While Active Learning Classrooms, or ALCs, offer rich new environments for learning, they present many new challenges to faculty because, among other things, they eliminate the room's central focal ...point and disrupt the conventional seating plan to which faculty and students have become accustomed.The importance of learning how to use these classrooms well and to capitalize on their special features is paramount. The potential they represent can be realized only when they facilitate improved learning outcomes and engage students in the learning process in a manner different from traditional classrooms and lecture halls.This book provides an introduction to ALCs, briefly covering their history and then synthesizing the research on these spaces to provide faculty with empirically based, practical guidance on how to use these unfamiliar spaces effectively. Among the questions this book addresses are:
How can instructors mitigate the apparent lack of a central focal point in the space?
What types of learning activities work well in the ALCs and take advantage of the affordances of the room?
How can teachers address familiar classroom-management challenges in these unfamiliar spaces?
If assessment and rapid feedback are critical in active learning, how do they work in a room filled with circular tables and no central focus point?
How do instructors balance group learning with the needs of the larger class?
How can students be held accountable when many will necessarily have their backs facing the instructor?
How can instructors evaluate the effectiveness of their teaching in these spaces?This book is intended for faculty preparing to teach in or already working in this new classroom environment; for administrators planning to create ALCs or experimenting with provisionally designed rooms; and for faculty developers helping teachers transition to using these new spaces.
Instructors have inherited a model for conscientious instruction that suggests they must cover all the material outlined in their syllabus, and yet this model frequently diverts time away from ...allowing students to engage meaningfully with the content during class. We outline the historical forces that may have conditioned this teacher-centered model as well as the disciplinary pressures that inadvertently reward it. As a way to guide course revision and move to a learner-centered teaching approach, we propose three evidence-based strategies that instructors can adopt: 1) identify the core concepts and competencies for your course; 2) create an organizing framework for the core concepts and competencies; and 3) teach students how to learn in your discipline. We further outline examples of actions that instructors can incorporate to implement each of these strategies. We propose that moving from a content-coverage approach to these learner-centered strategies will help students better learn and retain information and apply it to new situations.
Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache ...attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches.
This chapter provides practical strategies for addressing common challenges that arise for teachers in active learning classrooms. Our strategies come from instructors with experience teaching in ...these environments.
Human ether-a-go-go- related gene ( HERG ) encodes the rapid, outwardly rectifying K + current I Kr that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or ...unintended pharmaceutical block of I Kr can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653)
that is highly conserved among evolutionarily divergent K + channels. HERG-A653 is close to the âglycine hingeâ implicated in K + channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted
an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems
to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V 1/2 of activation ranging from â23.6 (A653S) to â62.5 (A653V) compared to â11.2 mV for wild-type (WT). Deactivation was also
drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above
the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and
prolonged holding potentials at â130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the I Kr inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests
that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing
a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional
role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the
channel activation threshold.
Human ether-a-go-go-related gene (HERG) encodes the pore-forming subunit of IKr, a cardiac K+channel. Although many commonly used drugs block IKr, in certain individuals, this action evokes a ...paradoxical life-threatening cardiac rhythm disturbance, known as the acquired long QT syndrome (aLQTS). Although aLQTS has become the leading cause of drug withdrawal by the U.S. Food and Drug Administration, DNA sequencing in aLQTS patients has revealed HERG mutations only in rare cases, suggesting that unknown HERG modulators are often responsible. By using the worm Caenorhabditis elegans, we have developed in vivo behavioral assays that identify candidate modulators of unc-103, the worm HERG orthologue. By using RNA-interference methods, we have shown that worm homologues of two HERG-interacting proteins, Hyperkinetic and K channel regulator 1 (KCR1), modify unc-103 function. Examination of the human KCR1 sequence in patients with drug-induced cardiac repolarization defects revealed a sequence variation (the substitution of isoleucine 447 by valine, I447V) that occurs at a reduced frequency (1.1%) relative to a matched control population (7.0%), suggesting that I447V may be an allele for reduced aLQTS susceptibility. This clinical result is supported by in vitro studies of HERG dofetilide sensitivity by using coexpression of HERG with wild-type and I447V KCR1 cDNAs. Our studies demonstrate the feasibility of using C. elegans to assay and potentially identify aLQTS candidate genes.
Abstract The human ether-a-go-go related gene (HERG) constitutes the pore forming subunit of IKr , a K+ current involved in repolarization of the cardiac action potential. While mutations in HERG ...predispose patients to cardiac arrhythmias (Long QT syndrome; LQTS), altered function of HERG regulators are undoubtedly LQTS risk factors. We have combined RNA interference with behavioral screening in Caenorhabditis elegans to detect genes that influence function of the HERG homolog, UNC-103. One such gene encodes the worm ortholog of the rho-GTPase activating protein 6 (ARHGAP6). In addition to its GAP function, ARHGAP6 induces cytoskeletal rearrangements and activates phospholipase C (PLC). Here we show that IKr recorded in cells co-expressing HERG and ARHGAP6 was decreased by 43% compared to HERG alone. Biochemical measurements of cell-surface associated HERG revealed that ARHGAP6 reduced membrane expression of HERG by 35%, which correlates well with the reduction in current. In an atrial myocyte cell line, suppression of endogenous ARHGAP6 by virally transduced shRNA led to a 53% enhancement of IKr . ARHGAP6 effects were maintained when we introduced a dominant negative rho-GTPase, or ARHGAP6 devoid of rhoGAP function, indicating ARHGAP6 regulation of HERG is independent of rho activation. However, ARHGAP6 lost effectiveness when PLC was inhibited. We further determined that ARHGAP6 effects are mediated by a consensus SH3 binding domain within the C-terminus of HERG, although stable ARHGAP6–HERG complexes were not observed. These data link a rhoGAP-activated PLC pathway to HERG membrane expression and implicate this family of proteins as candidate genes in disorders involving HERG.
Serotonin transporters (SERTs) are targets for drugs such as Prozac that increase serotonin (5HT) levels by blocking 5HT reuptake. Although SERTs saturate in the micromolar range, synaptic 5HT may ...exceed 1 mM. To examine SERT's response to high 5HT concentrations, we expressed Drosophila SERT (dSERT) in Xenopus oocytes and found that transport continued to increase with concentration up to 0.3 mM 5HT. As 5HT is a monovalent cation, its entry through an ion channel in SERT might explain uptake at high concentrations. We therefore investigated dSERT using traditional ion channel methods, including mole-fraction experiments under voltage clamp. We propose that SERTs may function as 5HT-permeable channels, and that this mechanism may be important for clearance of the neurotransmitter at high concentrations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
The cardiac potassium channel encoded by the human ether‐à‐go‐go related gene (HERG) is blocked by a diverse array of common therapeutic compounds. Even transient exposure to such agents may ...provoke the life‐threatening cardiac arrhythmia torsades de pointes in some, but not all, individuals. Although the molecular and genetic factors predicting such wide variability in drug response remain unclear, known sequence variations within the coding region of HERG do not explain the adverse drug response in many cases. Although other proteins can modulate HERG function, no studies have identified protein partners capable of limiting the pharmacological sensitivity of HERG. Here we show that KCR1, a protein identified previously in rat cerebellum, is a plasma membrane‐associated protein expressed at the RNA level in the human heart and can be immunoprecipitated with HERG. Functionally, KCR1 reduces the sensitivity of HERG to classic proarrhythmic HERG blockers (sotalol, quinidine, dofetilide) in both cardiac and noncardiac cell lines. We propose that KCR1, when coupled to HERG, may limit the sensitivity of HERG to proarrhythmic drug blockade and may be a rational target for modifying the proarrhythmic effects of otherwise clinically useful compounds.
The human ether a go-go-related gene (HERG) encodes ion channels that produce IKr (ref. 2), a potassium current that drives repolarization in many excitable cells. When the concentration of ...extracellular potassium ions (K+o) is raised, outward K+ current through HERG channels is paradoxically increased, despite a reduced electrochemical gradient, but the molecular mechanism is not fully understood. Here we show that extracellular sodium ions potently blocked HERG current in K+o-free conditions, and that low K+o (<5 mM) in the physiological range opposed block by sodium; hence the fine tuning that extracellular K+ confers on IKr actually represents modulation of sodium block by potassium.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
