Studies of NMDA receptor function and stoichiometry with truncated and tandem subunits

The subunits that compose eukaryotic glutamate ion channel receptors have three transmembrane domains (TMs) and terminate with intracellular tails that are important for controlling channel expression and localization. Truncation of NMDA receptor subunits before the final TM showed that this TM and intracellular tail region are necessary to form functional channels. However, it is shown here that these truncated subunits may be partially rescued by coexpressing the final TM and tail as a separate protein. The whole-cell currents so produced are somewhat lower than with full-length subunits, and they do not show the sag characteristic of currents from channels containing NR1 and NR2A subunits in the continued presence of an agonist. In addition, these truncated subunits were joined to full-length subunits to generate tandems. The functional expression of these tandems confirmed the tetrameric structure of NMDA receptors and also suggested that the subunits making up NMDA receptors are arranged as a dimer of dimers in the receptors with a 1-1-2-2 orientation of the subunits in the channel, and not in an alternating pattern of subunits around the pore. These results may redirect future studies into the mechanism of binding and gating in these receptors toward schemes including dimers, and may also be relevant to studies of glutamate receptor ion channels in general

Limits of sensing temporal concentration changes by single cells

Berg and Purcell [Biophys. J. 20, 193 (1977)] calculated how the accuracy of concentration sensing by single-celled organisms is limited by noise from the small number of counted molecules. Here we generalize their results to the sensing of concentration ramps, which is often the biologically relevant situation (e.g. during bacterial chemotaxis). We calculate lower bounds on the uncertainty of ramp sensing by three measurement devices: a single receptor, an absorbing sphere, and a monitoring sphere. We contrast two strategies, simple linear regression of the input signal versus maximum likelihood estimation, and show that the latter can be twice as accurate as the former. Finally, we consider biological implementations of these two strategies, and identify possible signatures that maximum likelihood estimation is implemented by real biological systems.Comment: 11 pages, 2 figure

Entropy Production of Brownian Macromolecules with Inertia

We investigate the nonequilibrium steady-state thermodynamics of single Brownian macromolecules with inertia under feedback control in isothermal ambient fluid. With the control being represented by a velocity-dependent external force, we find such open systems can have a negative entropy production rate and we develop a mesoscopic theory consistent with the second law. We propose an equilibrium condition and define a class of external forces, which includes a transverse Lorentz force, leading to equilibrium.Comment: 10 pages, 1 figur

Clinical outcomes for young people with screening-detected and clinically-diagnosed rheumatic heart disease in Fiji.

Echocardiographic screening is under consideration as a disease control strategy for rheumatic heart disease (RHD). However, clinical outcomes of young people with screening-detected RHD are unknown. We aimed to describe the outcomes for a cohort with screening-detected RHD, in comparison to patients with clinically-diagnosed RHD. A retrospective cohort study included all young people with screening-detected RHD in the Central Division of Fiji in the primary cohort. Screen-negative and clinically-diagnosed comparison groups were matched 1:1 to the primary cohort. Data were collected on mortality, clinical complications and healthcare utilisation from the electronic and paper health records and existing databases. Seventy participants were included in each group. Demographic characteristics of the groups were similar (median age 11years, 69% female, median follow-up 7years). There were nine (12.9%) RHD-related deaths in the clinically-diagnosed group and one (1.4%) in the screening-detected group (Incident Rate Ratio: 9.6, 95% CI 1.3-420.6). Complications of RHD were observed in 39 (55.7%) clinically-diagnosed cases, four (20%) screening-detected cases and one (1.4%) screen-negative case. There were significant differences in the cumulative complication curves of the groups (p<0.001). Rates of admission and surgery were highest in the clinically-diagnosed group, and higher in the screening-detected than screen-negative group. Young people with screening-detected RHD have worse health outcomes than screen-negative cases in Fiji. The prognosis of clinically-diagnosed RHD remains poor, with very high mortality and complication rates. Further studies in other settings will inform RHD screening policy. Comprehensive control strategies are required for disease prevention

Population-based assessment of cardiovascular complications of rheumatic heart disease in Fiji: a record-linkage analysis

Objective: To determine population-based rates of nonfatal complications of rheumatic heart disease (RHD). Design: Retrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage. Setting: Fiji, an upper-middle-income country, where most of the population has access to government-funded health care services. Participants: National cohort of 2,116 patients with clinically apparent RHD aged 5-69 years during 2008-2012. Primary and secondary outcome measures: The primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator. Results: Among 2,116 patients in the national cohort (median age, 23.3 years; 57.7% female), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0–40 years (heart failure, 210/454, 46.2%; ischaemic stroke 31/134, 23.3%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared to men (incidence rate ratio 1.4, 95% CI 1.3–1.6, P<0.001). Hospitalisation for any RHD complication was associated with substantially increased risk of death (hazard ratio, 5.4, 95% CI, 3.4–8.8, P<0.001), especially after the onset of heart failure (hazard ratio, 6.6, 95% CI, 4.8–9.1, P<0.001). Conclusions: Our study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low- and middle-income countries worldwide. Hospitalisation for an RHD complication is associated with markedly increased risk of death, re- emphasising the importance of effective early prevention

Interferometric measurement of micro-g acceleration with levitated atoms

The sensitivity of atom interferometers is usually limited by the observation time of a free falling cloud of atoms in Earth's gravitational field. Considerable efforts are currently made to increase this observation time, e.g. in fountain experiments, drop towers and in space. In this article, we experimentally study and discuss the use of magnetic levitation for interferometric precision measurements. We employ a Bose-Einstein condensate of cesium atoms with tuneable interaction and a Michelson-interferometer scheme for the detection of micro-g acceleration. In addition, we demonstrate observation times of 1s, which are comparable to current drop-tower experiments, we study the curvature of our force field, and we observe the effects of a phase-shifting element in the interferometer paths

Moving Towards the Post p < 0.05 Era via the Analysis of Credibility

It is now widely accepted that the techniques of null hypothesis significance testing (NHST) are routinely misused and misinterpreted by researchers seeking insight from data. There is, however, no consensus on acceptable alternatives, leaving researchers with little choice but to continue using NHST, regardless of its failings. I examine the potential for the Analysis of Credibility (AnCred) to resolve this impasse. Using real-life examples, I assess the ability of AnCred to provide researchers with a simple but robust framework for assessing study findings that goes beyond the standard dichotomy of statistical significance/nonsignificance. By extracting more insight from standard summary statistics while offering more protection against inferential fallacies, AnCred may encourage researchers to move toward the post p < 0.05 era

Masculinity as Governance: police, public service and the embodiment of authority, c. 1700-1850

About the book: Public Men offers an introduction to an exciting new field: the history of masculinities in the political domain and will be essential reading for students and specialists alike with interests in gender or political culture. By building upon new work on gender and political culture, these new case studies explore the gendering of the political domain and the masculinities of the men who have historically dominated it. As such, Public Men is a major contribution to our understanding of the history of Britain between the Eighteenth and the Twentieth centuries

Supramolecular approach to new inkjet printing inks

Electronically complementary, low molecular weight polymers that self-assemble through tunable π−π stacking interactions to form extended supramolecular polymer networks have been developed for inkjet printing applications and successfully deposited using three different printing techniques. Sequential overprinting of the complementary components results in supramolecular network formation through complexation of π-electron rich pyrenyl or perylenyl chain-ends in one component with π-electron deficient naphthalene diimide residues in a chain-folding polyimide. The complementary π−π stacked polymer blends generate strongly colored materials as a result of charge-transfer absorption bands in the visible spectrum, potentially negating the need for pigments or dyes in the ink formulation. Indeed, the final color of the deposited material can be tailored by varying the end-groups of the π-electron rich polymer component. Piezoelectric printing techniques were employed in a proof of concept study to allow characterization of the materials deposited, and a thermal inkjet printer adapted with imaging software enabled in situ analysis of the ink drops as they formed and of their physical properties. Finally, continuous inkjet printing allowed greater volumes of material to be deposited, on a variety of different substrate surfaces, and demonstrated the utility and versatility of this novel type of ink for industrial applications

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials