for Ocean Energy Systems (OES) initiated the OES Wave Energy Conversion Modelling Task, which focused on the verification and validation of numerical models for simulating wave energy converters (WECs). The long-term goal is to assess the accuracy of and establish confidence in the use of numerical models used in design as well as power performance assessment of WECs. To establish this confidence, the authors used different existing computational modelling tools to simulate given tasks to identify uncertainties related to simulation methodologies: (i) linear potential flow methods; (ii) weakly nonlinear Froude–Krylov methods; and (iii) fully nonlinear methods (fully nonlinear potential flow and Navier–Stokes models). This article summarizes the code-to-code task and code-to-experiment task that have been performed so far in this project, with a focus on investigating the impact of different levels of nonlinearities in the numerical models. Two different WECs were studied and simulated. The first was a heaving semi-submerged sphere, where free-decay tests and both regular and irregular wave cases were investigated in a code-to-code comparison. The second case was a heaving float corresponding to a physical model tested in a wave tank. We considered radiation, diffraction, and regular wave cases and compared quantities, such as the WEC motion, power output and hydrodynamic loading. The Danish partners acknowledge the support from the Danish Energy Agency through project 374 64017-05197. The Swedish partners were supported by the Swedish Energy Agency under Grants P44423-1 and 375 P44432-1. J.V.R. and G.G. acknowledge the support by Science Foundation Ireland under Grant 13/IA/1886. This research was made possible by support from U.S. the Department of Energy’s EERE Water Power Technologies Office. Sandia National Laboratories is a multi-mission laboratory managed and operated by National Technology and Engineering Solutions of Sandia, LLC., a wholly owned subsidiary of Honeywell International, Inc., for the U.S. Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525. This work was authored (in part) by the National Renewable Energy Laboratory, operated by Alliance for Sustainable Energy, LLC, for the U.S. Department of Energy (DOE) under Contract No. DE-AC36-08GO28308. Funding was provided by the U.S. Department of Energy Office of Energy Efficiency and Renewable Energy Wind Energy Technologies Office. The views expressed in this article do not necessarily represent the views of the DOE or the U.S. Government. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledge that the U.S. Government retains a non-exclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this work, or allow others to do so, for U.S. Government purposes.

OBJECTIVES To measure serial interleukin (IL)-6 levels in newly diagnosed patients with giant cell arteritis (GCA), treated in a randomized controlled trial of modified-release prednisone (MR) vs immediate-release prednisolone (IR) used in a tapering regimen conforming to British Society for Rheumatology GCA guidelines. METHODS Patients (n = 12) were randomized into 2 treatment arms (7 MR, 5 IR) and followed over 26 weeks. We measured IL-6 with additional markers. RESULTS A significantly higher overall mean IL-6 level (P

Study objective Online educational resources such as blogs are increasingly used for education by emergency medicine clinicians. The Social Media Index was developed to quantify their relative impact. The Medical Education Translational Resources: Indicators of Quality (METRIQ) study was conducted in part to determine the association between the Social Media Index score and quality as measured by gestalt and previously derived quality instruments. Methods Ten blogs were randomly selected from a list of emergency medicine and critical care Web sites. The 2 most recent clinically oriented blog posts published on these blogs were evaluated with gestalt, the Academic Life in Emergency Medicine Approved Instructional Resources (ALiEM AIR) score, and the METRIQ-8 score. Volunteer raters (including medical students, emergency medicine residents, and emergency medicine attending physicians) were identified with a multimodal recruitment methodology. The Social Media Index was calculated in February 2016, November 2016, April 2017, and December 2017. Pearson's correlations were calculated between the Social Media Index and the average rater gestalt, ALiEM AIR score, and METRIQ-8 score. Results A total of 309 of 330 raters completed all ratings (93.6%). The Social Media Index correlated moderately to strongly with the mean rater gestalt ratings (range 0.69 to 0.76) and moderately with the mean rater ALiEM AIR score (range 0.55 to 0.61) and METRIQ-8 score (range 0.53 to 0.57) during the month of the blog post's selection and for 2 years after. Conclusion The Social Media Index's correlation with multiple quality evaluation instruments over time supports the hypothesis that it is associated with overall Web site quality. It can play a role in guiding individuals to high-quality resources that can be reviewed with critical appraisal techniques.

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

Contemporary philosophers generally ignore the topic of duties to the self. I contend that they are mistaken to do so. The question of whether there are such duties, I argue, is of genuine significance when constructing theories of practical reasoning and moral psychology. In this essay, I show that much of the potential importance of duties to the self stems from what has been called the “second-personal” character of moral duties—the fact that the performance of a duty is “owed to” someone. But this is problematic, as there is reason to doubt whether a person can genuinely owe to herself the performance of an action. Responding to this worry, I show that temporal divisions within an agent's life enable her to relate to herself second-personally, in the way required by morality. The upshots, I argue, are that we need an intra-personal theory of justice that specifies the extent of a person's authority over herself, and that we need to rethink our theories of moral emotions in order to specify how an individual ought to respond to attacks on her interests and autonomy that she herself perpetrates.

Abstract Nineteenth-century German opera composer Richard Wagner was very knowledgeable about Buddhism and its teachings, at least for a European of that time, and he incorporated his knowledge of those teachings into his last five music dramas: The Ring of the Nibelung (a four-opera cycle) and his final opera, Parsifal. The Ring is traditionally performed separately from Parsifal, but this article explains how there is a basis to connect these five great works into one cycle, even to the extent where the performance of a five-opera cycle would one day become a reality. The basis for this connection includes Wagner’s own strong belief in reincarnation, as well as Buddhism’s general teaching and explanation of karma and rebirth.

Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.

Study objective Open educational resources such as blogs are increasingly used for medical education. Gestalt is generally the evaluation method used for these resources; however, little information has been published on it. We aim to evaluate the reliability of gestalt in the assessment of emergency medicine blogs. Methods We identified 60 English-language emergency medicine Web sites that posted clinically oriented blogs between January 1, 2016, and February 24, 2016. Ten Web sites were selected with a random-number generator. Medical students, emergency medicine residents, and emergency medicine attending physicians evaluated the 2 most recent clinical blog posts from each site for quality, using a 7-point Likert scale. The mean gestalt scores of each blog post were compared between groups with Pearson's correlations. Single and average measure intraclass correlation coefficients were calculated within groups. A generalizability study evaluated variance within gestalt and a decision study calculated the number of raters required to reliably (>0.8) estimate quality. Results One hundred twenty-one medical students, 88 residents, and 100 attending physicians (93.6% of enrolled participants) evaluated all 20 blog posts. Single-measure intraclass correlation coefficients within groups were fair to poor (0.36 to 0.40). Average-measure intraclass correlation coefficients were more reliable (0.811 to 0.840). Mean gestalt ratings by attending physicians correlated strongly with those by medical students (r=0.92) and residents (r=0.99). The generalizability coefficient was 0.91 for the complete data set. The decision study found that 42 gestalt ratings were required to reliably evaluate quality (>0.8). Conclusion The mean gestalt quality ratings of blog posts between medical students, residents, and attending physicians correlate strongly, but individual ratings are unreliable. With sufficient raters, mean gestalt ratings provide a community standard for assessment.

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.

This paper is a continuation of our previous paper [1] (OMAE2014-23225) where we did a parametric study for wave-structure interaction of a hollow cylinder in regular sea waves without vessel motions. The effect of waves and current on the motion of the cylinder and the associated forces were evaluated using a state-of-the-art methodology [2] (OMAE2013-11569) for predicting the motions and loads of subsea equipment and structures during offshore operations. In this paper, we extend the solution to include wave – structure interaction in regular sea waves and vessel motions. The 5th order Stokes regular waves in CFD and vessel motions are included in the modeling. This methodology couples the transient CFD with a hydrodynamic motion analysis after diffraction analyses, instead of relying on the traditional approach which uses simplified equations or empirical formulae to estimate hydrodynamic coefficients [3], or using steady-state CFD simulation on stationary equipment and structures to predict drag and added masses on submerged structures. The time domain diffraction simulation is coupled with a multiphase CFD simulation of subsea equipment and structures in waves. A transient CFD model with rigid body motions for the equipment and structures calculates added masses, forces and moments on the equipment and structures for the diffraction analysis, while the diffraction analysis calculates linear and angular velocities for the CFD simulation. In this paper, simulations are performed to investigate effect of the vessel motions on the motion of a hollow cylinder in regular sea waves. The results are compared with that from the traditional approach. This coupled methodology has potential applications in analyses of the motions of subsea equipment and structures in waves during offshore operations. The results in this paper show wave-structure interaction of a hollow cylinder in regular sea waves, and the effect of vessel motions on the motion of the cylinder. The results provide better understanding of structure motion in regular waves with vessel motions using this coupled methodology. The coupled methodology eliminates the inaccuracy inherited from assumed or calculated hydrodynamic properties that are obtained by using simplified equations or empirical formulations, or by using steady-state CFD analyses in traditional decoupled approaches. The results show that the coupled physics of regular sea waves, vessel motions and cylinder motion is captured by using this methodology. The coupled physics is not captured by the traditional approach.Copyright © 2015 by ASME

Purpose: Gaucher disease is an exemplary orphan disorder. Enzyme replacement therapy with imiglucerase is effective, but very expensive. To improve the assessment of severity of disease and responses to this costly treatment, we have evaluated several enzymatic biomarkers and a newly-described chemokine. Subjects and methods: We studied 48 untreated adults with Type I Gaucher disease: 20 patients were studied after the introduction of enzyme replacement. Disease activity was monitored by serial measurement of platelet count, visceral volumes (spleen and liver) by magnetic resonance imaging, serum activities of total acid phosphatase, angiotensin-converting enzyme (ACE) and the lysosomal chitinase, chitotriosidase. Pulmonary and activation-regulated chemokine (PARC/CCL 18) was also determined in serurn by ELISA. Results: Serum PARC concentrations were elevated 10-40-fold in patients with Gaucher disease compared with 67 healthy controls, without overlap (P

The pharmacokinetic profile of cilomilast (Ariflo®), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of cilomilast in smokers and nonsmokers. Repeated administration of cilomilast had no effect on the steady-state pharmacokinetics of theophylline in either a pilot dose-ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC 0 - 1 2 and C m a x were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady-state pharmacokinetics of cilomilast when compared to placebo, as only slight average increases in cilomilast AUC 0 - 1 2 and C m a x (6% and 3%, respectively) were observed. In addition, mean cilomilast exposure (AUC 0 - ∞ ) was found to be similar in both smokers and nonsmokers (8.47 ′ 2.20 μg.h/mL and 7.70 ′ 2.25 μg.h/mL, respectively). Throughout all three studies, cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitois, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.

Rotliegend Auk Formation sandstones form the second most productive reservoir in the 30/24 fields and the major source of aquifer pressure support. In the Argyll Field, where the Zechstein oversteps beyond the Rotliegend on to Devonian continental sandstones, there were initial difficulties distinguishingbetween the Rotliegend and the Devonian. Four facies associations are present in the Rotliegend Auk Formation: aeolian slipface sands, aeolian wind-ripple sands, water-lain Weissliegend sands and other water-lain conglomerates, breccias and sands. Five reservoir zones consist of different proportions of these facies which infill topography and onlap the Argyll high. Their distribution and character reflect periods of sediment supply, subsidence and fluctuating climatic conditions towards the margin of an interior continental basin. The Auk Formation as a whole forms a high quality reservoir at depths of 3000–4000 m. The best intervals, with Darcy permeabilities, consist of coarse-grained Weissliegend sands. Two of the four initial wells in the Ardmore (Argyll) Field redevelopment are planned to target the Rotliegend reservoir.

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.

Deficiency of lysosomal acid β-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, α-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and 4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P