Project description:The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.
Project description:For over 50 years instructor humor has been recognized as a way to positively impact student cognitive and affective learning. However, no study has explored humor exclusively in the context of college science courses, which have the reputation of being difficult and boring. The majority of studies that explore humor have assumed that students perceive instructor humor to be funny, yet students likely perceive some instructor humor as unfunny or offensive. Further, evidence suggests that women perceive certain subjects to be more offensive than men, yet we do not know what impact this may have on the experience of women in the classroom. To address these gaps in the literature, we surveyed students across 25 different college science courses about their perceptions of instructor humor in college science classes, which yielded 1637 student responses. Open-coding methods were used to analyze student responses to a question about why students appreciate humor. Multinomial regression was used to identify whether there are gender differences in the extent to which funny, unfunny, and offensive humor influenced student attention to course content, instructor relatability, and student sense of belonging. Logistic regression was used to examine gender differences in what subjects students find funny and offensive when joked about by college science instructors. Nearly 99% of students reported that they appreciate instructor humor and reported that it positively changes the classroom atmosphere, improves student experiences during class, and enhances the student-instructor relationship. We found that funny humor tends to increase student attention to course content, instructor relatability, and student sense of belonging. Conversely, offensive humor tends to decrease instructor relatability and student sense of belonging. Lastly, we identified subjects that males were more likely to find funny and females were more likely to find offensive if a college science instructor were to joke about them.
Project description:Quantum supermaps are a higher-order genera- lization of quantum maps, taking quantum maps to quantum maps. It is known that any completely positive and trace non-increasing (CPTNI) map can be performed as part of a quantum measurement. By providing an explicit counterexample we show that, instead, not every quantum supermap sending a quantum channel to a CPTNI map can be realized in a measurement on quantum channels. We find that the supermaps that can be implemented in this way are exactly those transforming quantum channels into CPTNI maps even when tensored with the identity supermap. We link this result to the fact that the principle of causality fails in the theory of quantum supermaps.
Project description:Sub-angstrom resolution imaging of porous materials like zeolites is important to reveal their structure-property relationships involved in ion exchange, molecule adsorption and separation, and catalysis. Using multislice electron ptychography, we successfully measured the atomic structure of zeolite at sub-angstrom lateral resolution for 100-nanometer-thick samples. Both lateral and depth deformations of the straight channels are mapped, showing the three-dimensional structural inhomogeneity and flexibility. Since most zeolites in industrial applications are usually tens to hundreds of nanometers thick, the sub-angstrom resolution imaging and accurate measurements of depth-dependent local structures with electron ptychography at low-dose condition will find wide applications in porous materials close to their industrially relevant conditions.
Project description:The aim of this study was to investigate the effects on spontaneous beating rate of mouse atrial preparations following selective block of cardiac "funny" (f) channels, I(f), and/or suppression of sarcoplasmic reticulum (SR) function in the absence and presence of β-adrenoceptor stimulation. ZD7288 [to block I(f)] caused a substantial reduction (222 ± 13 bpm) in beating rate from 431 ± 14 to 209 ± 14 bpm, ryanodine alone (to block SR Ca(2+) release) reduced beating rate by 105 ± 11 bpm, with subsequent addition of ZD7288 further reducing rate by 57 ± 9 bpm. Cyclopiazonic acid (CPA) alone (to inhibit Ca(2+) reuptake by the SR) reduced beating rate by 148 ± 13 bpm with subsequent addition of ZD7288 further reducing rate by 79 ± 12 bpm. In additional experiments measuring Ca(2+) transients in the SA node region using Rhod-2, effects of ivabradine and ZD7288 on rate were again substantially reduced after CPA. Effects of CPA alone on rate developed much more slowly than effects on Ca(2+) transient amplitude. ZD7288, ivabradine, and CPA reduced the slope and maximum response of the log(concentration)-response curves for effects of isoprenaline on beating rate. Very little response to isoprenaline remained after treatment with CPA followed by ZD7288. Similar changes in isoprenaline log(concentration)-response curves were seen in guinea pig preparations. These observations are consistent with a role for Ca(2+) released from the SR in regulating I(f) and therefore beating rate of SA node preparations; there appear to be additional contributions of SR-derived Ca(2+) to effects of β-adrenoceptor stimulation on beating rate that are independent of I(f).
Project description:Processing of sensory information depends on the interactions between hierarchically connected neocortical regions, but it remains unclear how the activity in one area causally influences the activity dynamics in another and how rapidly such interactions change with time. Here, we show that the communication between the primary visual cortex (V1) and high-order visual area LM is context-dependent and surprisingly dynamic over time. By momentarily silencing one area while recording activity in the other, we find that both areas reliably affected changing subpopulations of target neurons within one hundred milliseconds while mice observed a visual stimulus. The influence of LM feedback on V1 responses became even more dynamic when the visual stimuli predicted a reward, causing fast changes in the geometry of V1 population activity and affecting stimulus coding in a context-dependent manner. Therefore, the functional interactions between cortical areas are not static but unfold through rapidly shifting communication subspaces whose dynamics depend on context when processing sensory information.
Project description:Nanofluidic sensing elements have been the focus of recent experiments for numerous applications ranging from nucleic acid fragment sizing to single-molecule DNA sequencing. These applications critically rely on high measurement fidelity, and methods to increase resolution are required. Herein, we describe fabrication and testing of a nanochannel device that enhances measurement resolution by performing multiple measurements (>100) on single DNA molecules. The enhanced measurement resolution enabled length discrimination between a mixture of ?-DNA (48.5 kbp) and T7 DNA (39.9 kbp) molecules, which were detected as transient current changes during translocation of the molecules through the nanochannel. As long DNA molecules are difficult to resolve quickly and with high fidelity with conventional electrophoresis, this approach may yield potentially portable, direct electrical sizing of DNA fragments with high sensitivity and resolution.
Project description:Secretins form megadalton bacterial-membrane channels in at least four sophisticated multiprotein systems that are crucial for translocation of proteins and assembled fibers across the outer membrane of many species of bacteria. Secretin subunits contain multiple domains, which interact with numerous other proteins, including pilotins, secretion-system partner proteins, and exoproteins. Our understanding of the structure of secretins is rapidly progressing, and it is now recognized that features common to all secretins include a cylindrical arrangement of 12-15 subunits, a large periplasmic vestibule with a wide opening at one end and a periplasmic gate at the other. Secretins might also play a key role in the biogenesis of their cognate secretion systems.
Project description:BackgroundDynamic risk models, which incorporate disease-free survival and repeated measurements over time, might yield more accurate predictions of future health status compared to static models. The objective of this study was to develop and apply a dynamic prediction model to estimate the risk of developing type 2 diabetes mellitus.MethodsBoth a static prediction model and a dynamic landmark model were used to provide predictions of a 2-year horizon time for diabetes-free survival, updated at 1, 2, and 3 years post-baseline i.e., predicting diabetes-free survival to 2 years and predicting diabetes-free survival to 3 years, 4 years, and 5 years post-baseline, given the patient already survived past 1 year, 2 years, and 3 years post-baseline, respectively. Prediction accuracy was evaluated at each time point using robust non-parametric procedures. Data from 2057 participants of the Diabetes Prevention Program (DPP) study (1027 in metformin arm, 1030 in placebo arm) were analyzed.ResultsThe dynamic landmark model demonstrated good prediction accuracy with area under curve (AUC) estimates ranging from 0.645 to 0.752 and Brier Score estimates ranging from 0.088 to 0.135. Relative to a static risk model, the dynamic landmark model did not significantly differ in terms of AUC but had significantly lower (i.e., better) Brier Score estimates for predictions at 1, 2, and 3 years (e.g. 0.167 versus 0.099; difference - 0.068 95% CI - 0.083 to - 0.053, at 3 years in placebo group) post-baseline.ConclusionsDynamic prediction models based on longitudinal, repeated risk factor measurements have the potential to improve the accuracy of future health status predictions.
Project description:The quality of topographic images obtained using atomic force microscopy strongly depends on the accuracy of the choice of scanning parameters. When using the most common scanning method - semicontact amplitude modulation (tapping) mode, the choice of scanning parameters is quite complicated, since it requires taking into account many factors and finding the optimal balance between them. A researcher's task can be significantly simplified by introducing new scanning techniques. Two such techniques are described: vertical and dissipation modes. Significantly simplified and formalized choice of the imaging parameters in these modes allows addressing a wide range of formerly challenging tasks - from scanning rough samples with high aspect ratio features to molecular resolution imaging.