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

Practice Feedback Interventions: 15 Suggestions for Optimizing Effectiveness

Electronic practice data are increasingly being used to provide feedback to encourage practice improvement. However, evidence suggests that despite decades of experience, the effects of such interventions vary greatly and are not improving over time. Guidance on providing more effective feedback does exist, but it is distributed across a wide range of disciplines and theoretical perspectives. Through expert interviews; systematic reviews; and experience with providing, evaluating, and receiving practice feedback, 15 suggestions that are believed to be associated with effective feedback interventions have been identified. These suggestions are intended to provide practical guidance to quality improvement professionals, information technology developers, educators, administrators, and practitioners who receive such interventions. Designing interventions with these suggestions in mind should improve their effect, and studying the mechanisms underlying these suggestions will advance a stagnant literature

B→D∗ℓνℓB \to D^*\ell\nu_\ell semileptonic form factors from lattice QCD with M\"obius domain-wall quarks

We calculate the form factors for the $B \to D^*\ell\nu_\ell$ decay in 2+1 flavor lattice QCD. For all quark flavors, we employ the M\"obius domain-wall action, which preserves chiral symmetry to a good precision. Our gauge ensembles are generated at three lattice cutoffs $a^{-1} \sim 2.5$, 3.6 and 4.5 GeV with pion masses as low as $M_\pi \sim 230$ MeV. The physical lattice size $L$ satisfies the condition $M_\pi L \geq 4$ to control finite volume effects (FVEs), while we simulate a smaller size at the smallest $M_\pi$ to directly examine FVEs. The bottom quark masses are chosen in a range from the physical charm quark mass to $0.7 a^{-1}$ to control discretization effects. We extrapolate the form factors to the continuum limit and physical quark masses based on heavy meson chiral perturbation theory at next-to-leading order. Then the recoil parameter dependence is parametrized using a model independent form leading to our estimate of the decay rate ratio between the tau ($\ell = \tau$) and light lepton ($\ell = e,\mu$) channels $R(D^*) = 0.252(22)$ in the Standard Model. A simultaneous fit with recent data from the Belle experiment yields $|V_{cb}| = 39.19(90)\times 10^{-3}$, which is consistent with previous exclusive determinations, and shows good consistency in the kinematical distribution of the differential decay rate between the lattice and experimental data.Comment: 37 pages, 13 figure

Reporting and design elements of audit and feedback interventions: a secondary review

BACKGROUND: Audit and feedback (A&F) is a frequently used intervention aiming to support implementation of research evidence into clinical practice with positive, yet variable, effects. Our understanding of effective A&F has been limited by poor reporting and intervention heterogeneity. Our objective was to describe the extent of these issues. METHODS: Using a secondary review of A&F interventions and a consensus-based process to identify modifiable A&F elements, we examined intervention descriptions in 140 trials of A&F to quantify reporting limitations and describe the interventions. RESULTS: We identified 17 modifiable A&F intervention elements; 14 were examined to quantify reporting limitations and all 17 were used to describe the interventions. Clear reporting of the elements ranged from 56% to 97% with a median of 89%. There was considerable variation in A&F interventions with 51% for individual providers only, 92% targeting behaviour change and 79% targeting processes of care, 64% performed by the provider group and 81% reporting aggregate patient data. CONCLUSIONS: Our process identified 17 A&F design elements, demonstrated gaps in reporting and helped understand the degree of variation in A&F interventions

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