Cyclic nucleotide-gated channels: structural basis of ligand efficacy and allosteric modulation

Most working proteins, including metabolic enzymes, transcription regulators, and membrane receptors, transporters, and ion channels, share the property of allosteric coupling. The term 'allosteric' means that these proteins mediate indirect interactions between sites that are physically separated on the protein. In the example of ligand-gated ion channels, the binding of a suitable ligand elicits local conformational changes at the binding site, which are coupled to further conformational changes in regions distant from the binding site. The physical motions finally arrive at the site of biological activity: the ion-permeating pore. The conformational changes that lead from the ligand binding to the actual opening of the pore comprise 'gating'. In 1956, del Castillo and Katz suggested that the competition between different ligands at nicotinic acetylcholine receptors (nAChRs) could be explained by formation of an intermediate, ligand-bound, yet inactive state of the receptor, which separates the active state of the receptor from the initial binding of the ligand (del Castillo & Katz, 1957). This 'binding-then-gating', two-step model went beyond the then-prevailing drug-receptor model that assumes a single bimolecular binding reaction, and paralleled Stephenson's conceptual dichotomy of 'affinity' and 'efficacy' (Stephenson, 1956). In 1965 Monod, Wyman and Changeux presented a simple allosteric model (the MWC model) (Monod et al. 1965) that explained the cooperative binding of oxygen to haemoglobin; it was adopted as an important paradigm for ligand-gated channels soon after its initial formulation (Changeux et al. 1967; Karlin, 1967; Colquhoun, 1973)

Electrically tuneable exciton-polaritons through free electron doping in monolayer WS2_2 microcavities

We demonstrate control over light-matter coupling at room temperature combining a field effect transistor (FET) with a tuneable optical microcavity. Our microcavity FET comprises a monolayer tungsten disulfide WS$_2$ semiconductor which was transferred onto a hexagonal boron nitride flake that acts as a dielectric spacer in the microcavity, and as an electric insulator in the FET. In our tuneable system, strong coupling between excitons in the monolayer WS$_2$ and cavity photons can be tuned by controlling the cavity length, which we achieved with excellent stability, allowing us to choose from the second to the fifth order of the cavity modes. Once we achieve the strong coupling regime, we then modify the oscillator strength of excitons in the semiconductor material by modifying the free electron carrier density in the conduction band of the WS$_2$. This enables strong Coulomb repulsion between free electrons, which reduces the oscillator strength of excitons until the Rabi splitting completely disappears. We controlled the charge carrier density from 0 up to 3.2 $\times$ 10$^{12}$ cm$^{-2}$, and over this range the Rabi splitting varies from a maximum value that depends on the cavity mode chosen, down to zero, so the system spans the strong to weak coupling regimes.Comment: Accepted for publicatio

Letter from Henry Otte

Letters concerning application for chorister and band leader position at the Agriculture College

Gaussian Optical Ising Machines

It has recently been shown that optical parametric oscillator (OPO) Ising machines, consisting of coupled optical pulses circulating in a cavity with parametric gain, can be used to probabilistically find low-energy states of Ising spin systems. In this work, we study optical Ising machines that operate under simplified Gaussian dynamics. We show that these dynamics are sufficient for reaching probabilities of success comparable to previous work. Based on this result, we propose modified optical Ising machines with simpler designs that do not use parametric gain yet achieve similar performance, thus suggesting a route to building much larger systems.Comment: 6 page

Governing Human Interactions with Migratory Animals, with a Focus on Humans Interacting with Fish in Lake Erie: Then, Now, and in the Future

Lake Erie fisherie

Governing Human Interactions with Migratory Animals, with a Focus on Humans Interacting with Fish in Lake Erie: Then, Now, and in the Future

Lake Erie fisherie

The President’s National Security Agenda Curtailing Ebola, Safeguarding the Future

A clear lesson of the Ebola epidemic in West Africa is the need for strong public health systems globally, including in the United States. Ebola has highlighted the dangers of weak public health systems, from the immense shortage of health workers in West Africa to the budget cuts at the U.S. Centers for Disease Control and Prevention. In response to Ebola and the broader threat of infectious disease, President Obama has proposed a $6.2 billion supplemental funding request to Congress. The supplemental would surge resources for containing and treating Ebola in West Africa -- including a reserve of funds to enable a robust, flexible response going forward--enhance prevention and detection of, and response to, Ebola in the United States, and buttress U.S. and partner country health systems to respond rapidly and flexibly to all infectious disease hazards in the future. The additional resources the supplemental would devote to the ongoing Ebola crisis is critically important. So is the supplemental request\u27s funding to prepare for the future, including developing treatment centers in the United States that would provide advanced care and isolation facilities, and funding for research and development for vaccines and medicines for Ebola and other novel infections. The request would also provide the first significant batch of funding to the Global Health Security Agenda, which President Obama unveiled in February 2014. The Global Health Security Agenda takes an all-hazards approach to building greater global capacity to prevent, detect, and respond to infectious diseases, from zoonotic diseases and antibiotic resistant bacteria to biosecurity and bioterror threats. From environmental degradation to increased human-animal interchange, the threats are only increasing. Strong public health systems at home and globally are our best defense. Congress should support the President\u27s supplemental funding request, furthering a bipartisan U.S. tradition of support for global health, continuing U.S. global leadership in the Ebola response, and preparing our country and our world for disease threats of the future

Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes

Several cDNA clones coding for the high molecular weight (alpha) subunit of the voltage-sensitive Na channel have been selected by immunoscreening a rat brain cDNA library constructed in the expression vector lambda gt11. As will be reported elsewhere, the amino acid sequence translated from the DNA sequence shows considerable homology to that reported for the Electrophorus electricus electroplax Na channel. Several of the cDNA inserts hybridized with a low-abundance 9-kilobase RNA species from rat brain, muscle, and heart. Sucrose-gradient fractionation of rat brain poly(A) RNA yielded a high molecular weight fraction containing this mRNA, which resulted in functional Na channels when injected into oocytes. This fraction contained undetectable amounts of low molecular weight RNA. The high molecular weight Na channel RNA was selected from rat brain poly(A) RNA by hybridization to a single-strand antisense cDNA clone. Translation of this RNA in Xenopus oocytes resulted in the appearance of tetrodotoxin-sensitive voltage-sensitive Na channels in the oocyte membrane. These results demonstrate that mRNA encoding the alpha subunit of the rat brain Na channel, in the absence of any beta-subunit mRNA, is sufficient for translation to give functional channels in oocytes