646 research outputs found
Developing an Effective Instrument for Assessing the Performance of Public University Presidents
Conducting a worthwhile assessment of the performance of university presidents poses unique challenges for higher education institutions. One of the most difficult issues is determining the content and format of the assessment instrument. Due to the breadth and complexity of the job, the list of potential criteria that could serve as content for the assessment instrument is almost limitless. There are also many format options with respect to the arrangement of the assessment instrument and plan for administering it. In order to fill an apparent gap in research on university president assessment, this study proposes a model for determining the content and format of an assessment instrument â the Assessment Instrument Development Approach (AIDA). The AIDA model incorporates a mixed-methods research design aimed at identifying the content and format of an assessment instrument that will produce reliable and valid results. Addressing the question, What approach can UNM and other public universities use to develop an effective performance assessment instrument for their president?\u27 this study critiqued the initial AIDA model and suggests a revised model based on study findings. Addressing the question, \u27What is the preferred content and format for a president performance assessment instrument?\u27 this study proposed an initial framework for the relationships among variables derived from pertinent theory and concepts pertaining to university president assessment. Considering the study results, a revised framework was developed along with example hypotheses that should be tested in future research to gain additional insights into performance assessment for university presidents. The results of this study reveal there are many candidate criteria and formats for assessing performance. What appears to be lacking in literature and in practice is a means to identify the best criteria and formats that will produce reliable, valid, and useful results for assessment of university presidents. The methods and findings described in this study provide additional insight into the \u27means\u27 for developing an assessment instrument and the \u27ends\u27 which are fair, equitable, and productive assessments of university president performance
A CationâÏ Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels
Open-channel blockers such as tetraethylammonium (TEA) have a long history as probes of the permeation pathway of ion channels. High affinity blockade by extracellular TEA requires the presence of an aromatic amino acid at a position that sits at the external entrance of the permeation pathway (residue 449 in the eukaryotic voltage-gated potassium channel Shaker). We investigated whether a cationâ{pi} interaction between TEA and such an aromatic residue contributes to TEA block using the in vivo nonsense suppression method to incorporate a series of increasingly fluorinated Phe side chains at position 449. Fluorination, which is known to decrease the cationâ{pi} binding ability of an aromatic ring, progressively increased the inhibitory constant Ki for the TEA block of Shaker. A larger increase in Ki was observed when the benzene ring of Phe449 was substituted by nonaromatic cyclohexane. These results support a strong cationâ{pi} component to the TEA block. The data provide an empirical basis for choosing between Shaker models that are based on two classes of reported crystal structures for the bacterial channel KcsA, showing residue Tyr82 in orientations either compatible or incompatible with a cationâ{pi} mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cationâ{pi} interaction with the permeation pathway. This choice is supported by high level ab initio calculations of the predicted effects of Phe modifications on TEA binding energy
Quasi-Moessbauer effect in two dimensions
Expressions for the absorption spectrum of a nucleus in a three- and a
two-dimensional crystal respectively are obtained analytically at zero and at
finite temperature respectively. It is found that for finite temperature in two
dimensions the Moessbauer effect vanishes but is replaced by what we call a
Quasi-Moessbauer effect. Possibilities to identify two-dimensional elastic
behavior are discussed.Comment: 18 pages, 5 figures, notation simplifie
Site-Specific Incorporation of Unnatural Amino Acids into Receptors Expressed in Mammalian Cells
AbstractWe describe an approach to achieve unnatural amino acid incorporation into channels and receptors expressed in mammalian cells. We show that microelectroporation provides a general method to deliver DNA, mRNA, and tRNA simultaneously. In both CHO cells and cultured neurons, microelectroporation efficiently delivers an in vitro transcribed, serine amber suppressor tRNA, leading to nonsense suppression in a mutant EGFP gene. In CHO cells, both natural and unnatural amino acids chemically appended to a suppressor tRNA are site specifically incorporated into the nicotinic acetylcholine receptor (nAChR). Electrophysiology confirms the expected functional consequences of the unnatural residue. The microelectroporation strategy described here is more general, less tedious, and less damaging to mammalian neuronal and nonneuronal cells than previous approaches to nonsense suppression in small cells and provides the first example of unnatural amino acid incorporation in mammalian cells using chemically aminoacylated tRNA
Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor
The binding of three distinct agonists - acetylcholine (ACh), nicotine, and epibatidine - to the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cationâÏ interaction with Trp α149, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cationâÏ interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp α149 suggests that a novel aromatic C - H···O=C hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information
Successful Cessation Programs that Reduce Comorbidity May Explain Surprisingly Low Smoking Rates Among Hospitalized COVID-19 Patients
A recent, non-peer-reviewed meta-analysis suggests that smoking may reduce the risk of hospitalization with COVID-19 because the prevalence of smoking among hospitalized COVID-19 is less than that of the general population. However, there are alternative explanations for this phenomena based on (1) the failure to report, or accurately record, smoking history during emergency hospital admissions and (2) a pre-disposition to avoid smoking among COVID-19 patients with tobacco-related comorbidities (a type of âreverseâ causation). For example, urine testing of hospitalized patients in Australia for cotinine showed that smokers were under-counted by 37% because incoming patients failed to inform staff about their smoking behavior. Face-to-face interviews can introduce bias into the responses to attitudinal and behavioral questions not present in the self-completion interviews typically used to measure smoking prevalence in the general population. Subjects in face-to-face interviews may be unwilling to admit socially undesirable behavior and attitudes under direct questioning. Reverse causation may also contribute to the difference between smoking prevalence in the COVID-19 and general population. Patients hospitalized with COVID-19 may be simply less prone to use tobacco than the general population. A potentially robust âreverse causationâ hypothesis for reduced prevalence of smokers in the COVID-19 population is the enrichment of patients in that population with serious comorbidities that motivates them to quit smoking. We judge that this âsmoking cessationâ mechanism may account for a significant fraction of the reduced prevalence of smokers in the COVID-19 population. Testing this hypothesis will require a focused research program
Tyrosine Residues That Control Binding and Gating in the 5-Hydroxytryptamineâ Receptor Revealed by Unnatural Amino Acid Mutagenesis
The mechanism by which agonist binding triggers pore opening in ligand-gated ion channels is poorly understood. Here, we used unnatural amino acid mutagenesis to introduce subtle changes to the side chains of tyrosine residues (Tyr141, Tyr143, Tyr153, and Tyr234), which dominate the 5-HTâ receptor binding site. Heterologous expression in oocytes, combined with radioligand binding data and a model of 5-HT (serotonin) computationally docked into the binding site, has allowed us to determine which of these residues are responsible for binding and/or gating. We have shown that Tyr 143 forms a hydrogen bond that is essential for receptor gating but does not affect binding, whereas a hydrogen bond formed by Tyr153 is involved in both binding and gating of the receptor. The aromatic group of Tyr234 is essential for binding and gating, whereas its hydroxyl does not affect binding but plays a steric role in receptor gating. Tyr141 is not involved in agonist binding or receptor gating but is important for antagonist interactions. These data, combined with a new model of the nonliganded 5-HTâ receptor, lead to a mechanistic explanation of the interactions that initiate the conformational change leading to channel opening. Thus, we suggest that agonist entry into the binding pocket may displace Tyr143 and Tyr153 and results in their forming new hydrogen bonds. These bonds may form part of the network of bond rearrangements that trigger the conformational change leading to channel opening. Similar rearrangements may initiate gating in all Cys-loop receptors
Nicotine binding to brain receptors requires a strong cationâÏ interaction
Nicotine addiction begins with high-affinity binding of nicotine to
acetylcholine (ACh) receptors in the brain. The end result is over
4,000,000 smoking-related deaths annually worldwide and the
largest source of preventable mortality in developed countries.
Stress reduction, pleasure, improved cognition and other central
nervous system effects are strongly associated with smoking.
However, if nicotine activated ACh receptors found in muscle as
potently as it does brain ACh receptors, smoking would cause intolerable
and perhaps fatal muscle contractions. Despite extensive
pharmacological, functional and structural studies of ACh receptors,
the basis for the differential action of nicotine on brain compared
with muscle ACh receptors has not been determined. Here we
show that at the α4ÎČ2 brain receptors thought to underlie nicotine
addiction, the high affinity for nicotine is the result of a strong
cationâÏ interaction to a specific aromatic amino acid of the receptor,
TrpB. In contrast, the low affinity for nicotine at the muscle type ACh
receptor is largely due to the fact that this key interaction is
absent, even though the immediate binding site residues, including
the key amino acid TrpB, are identical in the brain and muscle
receptors. At the same time a hydrogen bond from nicotine to the
backbone carbonyl of TrpB is enhanced in the neuronal receptor
relative to the muscle type. A point mutation near TrpB that differentiates
α4ÎČ2 and muscle-type receptors seems to influence the
shape of the binding site, allowing nicotine to interact more strongly
with TrpB in the neuronal receptor. ACh receptors are established
therapeutic targets for Alzheimerâs disease, schizophrenia,
Parkinsonâs disease, smoking cessation, pain, attention-deficit
hyperactivity disorder, epilepsy, autism and depression. Along with
solving a chemical mystery in nicotine addiction, our results provide
guidance for efforts to develop drugs that target specific types of
nicotinic receptors
Chemical-Scale Studies on the Role of a Conserved Aspartate in Preorganizing the Agonist Binding Site of the Nicotinic Acetylcholine Receptor
The nicotinic acetylcholine receptor and related Cys-loop receptors are ligand-gated ion channels that mediate fast synaptic transmission throughout the central and peripheral nervous system. A highly conserved aspartate residue (D89) that is near the agonist binding site but does not directly contact the ligand plays a critical part in receptor function. Here we probe the role of D89 using unnatural amino acid mutagenesis coupled with electrophysiology. Homology modeling implicates several hydrogen bonds involving D89. We find that no single hydrogen bond is essential to proper receptor function. Apparently, the side chain of D89 establishes a redundant network of hydrogen bonds; these bonds preorganize the agonist binding site by positioning a critical tryptophan residue that directly contacts the ligand. Earlier studies of the D89N mutant led to the proposal that a negative charge at this position is essential for receptor function. However, we find that receptors with neutral side chains at position 89 can function well, if the side chain is less perturbing than the amide of asparagine (nitro or keto groups allow function) or if a compensating backbone mutation is introduced to relieve unfavorable electrostatics
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