Abstract While T cell activation has been correlated with half-life of the TCR-pMHC interaction, the importance of on-rate is only now being realized. In contrast to other studies, our lab has generated a system that separates the kon component from koff by comparing the response of two T cells, 3L2 and M2. 3L2 responds specifically to Hb(64-76) peptide presented on I-Ek. M2 differs from 3L2 by two point mutations in the CDR1α loop, resulting in a 4-fold higher affinity for Hb(64-76) due entirely to a faster kon. We generated an M2 TCR transgenic mouse to compare the affect of kon on T cell responses in vivo and in vitro to 3L2 T cells. M2 expressing T cells are positively selected and detected with a clonotypic antibody in the periphery though at a reduced number in comparison to 3L2. This could be due to decreased positive selection and/or increased negative selection of M2 T cells by alteration of the kinetics of M2 interactions with endogenous pMHC. M2 responds to 12 Hb(64-76) altered peptides (APLs) that are null peptides for 3L2 and has increased reactivity to APLs that are agonists for 3L2. M2 cells have a greater proliferative response at day 3 than 3L2 when exposed to Hb(64-76). While both M2 and 3L2 proliferate by day 3, a larger number of M2 cells than 3L2 cells have divided. This suggests that a fast kon increases early T cell responses. By selectively altering kon, we have revealed the importance of kon for TCR binding pMHC in T cell development and activation.
udden death as a result of cardiac arrhythmia is probably the most common symptom associated with cardiac disease.It occurs not only in people with known cardiac disease, most notably congestive heart failure, but also in young, apparently healthy individuals who have no apparent structural heart disease.Frequently, in this latter group, these fatal arrhythmias are associated with exercise and increased -adrenergic stimulation.One possible mechanism for how these arrhythmias could occur in otherwise "normal" individuals is an aberrant release of Ca 2ϩ from the sarcoplasmic reticulum (SR), which in turn could cause delayed afterdepolarizations 1 that can trigger potentially fatal ventricular arrhythmias.Unlike skeletal muscle, where excitation-contraction coupling (EC coupling) is intermittent and mediated through a mechanical coupling between the slow voltage-gated Ca 2ϩ channel (dihydropyridine receptor, DHPR) in the sarcolemma and the skeletal isoform of the large-conductance calcium release channel in the SR (ryanodine receptor, RyR), RyR1 in cardiac muscle EC coupling is rhythmic and the cardiac isoform of RyR (RyR2) is activated by the inward Ca 2ϩ influx through the cardiac DHPR via Ca 2ϩ -induced Ca 2ϩ release (CICR). 2In the heart, RyR2 does not act in a vacuum but rather is part of a macromolecular complex containing the immunophilin FKBP12.6,phosphorylases, and phosphatases, 3 in addition to the DHPR and several other proteins including calsequestrin, triadin, junctin, and junctophilin, to name only a few, that make up the calcium release unit (CRU). 4Heart failure has been associated with disruption of this macromolecular complex secondary to hyperphosphorylation of RyR2 and the associated dissociation of FKBP12.6. 5 Interestingly, mice that carry two null alleles for FKBP12.6 have been shown to have exercise-and catecholamineinduced fatal ventricular arrhythmias suggesting that this is a crucial subunit for controlling ventricular Ca 2ϩ homeostasis. 6ecently, 11 missense mutations of RyR2 and one missense mutation of calsequestrin have been associated with a group of closely associated cardiomyopathies that are characterized by early sudden death: catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular cardiomyopathy (ARVD2), and familial polymorphic ventricular tachycardia. 7-10Interestingly, the
Reviewed by: Visioning Augustine by John C. Cavadini Paul Allen Visioning Augustine by John C. Cavadini (Oxford: Wiley Blackwell, 2019), xxvi + 322 pp. This volume of twelve essays by a leading American Catholic theologian brings together a number of analyses of key Augustinian themes from research conducted during the past thirty years. These chapters have already appeared in learned journals before their re-edition here. This collection of essays is occasioned by requests from the author’s colleagues and students, as he states in the preface. The publication of these articles in a single volume constitutes an important milestone in the evolution of contemporary Augustinian studies. The strength of Cavadini’s approach is his mingling of insights from textual, historical interpretation astride his adoption of a systematic theological perspective. There is also the slightly contrarian (and therefore welcome) impulse to take seriously the views that Augustine actually held, as opposed to the views that are still inaccurately ascribed to him. The overall impression of this multivalent portrait of Augustine is refreshing and somewhat bracing as well. Nevertheless, Cavadini steers clear of claims that move too far beyond the texts he is working carefully to unveil. As such, his approach is a sober corrective to an overly hermeneutical approach that would over-emphasize his philosophical novelty (e.g.: an existentialist avant le lettre) at the expense of his theological specificity. This collection is also a properly academic work, not a general treatment. As such, this book corrects some recent popularizations of Augustine that glossed over the more demanding claims Augustine makes on his readers. As standalone essays, the book’s chapters deal with key themes that preoccupied Augustine, namely the Trinity, sex and the body, the Eucharist, creation, salvation, and the relationship between philosophy and theology. In line with the guild of historical theology, Cavadini shows an interest in the structure of Augustine’s arguments. Such a focus yields insights, such as the comparison between De Trinitate and De civitate Dei. Usually cited for their vast differences in form and argument, Cavadini shows that these two major works actually converge on the nature and value of an apologetic approach while neither ever cedes the category of the revelatory to that of the neo-Platonic as Augustine’s intellectual plumbline. [End Page 1399] Some surprises emerge nonetheless, such as the idea that mercy is a hermeneutical key for Augustine. This is mentioned in the foreword to the book by Mark Therrien, a former student of Cavadini’s, and the author delivers on this claim at several junctures. Some of the best surprises are the asides and pointers to richer insights that appear in the footnotes. Somewhat missing is an attention to Augustine’s extensive biblical commentaries, although of course that is determined by the focus on the great contested themes in the magna opera: De civitate Dei, Confessiones, and De Trinitate. However, there is some analysis of Augustine’s sermons in chapter 5, an effort to probe to what extent Augustine simplifies his portrait of God there, in comparison with his treatment of God in De Triniate. The answer, it turns out, is that he does not simplify: both works share the structure of faith seeking understanding. One feature of Cavadini’s articles is the subtle way he engages in dialectical reasoning when it comes to Augustine’s critics. Yet, he foregoes explicitly dialectical engagements in favor of a straightforward engagement with the primary texts. The exceptions to this tendency are few but very telling. One is Cavadini’s adroit acknowledgement of Rowan Williams’s view of the imago Dei as the proper analogy for the Trinitarian relations in God. For Cavadini, the ecclesial location of a converted, faithful person is a corrective to Williams’s “over-spiritualized” interpretation of self-transcendence. According to Williams, the assent to true justice and charity is sufficient to identify the faith of the individuals who will make up the totus Christus in the fulfillment of time. But, in Cavadini’s way of construing it, “true worship” suggests a visible, ecclesial locus for each Christian. Herein lies the anthropological analogate for the Trinitarian life of God. Another dialectical moment comes with a brief mention of...
Vection is an illusory perception of self-motion that can occur when visual motion fills the majority of the visual field. This study examines the effect of the duration of visual field movement (VFM) on the perceived strength of self-motion using an inertial nulling (IN) and a magnitude estimation technique based on the certainty that motion occurred (certainty estimation, CE). These techniques were then used to investigate the association between migraine diagnosis and the strength of perceived vection. Visual star-field stimuli consistent with either looming or receding motion were presented for 1, 4, 8 or 16s. Subjects reported the perceived direction of self-motion during the final 1s of the stimulus. For the IN method, an inertial nulling motion was delivered during this final 1s of the visual stimulus, and subjects reported the direction of perceived self-motion during this final second. The magnitude of inertial motion was varied adaptively to determine the point of subjective equality (PSE) at which forward or backward responses were equally likely. For the CE trials the same range of VFM was used but without inertial motion and subjects rated their certainty of motion on a scale of 0–100. PSE determined with the IN technique depended on direction and duration of visual motion and the CE technique showed greater certainty of perceived vection with longer VFM duration. A strong correlation between CE and IN techniques was present for the 8s stimulus. There was appreciable between-subject variation in both CE and IN techniques and migraine was associated with significantly increased perception of self-motion by CE and IN at 8 and 16s. Together, these results suggest that vection may be measured by both CE and IN techniques with good correlation. The results also suggest that susceptibility to vection may be higher in subjects with a history of migraine.
Photoneutron yields from hydrogen, carbon, nitrogen, oxygen, water, polyethylene, tissue substitute and CR-39 have been calculated for the photon energy range of 2 to 30 MeV, using a previously established method. The data are useful for estimating neutron production in these and other similar materials located in the vicinity of a megavoltage radiotherapy beam. Such substances are often used as filtration, phantom or scattering material and as components of neutron dosimetry detectors. It is pointed out that photoneutrons produced in such materials may need to be taken into consideration when carrying out neutron dosimetry in the presence of even relatively low energy photons.
The purpose of these experiments was to determine whether detecting brief decrements in noise level (“gaps”) varies with the spectral content and bandwidth of noise in mice as it does in humans. The behavioral effect of gaps was quantified by their inhibiting a subsequent acoustic startle reflex. Gap durations from 1 to 29 ms were presented in five adjacent 1-octave noise bands and one 5-octave band, their range being 2 kHz to 64 kHz. Gaps ended 60 ms before the startle stimulus (experiment 1) or at startle onset (experiment 2). Asymptotic inhibition was greater for higher-frequency 1-octave bands and highest for the 5-octave band in both experiments, but time constants were related to frequency only in experiment 1. For the lowest band (2–4 kHz) neither noise decrements (experiment 1 and 2) nor increments (experiment 3) had any behavioral consequence, but this band was effective when presented as a pulse in quiet (experiment 4). The lowest frequencies in the most effective 1-octave band were one octave above the spectral region where mice have their best absolute thresholds. These effects are similar to those obtained in humans, and reveal a special contribution of wide band, high-frequency stimulation to temporal acuity.
Abstract Das elektrochemische Verhalten von polykristallinem Fe 2 O 3 in wäßriger Perchlorsäure wird durch einen Festkörper‐Diffusionsprozeß maßgeblich beeinflußt wobei die Stöchiometrie der Kristalle durch das Potential zwischen Festkörper und Lösung bestimmt wird und die Diffusion von Wasserstoff in den Kristall Veränderungen der Stöchiometrie innerhalb des Kristalls verursacht.
Analyzes the scientific foundations of commonly-used drugs, investigating agents that are not currently used or widely recognized as beneficial, but that may be of significant therapeutic value. This volume presents recent data regarding human heart failure.
