In mammals, a network of cellular circadian clocks organizes physiology and behavior along the 24‐h day cycle. The traditional hierarchical model of circadian clock organization with a central pacemaker and peripheral slave oscillators has recently been challenged by studies combining tissue‐specific mouse mutants with transcriptome analyses. First, a surprisingly small number of tissue rhythms are lost when only local clocks are ablated and, second, transcriptional circadian rhythms appear to be regulated by a complex mix of local and systemic (...) factors. As reviewed here, these findings suggest a more integrated model of clock network interaction with the central pacemaker as the main source of behavioral and systemic–physiological rhythms and peripheral clocks controlling some local rhythms while at the same time acting as gatekeepers that temporally adjust cellular responses to external stimuli. (shrink)

Daily rhythms are a ubiquitous feature of living systems. Generally, these rhythms are not just passive consequences of cyclic fluctuations in the environment, but instead originate within the organism. In mammals, including humans, the master pacemaker controlling 24‐hour rhythms is localized in the suprachiasmatic nuclei of the hypothalamus. This circadian clock is responsible for the temporal organization of a wide variety of functions, ranging from sleep and food intake, to physiological measures such as body temperature, heart rate and (...) hormone release. The retinal circadian clock was the first extra‐SCN circadian oscillator to be discovered in mammals and several studies have now demonstrated that many of the physiological, cellular and molecular rhythms that are present within the retina are under the control of a retinal circadian clock, or more likely a network of hierarchically organized circadian clocks that are present within this tissue. BioEssays 30:624–633, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A vast network of cellular circadian clocks regulates 24‐hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light‐reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional (...) mouse genetics suggesting that resetting of the circadian system occurs in a more “federated” and tissue‐specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions. (shrink)

The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators (...) include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by “neural temporal unit,” defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain. (shrink)

In higher eukaryotes, circadian behaviour patterns have been dissected at the molecular level in Drosophila and, more recently, in the mouse. Considerable progress has been made in identifying some of the molecular components of the clock in the fly, where two genes, period (per) and timeless (tim), are essential for behavioural rhythmicity. The PER and TIM proteins show circadian cycles in abundance, and are part of a negative feedback loop with their own mRNAs. Within the pacemaker neurons, the (...) PER and TIM products are believed to form a complex which allows them to translocate to the nucleus, but how they repress their own transcription is unclear. TIM is rapidly degraded by light, a feature which permits a compelling molecular description of both behavioural light entrainment and phase responses to light pulses. The regulation of per and tim is altered in different Drosophila tissues, however, and comparative analyses of the two genes outside the Diptera reveals further unusual patterns of tissue‐specific regulation. Evolution appears to have modified the way in which the two genes are utilised to generate circadian phenotypes. More recently, the cloning of mouse clock genes, including putative per homologues, opens up exciting possibilities for mammalian molecular chronobiology. (shrink)

There is considerable evidence that animals can time multiple intervals that occur separately or concurrently. Such simultaneous temporal processing occurs both in temporal discrimination procedures and in classical conditioning procedures. The first part of the chapter will consist of the review of the evidence for simultaneous temporal processing, and the conditions under which the different intervals have influences on each other. The second part of the chapter will be a brief description of two timing theories: Scalar Timing Theory and a (...) Packet Theory of Timing. Scalar Timing Theory consists of a pacemaker-switch-accumulator system that serves as a clock, a memory that consists of examples of previously reinforced intervals, and a decision process that involves a comparison of ratios to a criterion; the Packet Theory of Timing consists of a conditional expected time function that serves as a clock, a memory that consists of weighted sums of these values, and a probabilistic decision process that produces packets of responses. Both of these theories will be applied to an example of simultaneous temporal processing by rats, and will serve as the basis for some general comments about the basis for selecting and evaluating quantitative theories of timing. (shrink)

The effect of an olfactory stimulation on the perception of time was investigated through two different experiments based on temporal bisection tasks. In experiment 1, the durations to be classified as either short or long were centered on 400 ms while in Experiment 2 there were centered on 2000 ms. The participants were different in the two experiments (36 subjects in each one). In each experiment, half of the subjects learnt the anchor durations when smelling an unpleasant odor (decanoic acid) (...) and the other half when smelling no odor. After the learning phase, both groups were tested with and without odor. The results showed opposite effects depending on the duration range. The subjects underestimated the time in the presence of the unpleasant odor in the short duration range while they overestimated it in the long duration range. The results have been discussed in the framework of the pacemaker-counter clock model and a potential emotional effect induced by the odor on the subjective time perception has also been considered. (shrink)

Previous research has reported that ethical values of business students are lower than those of their peers in other majors. The purpose of this study was to investigate whether a self-selection bias with respect to ethical values exists among students enrolled as business majors when compared with students planning to enter the engineering profession. Engineering students are exposed to a similar technical orientation in academic curricula and also supply the market for managers.A survey instrument was administered to 195 students enrolled (...) in undergraduate business and engineering programs and a graduate business program. The research instrument measured how business and engineering students perceive their own ethical beliefs and actions and how they perceived the ethical beliefs and actions of their peers. (shrink)

O artigo traz resultados de uma investigação de mestrado que teve por objetivo pesquisar as concepções de um grupo de professores a respeito das funções que os mesmos exercem frente à sociedade contemporânea. Partiu-se da premissa de que suas concepções guardam relação com suas práticas educativas e pedagógicas. Trata-se de uma pesquisa desenvolvida na perspectiva qualitativa, com cinquenta e um professores que atuam em seis escolas estaduais da cidade de Ponta Grossa-PR. Elegeu-se como aporte teórico autores que tratam da formação (...) de professores e da profissão docente, como Freire, Imbernón, Ens e Behrens, Tozetto, Sacristán e Tedesco. Os dados foram coletados por meio de questionários, categorizados e analisados seguindo os pressupostos na Análise de Conteúdo. Três categorias foram configuradas a partir de significantes presentes nas respostas dos professores participantes: Categoria I – Professor como um sujeito transformador: educação em uma forma ampla, Categoria II – Professor como profissional do conhecimento, e Categoria III – Professor enquanto sujeito que desempenha vários papéis sociais. Essas categorias nos possibilitaram inferir que as concepções dos professores em relação ao seu papel na sociedade contemporânea vão além da função social da escola, pois centram-se primeiramente na figura de um profissional transformador do mundo; seguida da noção de profissional do conhecimento e, por fim, da ideia de um profissional que desempenha vários papéis sociais. A pesquisa também apontou uma necessária redefinição da profissão docente para que os professores assumam novas competências profissionais na contemporaneidade. Palavras-chave: Profissão docente. Função dos professores. Sociedade contemporânea. Concepções. (shrink)

In spite of ethical analyses assimilating the palliative deactivation of pacemakers to commonly accepted withdrawings of life-sustaining therapy, many clinicians remain ethically uncomfortable with pacemaker deactivation at the end of life. Various reasons have been posited for this discomfort. Some cardiologists have suggested that reluctance to deactivate pacemakers may stem from a sense that the pacemaker has become part of the patient’s “self.” The authors suggest that Daniel Sulmasy is correct to contend that any such identification of the (...) pacemaker is misguided. The authors argue that clinicians uncomfortable with pacemaker deactivation are nevertheless correct to see it as incompatible with the traditional medical ethics of withdrawal of support. Traditional medical ethics is presently taken by many to sanction pacemaker deactivation when such deactivation honors the patient’s right to refuse treatment. The authors suggest that the right to refuse treatment applies to treatments involving ongoing physician agency. This right cannot underwrite patient demands that physicians reverse the effects of treatments previously administered, in which ongoing physician agency is no longer implicated. The permanently indwelling pacemaker is best seen as such a treatment. As such, its deactivation in the pacemaker-dependent patient is best seen not as withdrawal of support but as active ending of life. That being the case, clinicians adhering to the usual ethical analysis of withdrawal of support are correct to be uncomfortable with pacemaker deactivation at the end of life. (shrink)

One day soon it may be possible to replace a failing heart, liver, or kidney with a long-lasting mechanical replacement or perhaps even with a 3-D printed version based on the patient's own tissue. Such artificial organs could make transplant waiting lists and immunosuppression a thing of the past. Supposing that this happens, what will the ongoing care of people with these implants involve? In particular, how will the need to maintain the functioning of artificial organs over an extended period (...) affect patients and their doctors and the responsibilities of those who manufacture such devices? Drawing on lessons from the history of the cardiac pacemaker, this article offers an initial survey of the ethical issues posed by the need to maintain and service artificial organs. We briefly outline the nature and history of cardiac pacemakers, with a particular focus on the need for technical support, maintenance, and replacement of these devices. Drawing on the existing medical literature and on our conversations and correspondence with cardiologists, regulators, and manufacturers, we describe five sources of ethical issues associated with pacemaker maintenance: the location of the devices inside the human body, such that maintenance generates surgical risks; the complexity of the devices, which increases the risk of harms to patients as well as introducing potential injustices in access to treatment; the role of software—particularly software that can be remotely accessed—in the functioning of the devices, which generates privacy and security issues; the impact of continual development and improvement of the device; and the influence of commercial interests in the context of a medical device market in which there are several competing products. Finally, we offer some initial suggestions as to how these questions should be answered. (shrink)

The question of whether it is permissible to deactivate a pacemaker at the end of life has been addressed in medical journals but rarely in ethics journals. The ethics of pacemaker deactivation is especially challenging because of the disparate ways the devices are viewed by both medical professionals and patients. Some consider pacemakers replacement therapy, and some consider them substitutive therapy. If they are the former, then deactivation would not be permitted, since a replacement device is considered a (...) part of the body, akin to a new heart. Some ask whether pacemakers are natural or artificial; if pacemakers are artificial, deactivation would be permissible. Another factor is whether a patient is pacemaker dependent. Some medical experts decide the issue of deactivation on the basis of patient autonomy. Others weigh in on whether pacemakers are ordinary or extraordinary means of care. This paper examines each proposal and concludes tentatively that pacemaker deactivation is not permissible at the end of life. National Catholic Bioethics Quarterly 15.1 : 39–51. (shrink)

The pacemaker-accumulator model provides a framework in which the results of different duration estimation tasks are commonly accounted for. Nevertheless, the model remains abstract and it does not provide proper explanations nor predictions for duration estimations in various experimental set-ups. This paper aims to address these shortcomings by explicating an experiential pacemaker-accumulator model that supplements the standard pacemaker-accumulator model with two claims. Both of them concern the role that experiences play in duration estimation tasks and are also (...) partly supported by studies not directly related to duration estimation. First, the internal responses based on which the switch between the pacemaker and the accumulator operates are the same as the neural processes that realize conscious access to experiences. Second, the processes that realize the experiences of stimuli realize the function of the pacemaker. By supplementing the standard pacemaker-accumulator model with these claims, the model affords proper explanations for the systematic errors and empirically testable predictions in duration estimations tasks. One likely consequence of the model is that the experience of duration and the duration of experience can differ. (shrink)

Religious toleration first became legally enshrined in Europe in the 16th and 17th centuries. Religious toleration led to the practice of more general inter-subjective recognition of members of democratic states which took precedence over differences of conviction and practice. After considering the extent to which a democracy may defend itself against the enemies of democracy and to which it should be prepared to tolerate civil disobedience, the article analyses the contemporary dialectic between the notion of civil inclusion and multiculturalism. Religious (...) toleration is seen as the pacemaker for modern multiculturalism, in which the claims of minorities to civic inclusion are recognized so long as members of all groups understand themselves to be citizens of one and the same political community. Footnotes1 Royal Institute of Philosophy Annual Lecture, 2003. (shrink)

Biological pacemakers can be achieved by various gene‐based and cell‐based approaches. Embryonic stem cells (ESCs)‐derived pacemaker cells might be the most promising way to form biological pacemakers, but there are challenges as to how to control the differentiation of ESCs and to overcome the neoplasia, proarrhythmia, or immunogenicity resulting from the use of ESCs. As a potential approach to solve these difficult problems, tissue‐engineering techniques may provide a precise control on the different cell components of multicellular aggregates and the (...) forming of a construct with‐defined architectures and functional properties. The combined interactions between ESC‐derived pacemaker cells, supporting cells, and matrices may completely reproduce pacemaker properties and result in a steady functional unit to induce rhythmic electrical and contractile activities. As ESCs have a high capability for self‐renewal, proliferation, and potential differentiation, we hypothesize that ESCs can be used as a source of pacemaker cells for tissue‐engineering applications and the ambitious goal of biological cardiac pacemakers may ultimately be achieved with ESCs via tissue‐engineering technology. -/- . (shrink)

A 68-year-old patient who suffered from gastric cancer diagnosed 8 months earlier presented with multiple peritoneal and hepatic metastasis, despite several rounds of chemo- and radiotherapy. After admission to hospital, his general condition quickly became severely compromised. He was nearly emaciated, despite being on partial parenteral feeding. Four years earlier, due to a cardiac arrhythmia that was refractory to medication, the patient had a cardiac pacemaker implanted, regulated to go off at frequencies of below 70 beats per minute. Given (...) the patient's terminal situation, the team started developing some doubts about the pacemaker's effects during his dying process. The patient had mentioned his intention to donate his pacemaker after his death, but had not asked for its deactivation. The specialists were not sure about the effect of the pacemaker in unnecessarily prolonging the patient's final hour. Nevertheless, they opposed deactivation, which they considered ethically uncertain. The family, who had been initially for the deactivation, decided against it. The patient's condition was progressively deteriorating, as he was falling into a state of sopor and, later, into a coma. (shrink)

According to the World Health Organization cardiovascular disease is the leading cause of death globally. Over 80% of CVD deaths take place in low- and middle-income countries. It is estimated that 1 million to 2 million people worldwide die each year due to lack of access to an implantable cardiac defibrillator or a pacemaker. Despite the medical, legal, cultural and ethical controversies surrounding the pacemaker reutilization, studies done so far on the reuse of postmortem pacemakers show it to (...) be safe and effective with an infection rate of 1.97% and device malfunction rate of 0.68%. Pacemaker reutilization can be effectively and safely done and does not pose significant additional risk to the recipient. Heart patients with reused pacemakers have an improved quality of life compared to those without pacemakers. The thesis of this paper is that pacemaker reutilization is a life-saving initiative in LMICs of Nigeria and Ghana. It is cost effective; consistent with the principles of beneficence, nonmaleficence, and justice with a commitment to stewardship of resources and the Common Good. Used pacemakers with adequate battery life can be properly sterilized for use by patients in LMICs who cannot afford the cost of a new pacemaker. (shrink)

In this case report, we describe a woman with advancing dementia who still retained decisional capacity and was able to clearly articulate her request for deactivation of her implanted cardiac pacemaker—a scenario that would result in her death. In this case, the patient had the autonomy to make her decision, but clinicians at an outside hospital refused to deactivate her pacemaker even though they were in unanimous agreement that the patient had capacity to make this decision, citing personal (...) discomfort and a belief that her decision seemed out of proportion to her suffering. We evaluated her at our hospital, found her to have decision-making capacity, and deactivated her pacer resulting in her death about 9 days later. While some clinicians may be comfortable discussing patient preferences for device deactivation in patients who are imminently dying, we can find no reports in the literature of requests for device deactivation from patients with terminal diagnoses who are not imminently dying. (shrink)

Based on the case report of Nathan Goldstein et al., “But I have a pacer…there is no point in engaging in hypothetical scenarios”: A Non-imminently Dying Patient’s Request for Pacemaker Deactivation, it is reasonable to conclude that it was, all-things-considered, ethically appropriate to grant the patient’s request to deactivate her pacemaker. Philosophically, and as a clinical ethicist, I support the team’s decision to honor the patient’s request for pacemaker deactivation. However, it is worth exploring a bit further (...) whether the distress on the part of the outside hospital’s ethics committee and providers—who declined to honor the patient’s request for pacemaker deactivation—may actually track something of moral significance. In this commentary, I argue that there are reasonable grounds for holding that deactivation of a ‘biofixture’ such as a pacemaker may be more analogous in moral terms to medical aid in dying than it is to standard cases of withdrawal of life support at the end of a patient’s life. (shrink)

The “puzzle of the unmarked clock” derives from a conflict between the following: (1) a plausible principle of epistemic modesty, and (2) “Rational Reflection”, a principle saying how one’s beliefs about what it is rational to believe constrain the rest of one’s beliefs. An independently motivated improvement to Rational Reflection preserves its spirit while resolving the conflict.

This paper presents a novel theoretical framework arguing that linear time consciousness, far from being a natural or universal human experience, represents a historically specific capitalist and industrial construct that has become pathological in contemporary society. Drawing on Henri Bergson's concept of durée, Indigenous cyclical temporal frameworks, and empirical evidence from burnout research, I propose "temporal pluralism" as a decolonial intervention capable of addressing three critical contemporary crises: workplace burnout, climate fatalism, and AI alignment challenges. Through rigorous analysis of cross-cultural (...) temporal concepts, quantitative data on burnout correlations with time perspective, and theoretical modeling of AI temporal preferences, this work demonstrates that the hegemony of linear time creates systematic psychological, ecological, and technological pathologies. The paper concludes with a comprehensive policy framework for implementing temporal pluralism across institutional domains, offering a transformative approach to temporal organization that prioritizes human flourishing, ecological sustainability, and technological alignment over productivity maximization. (shrink)

Based on Nathan Goldstein’s case report, “But I have a pacer…there is no point in engaging in hypothetical scenarios”: A Non-imminently Dying Patient’s Request for Pacemaker Deactivation, it is reasonable to conclude that it was, all-things-considered, ethically appropriate to grant the patient’s request to deactivate her pacemaker. Philosophically, and as a clinical bioethicist, I support the team’s decision to honor the patient’s request for pacemaker deactivation. However, it is worth exploring a bit further whether the distress on (...) the part of the outside hospital’s ethics committee and providers—who declined to honor the patient’s request for pacemaker deactivation—may actually track something of moral significance. Might their discomfort around deactivation be “truth-tracking” in moral terms? (shrink)

Graphical AbstractThe variable photoperiods of Northern latitudes challenge the entrainment capacity of the circadian pacemaker, which evolved under constant photoperiods in Equatorial regions. Entrainment to the erratic photoperiods facilitated by artificial light presents an additional challenge. Metabolic dysfunction and obesity are potential consequences of such desynchronization of circadian and environmental rhythms.

The clock hypothesis of relativity theory equates the proper time experienced by a point particle along a timelike curve with the length of that curve as determined by the metric. Is it possible to prove that particular types of clocks satisfy the clock hypothesis, thus genuinely measure proper time, at least approximately? Because most real clocks would be enormously complicated to study in this connection, focusing attention on an idealized light clock is attractive. The present paper extends (...) and generalized partial results along these lines with a theorem showing that, for any timelike curve in any spacetime, there is a light clock that measures the curve’s length as accurately and regularly as one wishes. (shrink)

We study gravitational back-reaction within the Page-Wootters formulation of quantum mechanics by treating time as a quantum degree of freedom. Our model introduces a distinction between global “coordinate time,” represented as a relational quantum observable, and “proper time,” measured by internal quantum degrees of freedom of physical systems. By coupling mass-energy with coordinate time through a Wheeler-DeWitt-like constraint, we demonstrate the natural emergence of gravitational time dilation. In the presence of a massive object this agrees with time dilation in a (...) Schwarzchild metric at leading order if the interaction strength is taken to be representative of the gravitational coupling G. Additionally, when two particles independently couple to the time coordinate, a Newtonian gravitational interaction arises in the low-energy limit, showing how gravitational potential can emerge from non-interacting quantum systems. Our approach also reveals renormalization features, potentially softening high-energy divergences and suggesting that particles in superposition might introduce quantum corrections to gravitational time dilation. (shrink)

Cellular circadian clocks represent ancient anticipatory systems which co‐evolved with the first cells to safeguard their survival. Cyanobacteria represent one of the most ancient cells, having essentially invented photosynthesis together with redox‐based cellular circadian clocks some 2.7 billion years ago. Bioelectricity phenomena, based on redox homeostasis associated electron transfers in membranes and within protein complexes inserted in excitable membranes, play important roles, not only in the cellular circadian clocks and in anesthetics‐sensitive cellular sentience (awareness of environment), but also in the (...) coupling of single cells into tissues and organs of unitary multicellular organisms. This integration of cellular circadian clocks with cellular basis of sentience is an essential feature of the cognitive CBC‐Clock basis of cellular life. (shrink)