The urokinase receptor: a ligand or a receptor? Story of a sociable molecule

In this last decade, the structure and functions of the receptor for the urokinase-type plasminogen activator have been extensively studied and characterized. This interesting receptor plays a key role in cell adhesion, migration and proliferation. It was identified 20 years ago as the specific cell-surface molecule that could bind and concentrate urokinase on the cell membrane, thus initiating the proteolytic cascade promoted by the activation of plasminogen. The identification of new extracellular ligands, such as vitronectin, and of cell-surface interactors, such as integrins and fMet-Leu-Phe receptors, shed new light on its possible roles, totally independent of the enzymatic properties of its ligand. uPAR ligands and interactors and the functional consequences of the multiple binding capability of this intriguing receptor are reviewed here. Received 19 September 2005; received after revision 4 December 2005; accepted 6 December 2005     

Does a lot help a lot? Forecasting stock returns with pooling strategies in a data‐rich environment

A variety of recent studies provide a skeptical view on the predictability of stock returns. Empirical evidence shows that most prediction models suffer from a loss of information, model uncertainty, and structural instability by relying on low‐dimensional information sets. In this study, we evaluate the predictive ability of various lately refined forecasting strategies, which handle these issues by incorporating information from many potential predictor variables simultaneously. We investigate whether forecasting strategies that (i) combine information and (ii) combine individual forecasts are useful to predict US stock returns, that is, the market excess return, size, value, and the momentum premium. Our results show that methods combining information have remarkable in‐sample predictive ability. However, the out‐of‐sample performance suffers from highly volatile forecast errors. Forecast combinations face a better bias–efficiency trade‐off, yielding a consistently superior forecast performance for the market excess return and the size premium even after the 1970s.     

An ‘ecobox’ with a discontinuous temperature gradient and a continuous light intensity gradient

Summary An apparatus is described for culturing micro-algae in a discontinuous temperature gradient and a continuous light intensity gradient. The apparatus provides 100 different combinations of these abiotic factors at 1 time. The crossgradient culture apparatus is called ecobox.     

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     

Alsatian chemists in Paris in the 19th century: a network, a school?

During the nineteenth century French chemistry was marked by an outstanding number of Alsatian chemists whose scientific contributions cannot be ignored. Especially following the Franco-Prussian War, their regional origin was given a particular importance as a means of affirming their singularity on the French scientific scene. However, some questions may be raised: can we distinguish the Alsatians from other French chemists before 1870? Were they a homogeneous group sharing a common origin? The aim of this article therefore, is, to show that by their theoretical options within chemistry, their personal and professional relationships, as well as by their participation in various common initiatives, they organized themselves both formally and informally within the Parisian scientific community. Amongst these forms of organization the research school of Charles Adolphe Wurtz (1817-84) emerges as the nucleus of what we may envisage as a network of Alsatian chemists working in Paris, in the second half of the nineteenth century.     

‘Passie’ thinking,a hypothesis

Summary Based on observations and on analogical deductions from the organization of the cerebellum, a hypothesis of a passive process of thinking is described. According to it, we try to program the cerebrum for the handling of an idea, regarding its solution we are, however, exposed passively to the brain.     

‘Nobody could possibly misunderstand what a group is’: a study in early twentieth-century group axiomatics

In the early years of the twentieth century, the so-called ‘postulate analysis’—the study of systems of axioms for mathematical objects for their own sake—was regarded by some as a vital part of the efforts to understand those objects. I consider the place of postulate analysis within early twentieth-century mathematics by focusing on the example of a group: I outline the axiomatic studies to which groups were subjected at this time and consider the changing attitudes towards such investigations.

     

(±)9, 10-dihydroxy-Δ 6a(10a)-tetrahydrocanabinol and (±)8, 9-dihydroxy-Δ 6a(10a)-tetrahydrocannabinol: 2 new cannabinoids fromCannabis sativa L.

Summary The structures of 2 new polyhydroxylated cannabinoids, (±)9, 10-dihydroxy- ^6a(10a)-tetrahydorcannabinol and (±)8, 9-dihydroxy- ^6a(10a)-tetrahydrocannabinol, obtained from a hexane extract of an IndianCannabis variant were determined by spectral means and correlation with cannabinol.Acknowledgments. Supported by contract No. HSM-42-70-109 from the National Institute on Drug Abuse and the Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi. The authors are grateful to Mrs Glenda Lewis (Research Institute) for running the gas chromatographic analyses and to Mr C. Versluis (Analytical Chemistry Laboratory, University Of Utrecht, The Netherlands) for recording an element list of both compounds.Cannabis Herbarium specimens are stored in the herbarium, Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677, USA.     

‘The happy thought of a single man’: On the legendary beginnings of a style of reasoning

In this paper I direct attention to one feature of Hacking’s recent work on styles of reasoning and argue that this feature is of far greater philosophical significance than Hacking’s limited discussion of this suggests. The feature in question is his use of ‘legendary beginnings’ in setting out a given style, viz. the method of introducing a style of reasoning by recounting a popular and quasi-mythical narrative that ties the crystallisation of that style to a particular person in a particular place and at a particular time. Whilst Hacking both deploys and discusses this method, his comments suggest that this is primarily a stylistic device employed for reasons of expedience. In contrast, it is argued here that recounting the legendary origins of a style of reasoning affords a distinctive way of vindicating that style, a vindication from within the style itself.     

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 (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.     

Morphological and histochemical demonstration of a glycocalyx on the cell surface ofChattonella antiqua,a ‘naked flagellate’

Summary Electron microscopy demonstrated the presence of glycocalyx on the cell surface ofChattonella antiqua, which was previously believed to be naked. Histochemical analysis of this structure indicates that the glycocalyx consists of at least two different types of acidic complex carbohydrates, sulfated and nonsulfated, together with a neural carbohydrate-protein complex with 1,2-glycol groups and -D-mannosyl and -D-glucosyl residues.     

Darier’s disease: a calcium-signaling perspective

Ca²⁺ influx evoked across the plasma membrane upon internal store depletion is essential for a myriad of cellular functions including gene expression, cell proliferation, differentiation and even apoptosis. Darier’s disease (DD), an autosomal dominant inherited disorder of the skin, arising due to mutations in the isoform 2 of the sarco (endo) plasmic reticulum Ca²⁺ ATPase (SERCA2), exemplifies an anomaly of Ca²⁺ signaling disturbances. Owing to loss of function mutations in SERCA2, keratinocytes in DD patients have a reduced pool of endoplasmic reticulum (ER) Ca²⁺. Importantly, the status of ER Ca²⁺ is critical for the activation of a class of plasma membrane Ca²⁺ channels referred to as store operated Ca²⁺ channels (SOCs). The widely expressed transient receptor potential (TRP) family of channels is proposed to be SOCs. In this review we discuss DD from the viewpoint of Ca²⁺ signaling and present a potential role for TRPC1 in the disease pathogenesis. Received 30 August 2007; received after revision 17 October 2007; accepted 6 November 2007     

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.     

Which strategy for a protein crystallization project?

The three-dimensional, atomic-resolution protein structures produced by X-ray crystallography over the past 50+ years have led to tremendous chemical understanding of fundamental biochemical processes. The pace of discovery in protein crystallography has increased greatly with advances in molecular biology, crystallization techniques, cryocrystallography, area detectors, synchrotrons and computing. While the methods used to produce single, well-ordered crystals have also evolved over the years in response to increased understanding and advancing technology, crystallization strategies continue to be rooted in trial-and-error approaches. This review summarizes the current approaches in protein crystallization and surveys the first results to emerge from the structural genomics efforts.Received 1 July 2003; received after revision 6 August 2003; accepted 22 August 2003