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"Douglas, Steven D."
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The Disintegrating Conscience and the Decline of Modernity
This book considers how the modern concept of
\"conscience\" turns the historic commitment on its head, in a way
that underlies the decadence of modern society.
Steven D. Smith's books are always anticipated with great
interest by scholars, jurists, and citizens who see his work on
foundational questions surrounding law and religion as shaping the
debate in profound ways. Now, in The Disintegrating Conscience
and the Decline of Modernity , Smith takes as his starting
point Jacques Barzun's provocative assertion that \"the modern era\"
is coming to an end. Smith considers the question of decline by
focusing on a single theme-conscience-that has been central to much
of what has happened in Western politics, law, and religion over
the past half-millennium. Rather than attempting to follow that
theme step-by-step through five hundred years, the book adopts an
episodic and dramatic approach by focusing on three main figures
and particularly portentous episodes: first, Thomas More's
execution for his conscientious refusal to take an oath mandated by
Henry VIII; second, James Madison's contribution to Virginia law in
removing the proposed requirement of religious toleration in favor
of freedom of conscience; and, third, William Brennan's pledge to
separate his religious faith from his performance as a Supreme
Court justice. These three episodes, Smith suggests, reflect in
microcosm decisive turning points at which Western civilization
changed from what it had been in premodern times to what it is
today. A commitment to conscience, Smith argues, has been a central
and in some ways defining feature of modern Western civilization,
and yet in a crucial sense conscience in the time of Brennan and
today has come to mean almost the opposite of what it meant to
Thomas More. By scrutinizing these men and episodes, the book seeks
to illuminate subtle but transformative changes in the commitment
to conscience-changes that helped to bring Thomas More's world to
an end and that may also be contributing to the disintegration of
(per Barzun) \"the modern era.\"
eBook
Fictions, Lies, and the Authority of Law
Fictions, Lies, and the Authority of Law
discusses legal, political, and cultural difficulties that arise
from the crisis of authority in the modern world.
Is there any connection linking some of the maladies of modern
life-\"cancel culture,\" the climate of mendacity in public and
academic life, fierce conflicts over the Constitution, disputes
over presidential authority? Fictions, Lies, and the Authority
of Law argues that these diverse problems are all a
consequence of what Hannah Arendt described as the disappearance of
authority in the modern world. In this perceptive study, Steven D.
Smith offers a diagnosis explaining how authority today is based in
pervasive fictions and how this situation can amount to, as Arendt
put it, \"the loss of the groundwork of the world.\"
Fictions, Lies, and the Authority of Law considers a
variety of problems posed by the paradoxical ubiquity and absence
of authority in the modern world. Some of these problems are
jurisprudential or philosophical in character; others are more
practical and lawyerly-problems of presidential powers and
statutory and constitutional interpretation; still others might be
called existential. Smith's use of fictions as his purchase for
thinking about authority has the potential to bring together the
descriptive and the normative and to think about authority as a
useful hypothesis that helps us to make sense of the empirical
world. This strikingly original book shows that theoretical issues
of authority have important practical implications for the kinds of
everyday issues confronted by judges, lawyers, and other members of
society. The book is aimed at scholars and students of law,
political science, and philosophy, but many of the topics it
addresses will be of interest to politically engaged citizens.
eBook
Substance P Induces Rapid and Transient Membrane Blebbing in U373MG Cells in a p21-Activated Kinase-Dependent Manner
U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor (NK1R). Substance P (SP), the natural ligand for NK1R, triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293-NK1R cells. In both cell lines, the SP-induced morphological changes are Gq-independent, and they require the Rho, Rho-associated coiled-coil kinase (ROCK) signaling pathway. Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs. Colchicine, a tubulin polymerization inhibitor, blocked SP-induced blebbing in U373MG but not in HEK293-NK1R cells. Although p21-activated kinase (PAK) is expressed in both cell lines, SP induced rapid phosphorylation of PAK in U373MG, but failed to phosphorylate PAK in HEK293-NK1R cells. The cell-permeable Rho inhibitor C3 transferase inhibited SP-induced PAK phosphorylation, but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation, suggesting that Rho activates PAK in a ROCK-independent manner. Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293-NK1R cells.
Journal Article
Neurokinin 1 Receptor Mediates Membrane Blebbing and Sheer Stress-Induced Microparticle Formation in HEK293 Cells
Cell-derived microparticles participate in intercellular communication similar to the classical messenger systems of small and macro-molecules that bind to specialized membrane receptors. Microparticles have been implicated in the regulation of a variety of complex physiopathologic processes, such as thrombosis, the control of innate and adaptive immunity, and cancer. The neurokinin 1 receptor (NK1R) is a Gq-coupled receptor present on the membrane of a variety of tissues, including neurons in the central and peripheral nervous system, immune cells, endocrine and exocrine glands, and smooth muscle. The endogenous agonist of NK1R is the undecapeptide substance P (SP). We have previously described intracellular signaling mechanisms that regulate NK1R-mediated rapid cell shape changes in HEK293 cells and U373MG cells. In the present study, we show that the activation of NK1R in HEK293 cells, but not in U373MG cells, leads to formation of sheer-stress induced microparticles that stain positive with the membrane-selective fluorescent dye FM 2-10. SP-induced microparticle formation is independent of elevated intracellular calcium concentrations and activation of NK1R present on HEK293-derived microparticles triggers detectable calcium increase in SP-induced microparticles. The ROCK inhibitor Y27632 and the dynamin inhibitor dynasore inhibited membrane blebbing and microparticle formation in HEK293 cells, strongly suggesting that microparticle formation in this cell type is dependent on membrane blebbing.
Journal Article
Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor
The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a full-length receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-κB and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-κB, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKCδ but inhibited phosphorylation of PKCδ in cells expressing truncated NK1R. There are also differences in the timing of SP-induced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20-30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.
Journal Article
Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV
Background
Many HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND.
Methods
We have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection.
Results
Aprepitant inhibits HIV infection of human macrophages ex vivo with an ED
50
~ 5 µM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNFα. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation.
Conclusions
Our results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation.
Journal Article
The social psychology of experience : studies in remembering and forgetting
What informs the process of remembering and forgetting? Is it merely about our capability to store and retrieve experiences in a purely functional sense? What about ′collective memories′, not just those of the individual - how do these manifest themselves in the passages of time? The authors present a new, fascinating insight into the social psychology of experience drawing upon a number of classic works (particularly by Frederick Bartlett, Maurice Halbwachs & Henri Bergson) to help develop their argument. The significance of their ideas for developing a contemporary psychology of experience is illustrated with material from studies focused on settings at home and at work, in public and commercial organizations where remembering and forgetting are matters of concern, involving language and text based communication, objects and place. As their argument unfolds, the authors reveal that memories do not solely reside in a linear passage of time, linking past, present and future, nor do they soley rest within the indidvidual′s conciousness, but that memory sits at the very heart of ′lived experience′; whether collective or individual, the vehicle for how we remember or forget is linked to social interaction, object interaction and the different durations of living that we all have. It is very much connected to the social psychology of experience.
eBook
A Randomized, Placebo Controlled, Double Masked Phase IB Study Evaluating the Safety and Antiviral Activity of Aprepitant, a Neurokinin-1 Receptor Antagonist in HIV-1 Infected Adults
Neurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.
We conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm(3) and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.
Thirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was -0.02(-0.24,+0.20), -0.05(-0.21,+0.10), and +0.04(-0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.
Adverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.
ClinicalTrials.gov NCT00428519.
Journal Article