Calcium storage is one of the functions commonly attributed to the endoplasmic reticulum (ER) in non‐muscle cells. Several recent studies have added support to this concept. Analysis of reticuloplasm, the luminal ER content, has shown that it contains several proteins (reticuloplasmins) which are prospective calcium storage proteins. One of these, calreticulin, is also present in the sarcoplasmic reticulum (SR). In sea urchin eggs, a calsequestrin‐like protein has been clearly localised to the ER. The recent demonstration that the IP3 receptor, which (...) has similarities with the calcium release channel in the SR is also localised in the ER membrane suggests that calcium stored in the ER is important for intracellular signalling. The alternative view, that the physiologically important calcium store is a specialised organelle, the calciosome, is not supported by these observations. Recent evidence also suggests that ER calcium might be important in ER structure and in the retention of the luminal ER proteins. (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering (...) role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

There have been recent concerns about an “epidemic of loneliness” during the pandemic, given the pervasiveness of loneliness in the population and its harmful effects on health and well-being. Therefore, it is important to establish the correlates of loneliness. The purpose of the current study was to explore how loneliness relates to a construct termed mattering, which is the feeling of being important to other people. Mattering was assessed with multiple measures in the current study (e.g., mattering in general, fears (...) of not mattering, and mattering to peers). A sample of 172 female psychology undergraduate students aged 18–25 years completed self-report measures of general mattering, mattering to peers, anti-mattering, fear of not mattering, and state and trait loneliness. As predicted, lower levels of both general mattering and mattering to peers were associated with higher state loneliness. Higher feelings of anti-mattering (feelings of being invisible and insignificant to others) and fears of not mattering were associated with greater trait loneliness, as well as a reduced sense of mattering to friends. The findings illustrate that feeling as though one does not matter to others (i.e., feeling insignificant and unimportant) is associated with increased state and trait loneliness among young women. Implications are discussed for loneliness theory and how these results can enhance both clinical understanding and practice. (shrink)

A special issue of_ New German Critique_ The posthumous publication of Theodor W. Adorno’s works on music continues to reveal the special relationship between music and philosophy in his thinking. These important works have not, however, received as much scholarly attention as they deserve. Contributors to this issue seek to provide insight into some of the key themes raised in these works, including the sociology of musical genre, the historical transformation of music from the "heroic" or high-bourgeois era to late (...) modernity, the meaning of both performance and listening in the era of mass communication, and the specific challenges or deformations of the radio on musical form, a theme that implicates many of the digital practices of our own age. There is much left to discover in these new publications, and they pose again, with renewed vigor, the question of Adorno’s _Aktualität_—his polyvalent, untranslatable term for, among other things, the intellectual relationship between the present and the past. Contributors Daniel K. L. Chua, Lydia Goehr, Peter E. Gordon, Martin Jay, Brian Kane, Max Paddison, Alexander Rehding, Fred Rush, Martin Scherzinger. (shrink)

In this article we review the emerging literature on the self-transcendent emotions. We discuss how the self-transcendent emotions differ from other positive emotions and outline the defining features of this category. We then provide an analysis of three specific self-transcendent emotions—compassion, gratitude, and awe—detailing what has been learned about their expressive behavior, physiology, and likely evolutionary origins. We propose that these emotions emerged to help humans solve unique problems related to caretaking, cooperation, and group coordination in social interactions. In our (...) final section we offer predictions about the self-transcendent emotions that can guide future research. (shrink)

We introduce and discuss a concept of approximation of a topological algebraic system A by finite algebraic systems from a given class K. If A is discrete, this concept agrees with the familiar notion of a local embedding of A in a class K of algebraic systems. One characterization of this concept states that A is locally embedded in K iff it is a subsystem of an ultraproduct of systems from K. In this paper we obtain a similar characterization of (...) approximability of a locally compact system A by systems from K using the language of nonstandard analysis. In the signature of A we introduce positive bounded formulas and their approximations; these are similar to those introduced by Henson [14] for Banach space structures (see also [15, 16]). We prove that a positive bounded formula φ holds in A if and only if all precise enough approximations of φ hold in all precise enough approximations of A. We also prove that a locally compact field cannot be approximated arbitrarily closely by finite (associative) rings (even if the rings are allowed to be non-commutative). Finite approximations of the field R can be considered as possible computer systems for real arithmetic. Thus, our results show that there do not exist arbitrarily accurate computer arithmetics for the reals that are associative rings. (shrink)

How does creolization fare as a social-scientific concept? While Jane Gordon seeks to underscore the potential such a concept might have in the social sciences and philosophy, her discussants Gopal Guru, Kipton E. Jensen, Mickaella Perina, and Sundar Sarukkai draw attention to descriptive and normative issues that need to be addressed before arguments formulating and enacting creolization processes can be brought into domains of life from which they have been historically excluded.

For forty years, successive editions of Ethical Theory and Business have helped to define the field of business ethics. The 10th edition reflects the current, multidisciplinary nature of the field by explicitly embracing a variety of perspectives on business ethics, including philosophy, management, and legal studies. Chapters integrate theoretical readings, case studies, and summaries of key legal cases to guide students to a rich understanding of business ethics, corporate responsibility, and sustainability. The 10th edition has been entirely updated, ensuring that (...) students are exposed to key ethical questions in the current business environment. New chapters cover the ethics of IT, ethical markets, and ethical management and leadership. Coverage includes climate change, sustainability, international business ethics, sexual harassment, diversity, and LGBTQ discrimination. New case studies draw students directly into recent business ethics controversies, such as sexual harassment at Fox News, consumer fraud at Wells Fargo, and business practices at Uber. (shrink)

Human clinical research has become a huge economic enterprise (Morin et al. 2002; Noah 2002). Because the human subject at the center can be so easily marginalized, many commentators recommend spec...

Darwinian Evolution and Classical Liberalism brings together a collection of new essays that examine the multifaceted ferment between Darwinian biology and classical liberalism.

This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. “Social context” refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is (...) introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences. (shrink)

The co-occurrence of stress-induced posttraumatic stress disorder (PTSD) and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to (...) systematically highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing (NLP) to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin (OXT), Neuropeptide-Y (NPY), and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation. (shrink)

This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. ?Social context? refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is (...) introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:THE INSCRUTABILITY O:F MORAL EVIL IN KANT ((W:HENCE COMETH EVIL?" Late in his career, Immanuel Kant would turn his attention to this perennial question with an elaborate account of " radical evil " in Religion within the Limits of Reason Alone. His discussion produced consternation among his admirers, such as Goethe, and continues to produce puzzlement among his commentators. Among the chief difficulties facing the modern-day interpreter has been (...) the welter of complex terminology tossed up by Kant's attempts to tame his topic. The Kant specialist can justifiably suppose that if only he or she could un-scramble the terminology, grasp the intended interconnections among the terms, and set the discussion within the context of the entire critical philosophy, the result would be a reasonably clear view of Kant's theory of the nature and source of moral evil. There is of course some justification to this vaguely masochistic approach to the matter, yet such an approach, I fear, leads inevitably to frustration. This is because, despite all the appearances to the contrary, Kant never really explains moral evil in the discussion of radical evil in Religion. To be sure, he offers a definition of what moral evil is, by the terms of his philosophy. Nevertheless, he never really accounts for evil, nor does he offer anything remotely approaching an answer to my opening question. The deepest part of Kant's analysis is not a response to that question, but a link between moral evil and human freedom, and this link is utterly inexplicable, for the same reason that freedom itself is, for Kant, ultimately inexplicable. Thus, by this reading of the theory of radical evil, we are not finally led to comprehend Kant's view of evil. Instead, we are 246 THE INSCRUTABILITY OF MORAL EVIL IN KANT 247 reminded of the contingent nature of the exercise of freedom, the unfathomable quality of the process of character-building, and, finally, the sheer inscrutability of moral evil itself. Kant is theorizing about human nature in a way that gradually discloses the futility of domesticating this topic conceptually or rationally. This point is worth stressing, partly because of certain stereotypes that persist regarding the things Kant's philosophy supposedly renders in rational form. And, obviously, the point can be stressed in the present context by pursuing further the notion that moral evil is, for Kant, inscrutable. The inscrutability of moral evil does not pop into view all at once, for Kant's discussion in Religion is set in the context of a complex account of the structure of the will, the nature of the incentives capable of determining the will, and the issue of freedom. Consequently, in what follows I shall attempt to trace the Kantian line of thought lying behind his agnosticism regarding the source of moral evil. -IFor Kant, moral evil resides in a maxim.1 A maxim is for him a special kind of principle, one which guides or informs actionin effect, a "practical principle." The very idea of a maxim is a key element in Kant's efforts to determine how reason can be practical. Discourse about maxims is Kant's way of accounting for those practical principles by which we actually do act, instead of only those principles by which we ought ideally to act.2 In effect, a maxim is the guiding principle that I could state to myself were I to reflect upon the overall policy determining a given act (" I should enrich myself by whatever 1 Kant, Die Religion innerhalb der Grenzen der blossen Vernunft, ed. W. Weischedel (Frankfurt am Main: Suhrkamp, 1978), p. 6*7. English translation, Religion within the Limits of Reason Alone, trans. Theodore M. Greene and Hoyt H. Hudson (New York: Harper and Row, 1960), p. 17. Hereafter referred to as Religion, followed by page numbers in both Weischedel and Greene/Hudson, with all translations taken from the latter. 2 Kant, Foundations of the Metaphysics of Morals. trans. Lewis White Beeck, (New York: Bobbs-Merrill, 1950), pp. 17 n.l, 38 n.9. Q48 GORDON E. MICHALSON means possible," " I should at all times tell the truth "). This distinction between guiding principles by which we actually do... (shrink)

How should pragmatists respond to and contribute to the resolution of one of America's greatest and most enduring problems? Given that the most important thinkers of the pragmatist movement—Charles S. Peirce, William James, John Dewey, and George Herbert Mead—said little about the problem of race, how does their distinctly American way of thinking confront the hardship and brutality that characterizes the experience of many African Americans in this country? In 12 thoughtful and provocative essays, contemporary American pragmatists connect ideas with (...) action and theory with practice to come to terms with this seemingly intractable problem. Exploring themes such as racism and social change, the value of the concept of race, the role of education in ameliorating racism, and the place of democracy in dealing with the tragedy of race, the voices gathered in this volume consider how pragmatism can focus new attention on the problem of race. Contributors are Michael Eldridge, Eddie S. Glaude, Jr., Judith M. Green, D. Micah Hester, Donald F. Koch, Bill E. Lawson, David E. McClean, Gregory F. Pappas, Scott L. Pratt, Alfred E. Prettyman, John R. Shook, Paul C. Taylor, and Cornel West. (shrink)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor (...) evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation. (shrink)

Using a sample of 652 college students, we examined several implications of the hypothesis that the shape of the human penis evolved to enable males to substitute their semen for those of their rivals. The incidence of double mating by females appears sufficient to make semen displacement adaptive (e.g., one in four females acknowledge infidelity, one in eight admit having sex with two or more males in a 24-hour period, and one in 12 report involvement in one or more sexual (...) threesomes with two males). We also document several changes in post-ejaculatory behavior (e.g., reduced thrusting, penis withdrawal, loss of an erection) which may have evolved to minimize displacement of the male’s own semen. Consistent with predictions derived from a theoretical model (Gallup and Burch 2006), we discovered that most females report waiting at least 48 hours following an instance of infidelity before resuming sex with their in-pair partners. (shrink)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

Apoptosis is now widely recognized as a common form of cell death and represents a mechanism of cell clearance in many physiological situations where deletion of cells is required. Peptide growth factors, initially characterised as stimulators of cell proliferation, have now been shown to inhibit death in many cell types. Deprivation of growth factors leads to the induction of apoptosis, i.e. condensation of chromatin and degradation in oligonucleosomesized fragments, formation of plasma and nuclear membrane blebs and cell fragmentation into apoptotic (...) bodies which can be taken up by neighbouring cells. Here we discuss the mechanism(;s) by which growth factors may inhibit apoptosis. (shrink)

Reading speed matters in most real-world contexts, and it is a robust and easy aspect of reading to measure. Theories of reading should account for speed.

Background and AimsEnd-of-life discussions can be difficult for seriously ill adolescents and young adults. Researchers aimed to determine whether completing Voicing My CHOiCES —a research-informed advance care planning guide—increased communication with family, friends, or health care providers, and to evaluate the experience of those with whom VMC was shared.MethodsFamily, friends, or HCPs who the AYAs had shared their completed VMC with were administered structured interviews to assess their perception of the ACP discussion, changes in their relationship, conversation quality, and whether (...) the discussion prompted changes in care. Open-ended responses underwent thematic analysis.ResultsOne-month post-completion, 65.1% of AYA had shared VMC completion with a family member, 22.6% with a friend, and 8.9% with an HCP. Among a sample of respondents, family and friends reported a positive change in their relationship with the AYA. Participant descriptions of the experience fell into five themes: positive experience, difficult experience, appreciated a guide to facilitate discussion, provided relief, and created worry/anxiety. Only 1 HCP noted a treatment change. Family, friends, and HCP did not think the AYA would have discussed EoL preferences without completing VMC.ConclusionsVMC has potential to enhance communication about ACP between AYA and their family and friends, though less frequently with HCPs. Participants reported a positive change in their relationship with the AYA after discussing VMC, and described experiencing the conversation as favorable, even when also emotionally difficult. (shrink)

L'opera di Primo Levi presenta un caso straordinariamente ricco e in qualche modo enigmatico di intertestualità. Con questo volume si è cercato di tracciare i lineamenti di una mappa immaginaria, uno schema degli innesti, intertesti e trapianti che collegano l'opera leviana ai libri altrui.

This essay places some conceptual pressure on the model of a “learning process” in Jürgen Habermas’s Auch eine Geschichte der Philosophie, and it asks whether this model introduces a subtle asymmetry into the relationship between religion and secular philosophy. Such an asymmetry would seem to obtain insofar as religious tradition is granted a privileged or unique status as the source of normative insights that are then available for rational scrutiny and translation into secular life. The essay also draws a comparison (...) between Lessing and Habermas: Lessing, like Habermas, saw revelation as a source of instruction for humanity, and affirmed that religion could thereby play a role in the Erziehung des Menschengeschlechts. But Lessing was careful to say that no valuable normative contents are found in religion that could not also be derived by secular reason alone. Habermas’s genealogy of post-metaphysical thinking does not seem to confirm Lessing’s idea; instead, it appears to confirm an asymmetry in the relation between religion and secular philosophy. (shrink)