A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Effect of impact ionization on the saturation of 1s→2p+ shallow donor transition in n-GaAs

The magneto-photoconductivity due to 1s-2p+ optical transitions of shallow donors in n-GaAs has been investigated as a function of intensity for several bias voltages at low temperatures between 2K and 4.2 K. At low intensities a superlinear increase of the photoconductive signal with rising intensity has been observed which gets more pronounced at higher bias voltages and lower temperatures. The power broadening of the linewidth was found to be distinctly different from the behaviour expected for a two-level system. By a detailed analysis in terms of a nonlinear generation-recombination model it is shown that these effects may be attributed to impact ionization of the optically excited 2p+ states

Fault slip distribution of the 2014 Iquique, Chile, earthquake estimated from ocean-wide tsunami waveforms and GPS data

We applied a new method to compute tsunami Green’s functions for slip inversion of the 1 April 2014 Iquique earthquake using both near-field and far-field tsunami waveforms. Inclusion of the effects of the elastic loading of seafloor, compressibility of seawater, and the geopotential variation in the computed Green’s functions reproduced the tsunami travel-time delay relative to long-wave simulation, and allowed us to use far-field records in tsunami waveform inversion. Multiple time window inversion was applied to tsunami waveforms iteratively until the result resembles the stable moment-rate function from teleseismic inversion. We also used GPS data for a joint inversion of tsunami waveforms and co-seismic crustal deformation. The major slip region with a size of 100 km × 40 km is located down-dip the epicenter at depth ~28 km, regardless of assumed rupture velocities. The total seismic moment estimated from the slip distribution is 1.24 × 1021 Nm (Mw 8.0)

Dynamic Memory Design for Low Data-Retention Power

Abstract. The emergence of data-intensive applications in mobile en-vironments has resulted in portable electronic systems with increasingly large dynamic memories. The typical operating pattern exhibited by these applications is a relatively short burst of operations followed by longer periods of standby. Due to their periodic refresh requirements, dynamic memories consume substantial power even during standby and thus have a significant impact on battery lifetime. In this paper we investigate a methodology for designing dynamic mem-ory with low data-retention power. Our approach relies on the fact that the refresh period of a memory array is dictated by only a few, worst-case leaky cells. In our scheme, multiple refresh periods are used to reduce energy dissipation by selectively refreshing only the cells that are about to lose their stored values. Additional energy savings are achieved by using error-correction to restore corrupted cell values and thus allow for extended refresh periods. We describe an exact O(nk−1)-time algorithm that, given a memory array with n refresh blocks and two positive in-tegers k and l, computes k refresh periods that maximize the average refresh period of a memory array when refreshing occurs in blocks of l cells. In simulations with 16Mb memory arrays and a (72,64) modified Hamming single-error correction code, our scheme results in an average refresh period of up to 11 times longer than the original refresh period.

Cross-linkable molecular glasses: Low dielectric constant materials patternable in hydrofluoroethers

We report a new approach to solution-processable low-dielectric-constant (low-k) materials including photolithographic patterning of these materials in chemically benign and environmentally friendly solvents. A series of semiperfluorinated molecular glasses with styrenic substituents were successfully synthesized. These small molecular materials were thermally stable up to 400 °C and also exhibited an amorphous nature, which is essential to forming uniform films. Differential scanning calorimetry studies revealed that a cross-linking reaction occurred in the presence of acid, resulting in the formation of robust polymeric films. Atomic force microscopy images of the cross-linked films showed uniform and pinhole-free surface properties. Dielectric constants determined by a capacitance measurement were 2.6-2.8 (100 kHz) at ambient conditions, which are comparable to other polymeric low-k materials. The incorporation of semiperfluorinated substituents was effective in decreasing the dielectric constant; in particular, the fluorinated alkyl ether structure proved best. In addition, the fluorinated substituents contributed to good solubility in hydrofluoroether (HFE) solvents, which enabled the successful photolithographic patterning of those materials in HFEs down to a submicrometer scale. © 2009 American Chemical Society

Orthogonal lithography for organic electronics

Organic electronics has recently gained attention as a new field promising cheaper, flexible, and large-scale devices. Although photolithography has proven to be a high-resolution and high-throughput patterning method with excellent registration capabilities, the emerging field of organic electronics has been largely unsuccessful in adapting this well-established method as a viable approach to patterning. Chemical compatibility issues between organic materials and the processing solvents and chemicals required by photolithography have been the main problem. This challenge has led us to identify a set of non-damaging processing solvents and to develop alternative imaging materials in order to extend photolithographic patterning methods to organic electronics. We have identified supercritical carbon dioxide and hydrofluoroether (HFE) solvents as chemically benign to organic electronic materials and which are also suitable as processing solvents. We refer to these solvents as orthogonal in that they do not substantially interact with traditional aqueous and organic solvents. Multi-layered devices are easily realized by exploiting this orthogonality property; subsequent layers are deposited and patterned without damaging or otherwise adversely affecting previously deposited underlying layers. We have designed and synthesized novel photoresists, which are processible in these benign solvents. © 2010 Copyright SPIE - The International Society for Optical Engineering