On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.     

Estimation of psychomotor delay from the Fitts’ law coefficients

An intrinsic property of human motor behavior is a trade-off between speed and accuracy. This is classically described by Fitts’ law, a model derived by assuming that the human body has a limited capacity to transmit information in organizing motor behavior. However, Fitts’ law can also be realized as an emergent property of movements generated by delayed feedback. In this article, we describe the relationship between the Fitts’ law coefficients and the physiological parameters of the underlying delayed feedback circuit: the relaxation rate or time constant, and the psychomotor delay of the feedback process. This relationship is then used to estimate the motor circuit delay of several tasks for which Fitts’ law data are available in the literature. We consistently estimate the delay to be between 0 and 112 ms. A further consequence of this model is that not all combinations of slope and Y-intercept in Fitts’ law are possible when movements are generated by delayed feedback. In fact, it is only possible for an observed speed–accuracy trade-off to be generated by delayed feedback if the Fitts’ law coefficients satisfy ?0.482 ≤ a/b ≤ 3.343 [bits] where b represents the slope in bits per second and a represents the Y-intercept in seconds. If we assume human movement is generated by delayed feedback, then the Fitts’ law coefficients should always be restricted to this range of values.     

A ‘Goldilocks’ hypothesis for dispersal of biological control agents

The rate at which biological control agents disperse from release sites has important implications for their establishment and spread. Low rates of dispersal can yield spread that is too slow and may necessitate redistribution efforts for importation biological control and a high density of release sites for augmentation. Low dispersal rates may also lead to inbreeding at the site of release. On the other hand, high rates of dispersal can lead to Allee effects at the leading edge of the invasion front, potentially reducing the likelihood of establishment. Given these disadvantages associated with both low and high dispersal rates, we argue that intermediate rates of dispersal are likely to maximize the probability of establishment and appropriate spread for biological control agents released in the context of either importation or augmentative biological control. We consider this putative relationship a ‘Goldilocks hypothesis’ since it posits an optimum at intermediate values. In this review paper we begin by discussing the rationale for the Goldilocks hypothesis and then provide a case study from our work on importation biological control of the soybean aphid, Aphis glycines. Work on the soybean aphid parasitoid Binodoxys communis has shown that long-distance dispersal of immature parasitoids within winged migrating aphids is unlikely. This is likely good news for importation biological control because parasitoids dispersed in this manner would likely encounter crippling Allee effects. On the other hand, results from a field release study also suggest that female B. communis females (but not males) disperse actively from release sites. This female-biased dispersal may lead to strong mate-finding Allee effects and therefore may make establishment less likely.     

Russia’s Annexation of Crimea and the Passage of Ships Through Kerch Strait: A Law of the Sea Perspective

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This article discusses potential Ukrainian rights of passage through Kerch Strait against the background of restrictions on passage imposed by Russia since the annexation of Crimea, taking into account the ongoing arbitral proceedings under Annex VII of the UN Convention on the Law of the Sea. The article addresses first the question of the status of Kerch Strait and the Sea of Azov under the international law of the sea. In a second step, the article deals with the issue of potential Ukrainian passage rights through Kerch Strait based on the legal status discussed in the first section as well as relevant bilateral treaties between Ukraine and Russia.     

Emerging Law of the Sea Issues in the Antarctic Maritime Area: A Heritage for the New Century?

This article focuses on three emerging law of the sea issues for states cooperating in management of the Antarctic and its maritime area. The first of these is no newcomer: How to regulate the dramatic increase in illegal, unregulated and unreported fishing of Patagonian toothfish (Dissostichus eleginoides) in the Southern Ocean? The second question, according to the letter of the UN Convention on the Law of the Sea, awaits the countries claiming sovereignty over portions of territory in the Antarctic 10 years from the entry into force of the Convention for each of them. The question here is what to do with the requirement contained in that Convention relating to the submission of information on the outer limit of the continental shelf beyond 200 nautical miles to the Commission on the Continental Shelf? Finally, there is a third tricky question: Who is competent to regulate, and accordingly to ban, mineral activities in the Southern Ocean seabed? Is it the International Seabed Authority as the global body, or the Antarctic Treaty Consultative Parties through their regional cooperation? This question may well never be put on the policy agenda for any global forum; but it may well be posed at any time and by any third party, whether in the UN General Assembly or, more likely, in the Assembly of the International Seabed Authority.     

A ‘fast-food approach’ to the standardization of quadratic diversity

Abstract

Intuitively, a community composed of ecologically dissimilar taxa is more diverse than a community composed of more similar taxa. However, since traditional diversity indices such as Shannon's entropy or Simpson's diversity are computed solely from the relative abundances of a given species assemblage, they cannot account for ecological differences between species. There have been recent developments regarding the use of quadratic entropy, a diversity index that incorporates both species relative abundances and a measure of the pairwise ecological differences between species. In this paper we firstly show that under some specific circumstances quadratic entropy can be additively decomposed into α- β- and γ-diversities, a property that renders it a desirable measure of diversity in the ecological practice. Next, we suggest a quick and simple method for obtaining a standardized version of quadratic entropy that may allow an easier interpretation of the resulting diversity values.     

On ‘analytical models for the patchy spread of plant disease’

Epidemiologists are interested in using models that incorporate the effects of clustering in the spatial pattern of disease on epidemic dynamics. Bolker (1999, Bull. Math. Biol. 61, 849–874) has developed an approach to study such models based on a moment closure assumption. We show that the assumption works above a thre shold initial level of disease that depends on the spatial dispersal of the pathogen. We test an alternative assumption and show that it does not have this limitation. We examine the relation between lattice and continuous-medium implementations of the approach.     

Hunters’ preferences for engaging in control programs of introduced Eastern cottontails in Italy: a factorial survey approach

In Europe, invasive alien mammals are often controlled by voluntary hunters. However, no research investigated if control operations could be entirely performed by volunteers, nor how to maximize their recruitment. By using the Eastern cottontail (Sylvilagus floridanus) in Central Italy as a case study, we carried out a factorial survey over a sample of hunters (n =?134), exploring which attributes influenced their hypothetical participation to control programs for cottontails. Hunters were more willing to engage in control schemes if these included shooting sessions, not trapping. Moreover, they would have been more prone to control cottontails if they had received evidence of cottontail impacts over native wildlife or local crops. The geographical scale of the management plan and its goals and required efforts did not have any effect over the evaluation of management scenarios. As many European control schemes for invasive alien mammals are carried out in contexts where shooting is unfeasible, like urbanized neighborhoods, our findings show that agencies cannot entirely rely on volunteers and they should complement their limitations with full-time staff. Moreover, if wildlife agencies want to recruit volunteers, they should provide adequate information about the environmental and social impacts of invasive alien mammals.     

Spectators to the Spectacle of Law: The Formation of a ‘Validating Public’ at the International Criminal Tribunal for Rwanda

While the ethnography of contemporary courtrooms has been dominated by a concern with speech, this article considers how a silent, validating public is constructed within court complexes. Drawing on fieldwork at the International Criminal Tribunal for Rwanda (Arusha, Tanzania), I explore how the court's threshold practices form validating witnesses whose embodied deference contributes to the constitution of the courtroom as a space of privileged speech. I suggest, therefore, that court spectators are not incidental, but are integral to juridical spectacle and the authority of law.     

On the fiftieth anniversary of the Schaechter, Maaløe, Kjeldgaard experiments: implications for cell-cycle and cell-growth control

The Schaechter–Maaløe–Kjeldgaard papers, which have their 50^th anniversary this year, have major implications for understanding the cell cycle, control of cell growth, control of cell size, metabolic control, the basic bacterial growth curve, and myriad other bacterial and eukaryotic growth phenomena. These ideas have broad applications that should be considered in current studies of the cell cycle. In particular, the emphasis on steady‐state growth conditions, and clear and sharp changes in growth conditions were fundamental to their experiments and have been codified in the principles of the Copenhagen School of Microbiology. BioEssays 30:1019–1024, 2008. © 2008 Wiley Periodicals, Inc.     

On the Modularity of the Intrinsic Flexibility of the μ Opioid Receptor: A Computational Study

The µ opioid receptor (µOR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the µOR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the µOR would thus bring some indications regarding the highly efficient ability of the µOR to transduce cellular message. We therefore investigate the intrinsic flexibility of the µOR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the µOR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the µOR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the µOR binding site. Such property explains why the µOR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the µOR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of µOR on one hand, along with a clear rigidity of the central µOR domain on the other hand. Our results show how the modularity of the µOR flexibility is related to its pre-ability to activate and to present a basal activity.     

The Dispute Concerning the Delimitation of the Maritime Boundary Between Ghana and Côte d’Ivoire: Implications for the Law of the Sea

The final judgment in the maritime boundary delimitation case between Ghana and Côte d’Ivoire was delivered by an ad hoc special chamber (the Chamber) of the International Tribunal for the Law of the Sea (ITLOS) on 23 September 2017. The decision addressed important legal questions relating not only to maritime boundary delimitation but also to the balancing of various rights and interests at the provisional measures stage and international responsibility for unilateral resource exploitation activities in disputed zones pending delimitation. This article analyzes the decision of the Chamber with respect to its findings on tacit boundary agreements, delimitation methodology, and international responsibility.     

A Network Analysis of Countries’ Export Flows: Firm Grounds for the Building Blocks of the Economy

In this paper we analyze the bipartite network of countries and products from UN data on country production. We define the country-country and product-product projected networks and introduce a novel method of filtering information based on elements’ similarity. As a result we find that country clustering reveals unexpected socio-geographic links among the most competing countries. On the same footings the products clustering can be efficiently used for a bottom-up classification of produced goods. Furthermore we mathematically reformulate the “reflections method” introduced by Hidalgo and Hausmann as a fixpoint problem; such formulation highlights some conceptual weaknesses of the approach. To overcome such an issue, we introduce an alternative methodology (based on biased Markov chains) that allows to rank countries in a conceptually consistent way. Our analysis uncovers a strong non-linear interaction between the diversification of a country and the ubiquity of its products, thus suggesting the possible need of moving towards more efficient and direct non-linear fixpoint algorithms to rank countries and products in the global market.     

A review of the enforcement regime for vessel‐source oil pollution control

Abstract

The purpose of this article is to identify the currently applicable international law intended to regulate vessel‐source pollution. Part I delineates the elements relevant for this study. Part II discusses the development of a sequence of incremental conventions. Part III examines the significance and weaknesses of the 1973 MARPOL Convention with its 1978 Protocol and of the 1982 UN. Convention on the Law of the Sea. Part IV explores alternative and/or supplementary legal approaches for handling the vessel‐source oil pollution threat.