Capture of exocomets and the erosion of the Oort cloud due to stellar encounters in the Galaxy

Stars and planetary system

AMPA Receptor Activation Causes Silencing of AMPA Receptor-Mediated Synaptic Transmission in the Developing Hippocampus

Agonist-induced internalization of transmembrane receptors is a widespread biological phenomenon that also may serve as a mechanism for synaptic plasticity. Here we show that the agonist AMPA causes a depression of AMPA receptor (AMPAR) signaling at glutamate synapses in the CA1 region of the hippocampus in slices from developing, but not from mature, rats. This developmentally restricted agonist-induced synaptic depression is expressed as a total loss of AMPAR signaling, without affecting NMDA receptor (NMDAR) signaling, in a large proportion of the developing synapses, thus creating AMPAR silent synapses. The AMPA-induced AMPAR silencing is induced independently of activation of mGluRs and NMDARs, and it mimics and occludes stimulus-induced depression, suggesting that this latter form of synaptic plasticity is expressed as agonist-induced removal of AMPARs. Induction of long-term potentiation (LTP) rendered the developing synapses resistant to the AMPA-induced depression, indicating that LTP contributes to the maturation-related increased stability of these synapses. Our study shows that agonist binding to AMPARs is a sufficient triggering stimulus for the creation of AMPAR silent synapses at developing glutamate synapses

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial

Background:Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.Methods:In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.Results:The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log 10 CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log 10 CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated wit

Abstract 3568: CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides

Abstract: While cytochrome P450 enzymes (CYPs) are implicated in tumor angiogenesis through biosynthesis of epoxyeicosatrienoic acids (EETs), little is known about breast cancer cell-intrinsic CYPs that exhibit epoxygenase activity, such as CYP3A4. In an orthotopic breast cancer model, silencing of epithelial CYP3A4 suppressed angiogenesis-related escape of ER+ breast tumors from dormancy. While the diabetes drug metformin inhibits mitochondrial complex I and inhibits tumor growth, how it does so is unknown. Metformin inhibited CYP epoxygenase activity and co-crystallized in the active site of CYP3A4, hydrogen bonding with arginine 212, allowing the development of hexyl-benzyl-biguanide (HBB) as a CYP3A4 inhibitor using molecular modeling. HBB exhibited more than 10-fold greater potency than metformin for inhibition of ER+ mammary tumor growth and inhibited associated tumor angiogenesis. HBB inhibited EET biosynthesis ∼40-fold more potently than metformin and was ∼40-fold more potent for activation of AMPK phosphorylation. EETs suppressed and CYP silencing promoted AMPK phosphorylation, linking CYPs with AMPK regulation in breast cancer. HBB depolarized mitochondria, reduced oxygen consumption rates and suppressed the Warburg effect, while EETs restored the mitochondrial membrane potential. CYP3A4 silencing and HBB treatment increased reactive oxygen species (ROS) production, suggesting that CYPs suppress cancer cell death, in part, through suppression of ROS. CYP3A4 silencing sensitized breast cancer cells to hormonal therapy and chemotherapy, abrogated by EETs. Because EETs are autocrine, paracrine and endocrine, these results implicate CYPs in tumor growth, in part, through cell-cell mediation of mitochondrial homeostasis and demonstrate the potential of CYP3A4 as a therapeutic target in breast cancer. Citation Format: Zhijun Guo, Irina F. Sevrioukova, Eric Hanse, Ilia Denisov, Xia Zhang, Ting-Lan Chiu, Daniel Swedien, Justin Stamschror, Juan Alvarez, William Marerro Ortiz, Monique Morgan, Michael Maher, Kathryn J. Chavez, Dafydd Thomas, Young Kyung Bae, Jonathan Henriksen, Beverly Norris, Robert J. Schumacher, Henry Wang, Robin Bliss, Haitao Chu, Rebecca Cuellar, Thomas L. Poulos, Stephen G. Sligar, William Atkins, Stephen Schmechel, Jorge Capdevila, John Falck, Ian Blair, Jeffrey P. Jones, Gunda Georg, Kalpna Gupta, Ameeta Kelekar, Elizabeth Amin, David A. Potter. CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2015-356

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

(Cell Chemical Biology 24, 1259–1275; October 19, 2017) During the cropping of Figure 2H, the image of the p62 row was deleted in error and then remaining labels were shifted down by one row and were therefore out of registration with the images. Figure 2H has now been corrected in the article online and in print; the corrected Figure 2H is also shown below. The authors apologize for this labeling error

Riding on the Coat-Tails of Traditional Cultural Expressions

Matters related to the protection of traditional cultural expressions (‘TCEs’) or expressions of folklore (‘EoFs’) are sensitive and intricate as a blend of legal, economic, philosophical and anthropological considerations jostle to capture their core features. This results in disparate views surrounding what should qualify as TCEs or EoFs, who should be considered their ‘owner’ (assuming that ownership per se is conceptually compatible with these items), which is the most appropriate legal protection regime and how broad their scope of protection should be. Drawing from these various accounts on TCEs, this article focuses on the interaction between TCEs and EoFs originating on the European continent and the European Union (‘EU’) trade mark legislation. Specifically, this article examines whether the limitations of the effects of trade mark rights and of the absolute grounds of refusal, as developed by the case law of the Court of Justice of the European Union, are effective in preserving the cohesion of TCEs. This article advances the thesis that registration of TCEs and EoFs as trade marks generates an imbalance between the rights of the trade mark owner and the defences available to others under the EU trade mark law framework. Furthermore, such an imbalance is likely to hinder the unfettered circulation of TCEs and undermine their original meaning. Lastly, in some cases, trade mark registration of TCEs contributes to their appropriation and misappropriation. The article concludes that, de lege ferenda, the direct exclusion of TCEs as eligible subject matter for trade mark registration is preferable to seeking a post factum remedy

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

Plaatsspecifieke opslagbestrijding over twee jaar praktijprijp

In Wageningen wordt momenteel hard gewerkt aan een spuitmachine die plaatsspecifiek aardappelopslag uit een gewas kan verwijderen. Landbouwtechnisch ingenieur Ard Nieuwenhuizen heeft daarvoor samen met collega-technici een ingenieuze spuitmachine gemaakt. De eerste proefresultaten van het prototype zijn zeer hoopgevend. Over twee jaar kan de gebruikte techniek praktijkrijp zij

Internetprogramma geeft inzicht in eigen Phytophthora-strategie. (Internet site gives insight in effectiveness of growers personal potato late blight control strategies)

Om telers te helpen met hun bestrijdingsstrategie is het Agrobiocon programma 'Visualisatie infectie Phytophthora' ontwikkeld. Uitleg van mede ontwikkelaar Geert Kessel van Plant Research International van Wageningen U

Snel plantmonitoren met nieuwe cameratechniek (interview met Dr. V.G.A.A. Vleeshouwers)

De onderzoekers Henk Jalink en Rob van der Schoor van Wageningen UR hebben een innovatieve MIPS-LED camera ontwikkeld, waarmee collega-onderzoekers van de universiteit snel fotosynthese in planten kunnen vastleggen. Vivianne Vleeshouwers, is werkzaam bij Wageningen UR Plantenveredeling, en is een van de onderzoekers die de camera beproeft. Zij hoopt het apparaat te kunnen inzetten voor onderzoek naar phytophthoraresistentie in (nieuwe) aardappelrassen en wilde soorten