Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs

Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts

Translational control of the SigR-directed oxidative stress response in streptomyces via IF3-mediated repression of a noncanonical GTC start codon

The major oxidative stress response in Streptomyces is controlled by the sigma factor SigR and its cognate antisigma factor RsrA, and SigR activity is tightly controlled through multiple mechanisms at both the transcriptional and posttranslational levels. Here we show that sigR has a highly unusual GTC start codon and that this leads to another level of SigR regulation, in which SigR translation is repressed by translation initiation factor 3 (IF3). Changing the GTC to a canonical start codon causes SigR to be overproduced relative to RsrA, resulting in unregulated and constitutive expression of the SigR regulon. Similarly, introducing IF3* mutations that impair its ability to repress SigR translation has the same effect. Thus, the noncanonical GTC sigR start codon and its repression by IF3 are critical for the correct and proper functioning of the oxidative stress regulatory system. sigR and rsrA are cotranscribed and translationally coupled, and it had therefore been assumed that SigR and RsrA are produced in stoichiometric amounts. Here we show that RsrA can be transcribed and translated independently of SigR, present evidence that RsrA is normally produced in excess of SigR, and describe the factors that determine SigR-RsrA stoichiometry.IMPORTANCE In all sigma factor-antisigma factor regulatory switches, the relative abundance of the two proteins is critical to the proper functioning of the system. Many sigma-antisigma operons are cotranscribed and translationally coupled, leading to a generic assumption that the sigma and antisigma factors are produced in a fixed 1:1 ratio. In the case of sigR-rsrA, we show instead that the antisigma factor is produced in excess over the sigma factor, providing a buffer to prevent spurious release of sigma activity. This excess arises in part because sigR has an extremely rare noncanonical GTC start codon, and as a result, SigR translation initiation is repressed by IF3. This finding highlights the potential significance of noncanonical start codons, very few of which have been characterized experimentally. It also emphasizes the limitations of predicting start codons using bioinformatic approaches, which rely heavily on the assumption that ATG, GTG, and TTG are the only permissible start codons

Tunable variation of optical properties of polymer capped gold nanoparticles

Optical properties of polymer capped gold nanoparticles of various sizes (diameter 3-6 nm) have been studied. We present a new scheme to extract size dependent variation of total dielectric function of gold nanoparticles from measured UV-Vis absorption data. The new scheme can also be used, in principle, for other related systems as well. We show how quantum effect, surface atomic co - ordination and polymer - nanoparticle interface morphology leads to a systematic variation in inter band part of the dielectric function of gold nanoparticles, obtained from the analysis using our new scheme. Careful analysis enables identification of the possible changes to the electronic band structure in such nanoparticles.Comment: 13 pages,7 figures, 1 tabl

Fracton pairing mechanism for "strange" superconductors: Self-assembling organic polymers and copper-oxide compounds

Self-assembling organic polymers and copper-oxide compounds are two classes of "strange" superconductors, whose challenging behavior does not comply with the traditional picture of Bardeen, Cooper, and Schrieffer (BCS) superconductivity in regular crystals. In this paper, we propose a theoretical model that accounts for the strange superconducting properties of either class of the materials. These properties are considered as interconnected manifestations of the same phenomenon: We argue that superconductivity occurs in the both cases because the charge carriers (i.e., electrons or holes) exchange {\it fracton excitations}, quantum oscillations of fractal lattices that mimic the complex microscopic organization of the strange superconductors. For the copper oxides, the superconducting transition temperature $T_c$ as predicted by the fracton mechanism is of the order of $\sim 150$ K. We suggest that the marginal ingredient of the high-temperature superconducting phase is provided by fracton coupled holes that condensate in the conducting copper-oxygen planes owing to the intrinsic field-effect-transistor configuration of the cuprate compounds. For the gate-induced superconducting phase in the electron-doped polymers, we simultaneously find a rather modest transition temperature of $\sim (2-3)$ K owing to the limitations imposed by the electron tunneling processes on a fractal geometry. We speculate that hole-type superconductivity observes larger onset temperatures when compared to its electron-type counterpart. This promises an intriguing possibility of the high-temperature superconducting states in hole-doped complex materials. A specific prediction of the present study is universality of ac conduction for $T\gtrsim T_c$.Comment: 12 pages (including separate abstract page), no figure

The actinobacterial transcription factor RbpA binds to the principal sigma subunit of RNA polymerase

RbpA is a small non-DNA-binding transcription factor that associates with RNA polymerase holoenzyme and stimulates transcription in actinobacteria, including Streptomyces coelicolor and Mycobacterium tuberculosis. RbpA seems to show specificity for the vegetative form of RNA polymerase as opposed to alternative forms of the enzyme. Here, we explain the basis of this specificity by showing that RbpA binds directly to the principal σ subunit in these organisms, but not to more diverged alternative σ factors. Nuclear magnetic resonance spectroscopy revealed that, although differing in their requirement for structural zinc, the RbpA orthologues from S. coelicolor and M. tuberculosis share a common structural core domain, with extensive, apparently disordered, N- and C-terminal regions. The RbpA-σ interaction is mediated by the C-terminal region of RbpA and σ domain 2, and S. coelicolor RbpA mutants that are defective in binding σ are unable to stimulate transcription in vitro and are inactive in vivo. Given that RbpA is essential in M. tuberculosis and critical for growth in S. coelicolor, these data support a model in which RbpA plays a key role in the σ cycle in actinobacteria

Culture, entrepreneurship and uneven development: a spatial analysis

Interest in the proposed connection between culture and entrepreneurship has grown significantly in recent years. However, less attention has been given to the nature of the overall impact of this proposed association on development outcomes, particularly at a local level. In response, this paper analyses the relationship between the nature of the culture, entrepreneurship and development experienced across localities, proposing that the link between culture and development is mediated by entrepreneurship. It focuses upon the concept of community culture, as well as embracing a notion of development incorporating both economic and social well-being outcomes. Drawing upon a multivariate spatial analysis of data from localities in Great Britain, the findings indicate that differences in rates of entrepreneurship are strongly influenced by the community culture present in these localities. Furthermore, a bidirectional relationship is found to exist between entrepreneurship and economic and social development outcomes. It is concluded that the embeddedness of local community culture presents a significant challenge for those places seeking to promote entrepreneurially-driven development

Proporción diaria de alimento del diablillo antártico (pleuragramma antarcticum boulenger, 1902) en el este del mar de weddell

[EN] The daily ration of Pleuragramma antarcticum in the Eastern Weddell Sea was investigated from midwater and bottom trawl samples collected in the Antarctic in the summer of 1998. Using a gastric evacuation model that takes into account Weddell Sea temperature below zero and information on the prey type daily ration estimates were: 1.133% BW for immature fish of 10-16 cm and 0.484% BW for mature fish of 17-24 cm. The low daily ration intake was influenced by the low temperatures that limited the rate of gastric evacuation. This model seems more realistic than results from the classic Elliot & Persson and Eggers models that are also used in this paper, since their assumptions on feeding regularity are more rigid and they do not consider data of energy density of the prey[ES] La ración diaria de alimento de Pleuragramma antarcticum en el mar de Weddell es investigada en muestras de arrastres de fondo y pelágicas recogidas durante diferentes horas del día en el verano antártico de 1998. Utilizando un modelo de evacuación gástrica que tiene en cuenta la temperatura bajo del Mar de Weddell e información sobre el tipo de presa, las estimaciones de consumo diario fueron: 1.133% BW para peces inmaduros entre 10 -16 cm y 0.484% BW para peces maduros entre 17-24 cm. La baja ración diaria ingerida estuvo influida por las bajas temperaturas que limitan la tasa de evacuación gástrica. Este modelo parece más realista que los resultados de los modelos clásicos de Elliot & Persson and Eggers también empleados, ya que sus asunciones sobre su periodicidad de alimentación son más rígidas y no consideran datos de densidad energética de las presasThis work was conducted under the SCAR EASIZ programme, and was supported by the Alfred Wegener Institute and the Spanish Antarctic ProgrammePeer reviewe

Is Entrepreneurial Success Predictable? An Ex-Ante Analysis of the Character-Based Approach

This paper empirically analyzes whether the character-based approach, which focuses on the personality structure and the human capital of business founders, allows prediction of entrepreneurial success. A unique data set is used consisting of 414 persons whose personal characteristics were analyzed by different methods, namely an one-day assessment center (AC) and a standardized questionnaire, before they launched their business. Results are partly unexpected and weaker than previous ex-post findings: first, we found correlations between the AC data and the questionnaire in one subgroup only. Second, the predictive power of the AC data is slightly better than that of the questionnaire, but lower than expected in theory. Interestingly, for those subgroups where the AC data have low predictive power, the questionnaire does better. Third, when success is measured in terms of employees hired, the character-based approach is a poor predictor. Copyright 2008 The Authors.

Large scale cosmic-ray anisotropy with KASCADE

The results of an analysis of the large scale anisotropy of cosmic rays in the PeV range are presented. The Rayleigh formalism is applied to the right ascension distribution of extensive air showers measured by the KASCADE experiment.The data set contains about 10^8 extensive air showers in the energy range from 0.7 to 6 PeV. No hints for anisotropy are visible in the right ascension distributions in this energy range. This accounts for all showers as well as for subsets containing showers induced by predominantly light respectively heavy primary particles. Upper flux limits for Rayleigh amplitudes are determined to be between 10^-3 at 0.7 PeV and 10^-2 at 6 PeV primary energy.Comment: accepted by The Astrophysical Journa