The conduction pathway of potassium channels is water free under physiological conditions.

Ion conduction through potassium channels is a fundamental process of life. On the basis of crystallographic data, it was originally proposed that potassium ions and water molecules are transported through the selectivity filter in an alternating arrangement, suggesting a "water-mediated" knock-on mechanism. Later on, this view was challenged by results from molecular dynamics simulations that revealed a "direct" knock-on mechanism where ions are in direct contact. Using solid-state nuclear magnetic resonance techniques tailored to characterize the interaction between water molecules and the ion channel, we show here that the selectivity filter of a potassium channel is free of water under physiological conditions. Our results are fully consistent with the direct knock-on mechanism of ion conduction but contradict the previously proposed water-mediated knock-on mechanism

Lateral orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected sequential effects, including increased willingness to take risks following risky wins, and spatial ‘win-stay/lose-shift’ biases. Recordings from lateral orbitofrontal cortex (lOFC) revealed encoding of reward history and receipt, and optogenetic inhibition of lOFC eliminated rats’ increased preference for risk following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and the lOFC’s role in adaptive behavior promotes learning of more abstract biases (here, biases for the risky option), but not spatial ones

Analysis of time-profiles with in-beam PET monitoring in charged particle therapy

Background: Treatment verification with PET imaging in charged particle therapy is conventionally done by comparing measurements of spatial distributions with Monte Carlo (MC) predictions. However, decay curves can provide additional independent information about the treatment and the irradiated tissue. Most studies performed so far focus on long time intervals. Here we investigate the reliability of MC predictions of space and time (decay rate) profiles shortly after irradiation, and we show how the decay rates can give an indication about the elements of which the phantom is made up. Methods and Materials: Various phantoms were irradiated in clinical and near-clinical conditions at the Cyclotron Centre of the Bronowice proton therapy centre. PET data were acquired with a planar 16x16 cm$^2$ PET system. MC simulations of particle interactions and photon propagation in the phantoms were performed using the FLUKA code. The analysis included a comparison between experimental data and MC simulations of space and time profiles, as well as a fitting procedure to obtain the various isotope contributions in the phantoms. Results and conclusions: There was a good agreement between data and MC predictions in 1-dimensional space and decay rate distributions. The fractions of $^{11}$C, $^{15}$O and $^{10}$C that were obtained by fitting the decay rates with multiple simple exponentials generally agreed well with the MC expectations. We found a small excess of $^{10}$C in data compared to what was predicted in MC, which was clear especially in the PE phantom.Comment: 9 pages, 5 figures, 1 table. Proceedings of the 20th International Workshop on Radiation Imaging Detectors (iWorid2018), 24-28 June 2018, Sundsvall, Swede

Uncertainty Analysis in Population-Based Disease Microsimulation Models

Objective. Uncertainty analysis (UA) is an important part of simulation model validation. However, literature is imprecise as to how UA should be performed in the context of population-based microsimulation (PMS) models. In this expository paper, we discuss a practical approach to UA for such models. Methods. By adapting common concepts from published UA guidelines, we developed a comprehensive, step-by-step approach to UA in PMS models, including sample size calculation to reduce the computational time. As an illustration, we performed UA for POHEM-OA, a microsimulation model of osteoarthritis (OA) in Canada. Results. The resulting sample size of the simulated population was 500,000 and the number of Monte Carlo (MC) runs was 785 for 12-hour computational time. The estimated 95% uncertainty intervals for the prevalence of OA in Canada in 2021 were 0.09 to 0.18 for men and 0.15 to 0.23 for women. The uncertainty surrounding the sex-specific prevalence of OA increased over time. Conclusion. The proposed approach to UA considers the challenges specific to PMS models, such as selection of parameters and calculation of MC runs and population size to reduce computational burden. Our example of UA shows that the proposed approach is feasible. Estimation of uncertainty intervals should become a standard practice in the reporting of results from PMS models

The Effect of Disease Site (Knee, Hip, Hand, Foot, Lower Back or Neck) on Employment Reduction Due to Osteoarthritis

Osteoarthritis (OA) has a significant impact on individuals' ability to work. Our goal was to investigate the effects of the site of OA (knee, hip, hand, foot, lower back or neck) on employment reduction due to OA (EROA).This study involved a random sample of 6,000 patients with OA selected from the Medical Service Plan database in British Columbia, Canada. A total of 5,491 were alive and had valid addresses, and of these, 2,259 responded (response rate = 41%), from which 2,134 provided usable data. Eligible participants were 19 or older with physician diagnosed OA based on administrative data between 1992 and 2006. Data of 688 residents were used (mean age 62.1 years (27 to 86); 60% women). EROA had three levels: no reduction; reduced hours; and total cessation due to OA. The (log) odds of EROA was regressed on OA sites, adjusting for age, sex, education and comorbidity. Odds ratios (ORs) represented the effect predicting total cessation and reduced hours/total cessation. The strongest effect was found in lower back OA, with OR = 2.08 (95% CI: 1.47, 2.94), followed by neck (OR = 1.59; 95% CI: 1.11, 2.27) and knee (OR = 1.43; 95% CI: 1.02, 2.01). We found an interaction between sex and foot OA (men: OR = 1.94; 95% CI: 1.05, 3.59; women: OR = 0.89; 95% CI = 0.57, 1.39). No significant effect was found for hip OA (OR = 1.33) or hand OA (OR = 1.11). Limitations of this study included a modest response rate, the lack of an OA negative group, the use of administrative databases to identify eligible participants, and the use of patient self-reported data.After adjusting for socio-demographic variables, comorbidity, and other OA disease sites, we find that OA of the lower back, neck and knee are significant predictors for EROA. Foot OA is only significantly associated with EROA in males. For multi-site combinations, ORs are multiplicative. These findings may be used to guide resource allocation for future development/improvement of vocational rehabilitation programs for site-specific OA

COMPARING THE VALIDITY OF FIVE PARTICIPATION INSTRUMENTS IN PERSONS WITH SPINAL CONDITIONS

Objective: To evaluate and compare the construct validity of 5 participation instruments developed using the International Classification of Functioning, Disability and Health (ICF). Methods: A total of 545 subjects diagnosed and treated for a spinal condition at an acute hospital were followed-up and consented to complete a questionnaire. Subjects completed 5 participation instruments (Impact on Participation and Autonomy (IPA), Keele Assessment of Participation (KAP), Participation Measure-Post Acute Care (PM-PAC), Participation Objective Participation Subjective (POPS), World Health Organization Disability Assessment Schedule II (WHODAS II)). In addition, each subject completed a health status instrument and a quality of life instrument. The dimensionality, convergent/discriminant validity and known-group validity of the participation instruments were assessed. Results: A confirmatory factor analysis of the facture structure for the IPA and PM-PAC demonstrated adequate model fit. For convergent/discriminant validity, correlations were generally higher among similar domains of the WHODAS II, IPA, KAP and PM-PAC, and as expected the lowest correlations were observed with the objective domains of the POPS. Most instruments demonstrated known-group validity. Conclusion: Differences in the construct validity evidence of the POPS compared with the other 4 instruments were noted. To date, there is no gold standard for measuring participation, and clinicians and researchers should consider the type of information required prior to selecting an instrument

Direct detection of bound ammonium ions in the selectivity filter of ion channels by solid-state NMR.

The flow of ions across cell membranes facilitated by ion channels is an important function for all living cells. Despite the huge amount of structural data provided by crystallography, elucidating the exact interactions between the selectivity filter atoms and bound ions is challenging. Here, we detect bound 15 N-labeled ammonium ions as a mimic for potassium ions in ion channels using solid-state NMR under near-native conditions. The non-selective ion channel NaK showed two ammonium peaks corresponding to its two ion binding sites, while its potassium-selective mutant NaK2K that has a signature potassium- selective selectivity filter with four ion binding sites gave rise to four ammonium peaks. Ions bound in specific ion binding sites were identified based on magnetization transfer between the ions and carbon atoms in the selectivity filters. Magnetization transfer between bound ions and water molecules revealed that only one out of four ions in the selectivity filter of NaK2K is in close contact with water, which is in agreement with the direct knock-on ion conduction mechanism where ions are conducted through the channel by means of direct interactions without water molecules in between. Interestingly, the potassium-selective ion channels investigated here (NaK2K and, additionally, KcsA-Kv1.3) showed remarkably different chemical shifts for their bound ions, despite having identical amino acid sequences and crystal structures of their selectivity filters. Molecular dynamics simulations show similar ion binding and conduction behavior between ammonium and potassium ions and identify the origin of the differences between the investigated potassium channel

Use of Remote Sensing for Monitoring Climate Variability for Integrated Early Warning Systems: Applications for Human Diseases and Desert Locust Management

A number of the major human infectious diseases (like malaria and dengue) and Desert Locusts that still plague the developing world are sensitive to inter-seasonal and inter-decadal changes in environment and climate. Monitoring variations in environmental conditions such as rainfall and vegetation helps decision-makers at Ministries of Agriculture and Ministries of Health to assess the risk levels of Desert Locust outbreaks or malaria epidemics. The International research institute for climate and society (IRI) has developed products based on remotely sensed data to monitor those changes and provide the information directly to the decision-makers. This paper presents recent developments which use remote sensing to monitor climate variability, environmental conditions and their impacts on the dynamics of infectious diseases (malaria) and Desert Locust outbreaks

Interaction-induced Bose Metal in 2D

We show here that the regularization of the conductivity resulting from the bosonic interactions on the `insulating' (quantum disordered) side of an insulator-superconductor transition in 2D gives rise to a metal with a finite conductivity, $\sigma =(2/\pi) 4 e^2/h$, as temperature tends to zero. The Bose metal is stable to weak disorder and hence represents a concrete example of an interaction-induced metallic phase. Phenomenological inclusion of dissipation reinstates the anticipated insulating behaviour in the quantum-disordered regime. Hence, we conclude that the traditionally-studied insulator-superconductor transition, which is driven solely by quantum fluctuations, corresponds to a superconductor-metal transition. The possible relationship to experiments on superconducting thin films in which a low-temperature metallic phase has been observed is discussed.Comment: A figure has been added and the physics has been clarified. To appear in PR

Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft