The discovery of antidepressants: a winding path

Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, 'reversal' of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

Metabolic engineering of Saccharomyces cerevisiae: a key cell factory platform for future biorefineries

Metabolic engineering is the enabling science of development of efficient cell factories for the production of fuels, chemicals, pharmaceuticals, and food ingredients through microbial fermentations. The yeast Saccharomyces cerevisiae is a key cell factory already used for the production of a wide range of industrial products, and here we review ongoing work, particularly in industry, on using this organism for the production of butanol, which can be used as biofuel, and isoprenoids, which can find a wide range of applications including as pharmaceuticals and as biodiesel. We also look into how engineering of yeast can lead to improved uptake of sugars that are present in biomass hydrolyzates, and hereby allow for utilization of biomass as feedstock in the production of fuels and chemicals employing S. cerevisiae. Finally, we discuss the perspectives of how technologies from systems biology and synthetic biology can be used to advance metabolic engineering of yeast.     

CHFR: a key checkpoint component implicated in a wide range of cancers

CHFR (Checkpoint with Forkhead-associated and RING finger domains) has been implicated in a checkpoint regulating entry into mitosis. However, the details underlying its roles and regulation are unclear due to conflicting lines of evidence supporting different notions of its functions. We provide here an overview of how CHFR is thought to contribute towards regulating mitotic entry and present possible explanations for contradictory observations published on the functions and regulation of CHFR. Furthermore, we survey key data showing correlations between promoter hypermethylation or down-regulation of CHFR and cancers, with a view on the likely reasons why different extents of correlations have been reported. Lastly, we explore the possibilities of exploiting CHFR promoter hypermethylation status in diagnostics and therapeutics for cancer patients. With keen interest currently focused on the association between hypermethylation of CHFR and cancers, details of how CHFR functions require further study to reveal how its absence might possibly contribute to tumorigenesis.     

Trans-epoxide hydrolase: A key indicator enzyme for herbivory in arthropods

Summary An epoxide hydrolase selective for a trans-epoxide substrate is more commonly associated with arthropod herbivory than is a cis-selective epoxide hydrolase. The distinct selectivities in epoxide hydrolase activities between herbivorous pests and entomophagous arthropods used in their biological control may aid design of integrated pest management systems.We thank E.G. Grafius, F. Matsumura, J.R. Miller, K.L. Strickler and S.G. Wellso together with M.E. Whalon and D. Young at Michigan State University for insects and aid in identification respectively. T.L. Burger, Sr. and D. Perkins, both of the USDA, also supplied insects, and the NSF (DAR-8011600) provided support. R. Feyereisen and D. Vincent of the Department of Entomology, Oregon State University provided helpful commentary. C.A. Mullin is presently at the Pesticide Research Laboratory, Department of Entomology, The Pennsylvania State University, University Park, PA, 16802, USA. This is paper No. 10926 of the Mich. Agric. Exp. Stn and No. 6790 of the Oregon Agric. Exp. Stn journal series.     

Forecasting key macroeconomic variables from a large number of predictors: a state space approach

We use state space methods to estimate a large dynamic factor model for the Norwegian economy involving 93 variables for 1978Q2–2005Q4. The model is used to obtain forecasts for 22 key variables that can be derived from the original variables by aggregation. To investigate the potential gain in using such a large information set, we compare the forecasting properties of the dynamic factor model with those of univariate benchmark models. We find that there is an overall gain in using the dynamic factor model, but that the gain is notable only for a few of the key variables. Copyright © 2009 John Wiley & Sons, Ltd.     

Glutamate transporter EAAT2: regulation,function, and potential as a therapeutic target for neurological and psychiatric disease

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.     

Evidence for a novel racemization process of an asparaginyl residue in mouse lysozyme under physiological conditions

We examined chemical reactions in mouse lysozyme after incubation under physiological conditions (pH 7 and 37°C). After incubation for 8 weeks, racemization was observed specifically at Asn127 among the 19 Asp/Asn residues in mouse lysozyme. Furthermore, analysis of the primary structure showed that the racemized residue was not Asp, but Asn, which demonstrates that deamidation and isomerization did not occur. These results mean that this racemization occurs without forming a succinimide intermediate. This is the first example of D-asparaginyl formation in a protein occurring during the racemization process under physiological conditions.Received 16 September 2004; received after revision 26 October 2004; accepted 12 November 2004     

nDsbD: a redox interaction hub in the Escherichia coli periplasm

DsbD is a redox-active protein of the inner Escherichia coli membrane possessing an N-terminal (nDsbD) and a C-terminal (cDsbD) periplasmic domain. nDsbD interacts with four different redox proteins involved in the periplasmic disulfide isomerization and in the cytochrome c maturation systems. We review here the studies that led to the structural characterization of all soluble DsbD domains involved and, most importantly, of trapped disulfide intermediate complexes of nDsbD with three of its four redox partners. These results revealed the structural features enabling nDsbD, a ‘redox hub’ with an immunoglobulin-like fold, to interact efficiently with its different thioredoxin-like partners. Received 3 February 2006; received after revision 1 March 2006; accepted 5 April 2006     

Lecithin-chloroform interaction as a model for the action of general anesthetics

Riassunto Gli idrati di cloroformio sono stabilizzati in vitro dalle lecitine. Si possono così riconciliare la teoria dei clatrati e quella della fase lipidica per spiegare l'azione degli anestetici generali.     

Functional characterization of CP148, a novel key component for centrosome integrity in Dictyostelium

The Dictyostelium centrosome consists of a layered core structure surrounded by a microtubule-nucleating corona. A tight linkage through the nuclear envelope connects the cytosolic centrosome with the clustered centromeres within the nuclear matrix. At G2/M the corona dissociates, and the core structure duplicates, yielding two spindle poles. CP148 is a novel coiled coil protein of the centrosomal corona. GFP-CP148 exhibited cell cycle-dependent presence and absence at the centrosome, which correlates with dissociation of the corona in prophase and its reformation in late telophase. During telophase, GFP-CP148 formed cytosolic foci, which coalesced and joined the centrosome. This explains the hypertrophic appearance of the corona upon strong overexpression of GFP-CP148. Depletion of CP148 by RNAi caused virtual loss of the corona and disorganization of interphase microtubules. Surprisingly, formation of the mitotic spindle and astral microtubules was unaffected. Thus, microtubule nucleation complexes associate with centrosomal core components through different means during interphase and mitosis. Furthermore, CP148 RNAi caused dispersal of centromeres and altered Sun1 distribution at the nuclear envelope, suggesting a role of CP148 in the linkage between centrosomes and centromeres. Taken together, CP148 is an essential factor for the formation of the centrosomal corona, which in turn is required for centrosome/centromere linkage.     

Unipolar induction: a case study of the interaction between science and technology

Unipolar induction, discovered in 1832 by Michael Faraday, is the case of electromagnetic induction in which a conductor and magnet are in relative rotatory motion. Attempts by scientists and engineers in the nineteenth and twentieth centuries to understand unipolar induction by using magnetic lines of force displayed striking national differences that influenced where the first largescale unipolar dynamo was built. This episode is described, as well as the effect of unipolar induction on Albert Einstein's thinking toward the special theory of relativity, in sections 1–6. The analysis of electromagnetic induction in cases where the source of the magnetic field is in motion relative to the conductor is provided in sections 7–9.     

Biological properties of synthetic Ser4-Arg8-oxytocin (Ile3-Ser4-Arginine vasopressin): Role of the residue No. 4 in the hormone-pressor receptor interaction

Résumé Les propriétés pharmacologiques de la Ser⁴-Arg⁸-ocytocine (Ser⁴-vasotocine) synthétique ont été étudiées. La substitution en position 4 de la glutamine par la sérine diminue considérablement l'activité pressique de la vasotocine, ce qui montre l'importance de cette position dans les interactions entre les hormones neurohypophysaires et le récepteur vasopressique.

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The authors are indebted to Dr.Albert Jöhl (Ciba-Geigy Laboratories) for a sample of synthetic Ser⁴-Arg⁸-oxytocin. They thank Mrs.Christine Gaullier for ther skilled technical assistance.     

GFP tagging sheds light on protein translocation: implications for key methods in cell biology

Green fluorescent protein (GFP) is a powerful tool for studying gene expression, protein localization, protein–protein interactions, calcium concentrations, and redox potentials owing to its intrinsic fluorescence. However, GFP not only contains a chromophore but is also tightly folded in a temperature-dependent manner. The latter property of GFP has recently been exploited (1) to characterize the translocase of the outer mitochondrial membrane and (2) to discriminate between protein transport across and into biomembranes in vivo. I therefore suggest that GFP could be a valuable tool for the general analysis of protein transport machineries and pathways in a variety of organisms. Moreover, results from such studies could be important for the interpretation and optimization of classical experiments using GFP tagging.     

Evidence for a neuronal release of isotopically labelled γ-amino-n-butyric acid (GABA) from the rat dorsal medulla in vivo

Summary High potassium and electrical stimulation consistently increase efflux of labelled GABA from the in vivo superfused rat dorsal medulla in a calcium-dependent fashion. The depolarizing alkaloid, veratridine, also evokes a large increase in efflux of labelled GABA. These data strongly suggest release from a neurotransmitter pool in this region.Supported by grants from the Science Research Council to N.D. and C.G.D., FAPESP and CNPq (Brazil) to J.A.A. and CAPES and FAPESP (Brazil) to N.B.