Burnside’s engagement with the “modern theory of statistics”

The group theorist William Burnside devoted much of the last decade of his life to probability and statistics. The work led to contact with Ronald Fisher who was on his way to becoming the leading statistician of the age and with Karl Pearson, the man Fisher supplanted. Burnside corresponded with Fisher for nearly three years until their correspondence ended abruptly. This paper examines Burnside’s interactions with the statisticians and looks more generally at his work in probability and statistics. I am grateful to June Barrow-Green and Tony Mann for showing me important letters, to Susan Woodburn, Elise Bennetto and Jeniffer Beauchamps of the University of Adelaide for help with letters to Fisher and to Jonathan Harrison of St. John’s Cambridge for help with letters to Baker and White. Peter Neumann, the editor and a referee made helpful comments on an earlier draft.     

The landing zone – Ground for model transfer in chemistry

This essay proposes a new notion - the landing zone - in order to identify conceptual features that allow modelers to transfer mathematical tools across disciplinary borders. This discussion refers to the transferable models as ‘templates’. Templates are functions, equations, or computational methods that are capable of being generalized from a particular subject matter. There are formal and conceptual prerequisites for the transfer of a template to a new domain. A landing zone is an ontology that contributes to the satisfaction of these conditions for successful transfer. This paper presents a case study on a model in chemistry - the Quantum Theory of Atoms in Molecules (QTAIM) - that makes use of transferred templates from physics - the virial theorem and the wave function. The landing zone in this case is a new ontological notion, that of the topological atom, which prepares ground for the use of the virial theorem and the wave function in chemistry. The virial theorem requires that there exists in-principle stability to the system that it represents, and the wave function requires transformation in its representation that is justified. The ontology of QTAIM - the landing zone for these templates - grounds the scientific use of these templates in the context of chemistry.     

Galanin – 25 years with a multitalented neuropeptide

The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the overexpression of galanin in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in Alzheimer's patients.     

Galanin – 25 years with a multitalented neuropeptide

There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction.     

Galanin – 25 years with a multitalented neuropeptide

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly upregulated in many neuronal tissues after nerve injury or disease. Over the last 10 years we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.     

Galanin – 25 years with a multitalented neuropeptide

The skin, the largest organ of the body, functions as a barrier between the body proper and the external environment, as it is constantly exposed to noxious stressors. During the last few years, the concept of an interactive network involving cutaneous nerves, the neuroendocrine axis, and the immune system has emerged. The neuroendocrine system of the skin is composed of locally produced neuroendocrine mediators that interact with specific receptors. Among these mediators are neuropeptides, including members of the galanin peptide family--galanin, galanin-message-associated peptide, galanin-like peptide, and alarin--which are produced in neuronal as well as nonneuronal cells in the skin. Here we review the expression of the galanin peptides and their receptors in the skin, and the known functions of galanin peptides in different compartments of the skin. We discuss these data in light of the role of the galanin peptide family in inflammation and cell proliferation.     

Galanin – 25 years with a multitalented neuropeptide

Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics.     

Galanin – 25 years with a multitalented neuropeptide

Neuroanatomical localization and physiological properties of galanin suggest that the peptide may be involved in the regulation of seizures. Indeed, administration of galanin receptor agonists into brain areas pertinent to the initiation and propagation of epileptic activity attenuated seizure responses under conditions of animal models of epilepsy; pharmacological blocking of galanin receptors exerted proconvulsant effects. Functional deletion of both galanin and galanin type 1 receptor genes produced transgenic mice with either spontaneous seizure phenotype, or with enhanced susceptibility to seizure stimuli. At the same time, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection techniques, hindered the epileptic process. Galanin exerts anticonvulsant effects through both type 1 and type 2 receptors, with distinct downstream signaling cascades. Several synthetic agonists of galanin receptors with optimized bioavailability have been synthesized and inhibited experimental seizures upon systemic administration, thus opening an opportunity for the development of galanin-based antiepileptic drugs.     

Galanin – 25 years with a multitalented neuropeptide

The pathophysiology of depression remains unclear, but involves disturbances in brain monoaminergic transmission. Current antidepressant drugs, which act by enhancing this type of transmission, have limited therapeutic efficacy in a number of patients, and not rarely serious side-effects. Increasing evidence suggests that neuropeptides, including galanin, can be of relevance in mood disorders. Galanin is coexpressed with and modulates noradrenaline and serotonin systems, both implicated in depression. Pharmacological and genetic studies have suggested a role for galanin in depression-like behaviour in rodents, whereby the receptor subtype involved appears to play an important role. Thus, stimulation of GalR1 and/or GalR3 receptors results in depression-like phenotype, while activation of the GalR2 receptor attenuates depression-like behaviour. These findings suggest that galanin receptor subtypes represent targets for development of novel antidepressant drugs.     

Galanin – 25 years with a multitalented neuropeptide

Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.     

Galanin – 25 years with a multitalented neuropeptide

Galanin has diverse physiological functions, including nociception, arousal/sleep regulation, cognition, and many aspects of neuroendocrine activities that are associated with feeding, energy metabolism, thermoregulation, osmotic and water balance, and reproduction. This review will provide a brief overview of galanin actions in some major neuroendocrine processes. Most of the recent data are about the role of galanin in the central regulation of food intake and energy metabolism, and to some extent, in the regulation of reproduction. It seems that galanin plays a modulatory rather than regulatory role in the central and peripheral branches of the neuroendocrine systems. In the hypothalamus, it functions as a neurotransmitter/neuromodulator. In the pituitary and the peripheral endocrine glands, it acts via its receptors (GALRs) in a paracrine/autocrine fashion. The development of new, selective and potent antagonists of GALRs should keep advancing our knowledge not only in the physiology but also the pathophysiology of galanin as well.     

Galanin – 25 years with a multitalented neuropeptide

Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In the present review, we summarize the current data which constitute the basis of targeting GalR1, GalR2 and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors.     

The trefoil factor family – small peptides with multiple functionalities

The trefoil factor family (TFF) comprises a group of small peptides which are highly expressed in tissues containing mucus-producing cells – especially in the mucosa lining the gastrointestinal tract. The peptides seem crucial for epithelial restitution and may work via other pathways than the conventional factors involved in restitution. In vitro studies have shown that the TFFs promote restitution using multiple mechanisms. The peptides also have other functionalities including interactions with the immune system. Moreover, therapeutic effects of the TFFs have been shown in several animal models of gastrointestinal damage. Still it is not clear which of their in vitro properties are involved in the in vivo mode of action. This review describes the TFF family with emphasis on their biological properties and involvement in mucosal protection and repair. Received 10 October 2008; received after revision 07 November 2008; accepted 10 November 2008     

Hydrophobic properties of model compounds with peptide-like chemical environment: N-acetyl-N′-methyl-amino acid amides

Summary Capacity factors in reversed-phase HPLC and distribution constants in octan-l-ol/water of N-acetyl-N-methylamino acid amides have been measured as a function of temperature. The HPLC capacity factors are proposed as estimates of the hydrophobicity of the amino acid side chains.We acknowledge the interest in this work of Dr H. van Rooy, Dr J. Kinkel, Prof. W. Soudijn and Prof. E. Tomlinson.     

Forecasting under model uncertainty: Non-homogeneous hidden Markov models with Pòlya-Gamma data augmentation

We consider finite state-space non-homogeneous hidden Markov models for forecasting univariate time series. Given a set of predictors, the time series are modeled via predictive regressions with state-dependent coefficients and time-varying transition probabilities that depend on the predictors via a logistic/multinomial function. In a hidden Markov setting, inference for logistic regression coefficients becomes complicated and in some cases impossible due to convergence issues. In this paper, we aim to address this problem utilizing the recently proposed Pólya-Gamma latent variable scheme. Also, we allow for model uncertainty regarding the predictors that affect the series both linearly — in the mean — and non-linearly — in the transition matrix. Predictor selection and inference on the model parameters are based on an automatic Markov chain Monte Carlo scheme with reversible jump steps. Hence the proposed methodology can be used as a black box for predicting time series. Using simulation experiments, we illustrate the performance of our algorithm in various setups, in terms of mixing properties, model selection and predictive ability. An empirical study on realized volatility data shows that our methodology gives improved forecasts compared to benchmark models.     

The peroxisomal protein import machinery – a case report of transient ubiquitination with a new flavor

The peroxisomal protein import machinery displays remarkable properties. Be it its capacity to accept already folded proteins as substrates, its complex architecture or its energetics, almost every aspect of this machinery seems unique. The list of unusual properties is still growing as shown by the recent finding that one of its central components, Pex5p, is transiently monoubiquitinated at a cysteine residue. However, the data gathered in recent years also suggest that the peroxisomal import machinery is not that exclusive and similarities with p97/Cdc48-mediated processes and with multisubunit RING-E3 ligases are starting to emerge. Here, we discuss these data trying to distill the principles by which this complex machinery operates. Received 16 July 2008; received after revision 25 August 2008; accepted 29 August 2008     

Reasons for relativism: Feyerabend on the ‘Rise of Rationalism’ in ancient Greece

This paper argues that essential features of Feyerabend's philosophy, namely his radicalization of critical rationalism and his turn to relativism, could be understood better in the light of his engagement with early Greek thought. In contrast to his earlier, Popperian views he came to see the Homeric worldview as a genuine alternative, which was not falsified by the Presocratics. Unlike socio–psychological and externalist accounts my reading of his published and unpublished material suggests that his alternative reconstruction of the ancient beginnings of the Western scientific tradition motivate and justify his moderate Protagorean relativism.