Search

SUMMARYThe sleep and circadian systems act in concert to regulate sleep-wake timing, yet the molecular mechanisms that underpin their interaction to induce sleep remain unknown. Synaptic protein phosphorylation, driven by the kinase SIK3, correlates with sleep pressure, however it is unclear whether these phosphoproteome changes are causally responsible for inducing sleep. Here we show that the light-dependent activity of SIK1 controls the phosphorylation of a subset of the brain phosphoproteome to induce sleep in a manner that is independent of sleep pressure. By uncoupling phosphorylation and sleep induction from sleep pressure, we establish that synaptic protein phosphorylation provides a causal mechanism for the induction of sleep under different environmental contexts. Furthermore, we propose a framework that details how the salt-inducible kinases regulate the synaptic phosphoproteome to integrate exogenous and endogenous stimuli, thereby providing the molecular basis upon which the sleep and circadian systems interact to control the sleep-wake cycle.

The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism’s response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2., Graphical Abstract

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice., Sleep pressure and circadian rhythms influence one another. However, the regulatory mechanisms are unclear. Here, the authors show that adenosine A1/A2A receptor antagonists, such as caffeine, shift circadian rhythms and enhance the effects of light, providing a molecular link between sleep pressure and circadian rhythm.

Physiological responses to arm and leg-cycling are different, which may influence psychological and biological mechanisms that influence post-exercise cognitive performance. The aim of this study was to determine the effects of maximal and submaximal (absolute and relative intensity matched) arm and leg-cycling on executive function. Thirteen males (age, 24.7 ± 5.0 years) initially undertook two incremental exercise tests to volitional exhaustion for arm-cycling (82 ± 18 W) and leg-cycling (243 ± 52 W) for the determination of maximal power output. Participants subsequently performed three 20-min constant load exercise trials: (1) arm-cycling at 50% of the ergometer-specific maximal power output (41 ± 9 W), (2) leg-cycling at 50% of the ergometer-specific maximal power output (122 ± 26 W), and (3) leg-cycling at the same absolute power output as the submaximal arm-cycling trial (41 ± 9 W). An executive function task was completed before, immediately after and 15-min after each exercise test. Exhaustive leg-cycling increased reaction time (p < 0.05, d = 1.17), while reaction time reduced following exhaustive arm-cycling (p < 0.05, d = -0.62). Improvements in reaction time were found after acute relative intensity arm (p < 0.05, d = -0.76) and leg-cycling (p < 0.05, d = -0.73), but not following leg-cycling at the same absolute intensity as arm-cycling (p > 0.05). Improvements in reaction time following arm-cycling were maintained for at least 15-min post exercise (p = 0.008, d = -0.73). Arm and leg-cycling performed at the same relative intensity elicit comparable improvements in cognitive performance. These findings suggest that individuals restricted to arm exercise possess a similar capacity to elicit an exercise-induced cognitive performance benefit.

Microelectromechanical-systems (MEMS), microsystems technology (MST), and micromachines are roughly synonymous terms applied in the United States, Europe, and Japan respectively, to manufacturing technologies that are enabling the development of many exciting microscale or microminiaturized products. For convenience here, the terms are lumped together and labeled M3. In the parlance of management science, M3 technologies are: - exogenous (they originate from outside an existing or familiar frame of reference); and - disruptive (they are revolutionary rather than evolutionary). These technologies are creating a second micromanufacturing revolution - the first being microelectronics - as well as a fertile environment for discontinuous innovations that will revitalize existing industries and generate new markets.M3 technologies: - enable the manufacture of products that would otherwise be impossible toproduce; - improve manufacturing efficiencies by as much as an order of magnitude; - improve critical performance aspects of current products by as much as anorder of magnitude; and/or - improve product quality by reducing component size and number.

Since being globalized by inclusion in the 1980’s and 1990’s through several U.N. declarations and treaties, the Precautionary Principle has become a flashpoint internationally among scholars working in the fields of risk, international environmental law, European Union law and even U.S. federal law. The controversy surrounding the Precautionary Principle apparently arose and persists because the Principle is undertheorized. We revisit three fundamental questions: what is the Precautionary Principle, where did it come from, and how should we use it. Because the Precautionary Principle is a legal tool that is used internationally to manage technology, a comprehensive discussion of it is organically international and interdisciplinary. We argue that the Precautionary Principle is an index of formative measures of risk and fear; that its origins should be investigated specifically in relation to the particular legal instrument in question; and that it should be utilized only as an indicator of public perception and not as a prescriptive risk management tool. Because the Precautionary Principle is currently utilized internationally as a prescriptive tool, our recommendation is both controversial and non-trivial.

This paper considers ways in which a detailed understanding of classroom discourse can be achieved through the use of reflective practices and professional dialogue. For the teacher, understanding classroom communication, being able to ‘shape’ learner contributions and making strategic decisions in the moment-by-moment unfolding of a lesson are regarded as being crucial to developing SLA in the formal, L2 classroomcontext. The study reported here makes extensive use of a research instrument and a metalanguage designed to enable teachers make ‘good’ interactive decisions online by using samples of their own data. The collaborative process of interpreting data and ‘meaning-making’ in a reflective feedback interview provides teachers with a means to uncover the interactive details of their classes and make conscious changes to classroom actions.

This paper describes a model of flexible psychiatric outreach service in Canada designed to meet the needs of persons who are homeless or marginally housed and have mental illness. The activities of the Psychiatric Outreach Team of the Royal Ottawa Hospital for individual clients and the community agencies who serve them are profiled, followed by a demographic and mental and physical health profile of the clients seen in the past year. The differences from other models of service and the benefits and limitations of this unique multidisciplinary team are discussed, with implications for future service development for this vulnerable population.

This paper proposes a process model of reflective practice for second language teachers, designed to facilitate a closer understanding of language use and interactive decision-making. The L2 classroom is portrayed as a dynamic and complex series of inter-related contexts, in which interaction is central to teaching and learning. An understanding of the interactional organisation of the L2 classroom is achieved through the use of SETT (Self-Evaluation of Teacher Talk) procedures, supported by reflection and dialogue. Naturalistic research methods are used to gain insights into the emerging understanding and interactional competence of a small group of university EFL teachers. These methods are derived, in the first instance, from an institutional discourse conversational analysis methodology; secondly, from action research; thirdly from a sociocultural research perspective. Through a process of guided self-discovery involving dialogue and inquiry teachers are given an opportunity to see their classroom wor...

To what extent do teachers of EFL hinder or facilitate learner contributions by their use of language? How can teachers enhance the quantity and quality of learner output by more careful language use? In what ways do teachers deny learning opportunities by ‘filling in the gaps’ or ‘smoothing over’ learner contributions? Adopting the position that maximizing learner involvement is conducive to second language acquisition, this paper examines the ways in which teachers, through their choice of language, construct or obstruct learner participation in face-to-face classroom communication. From the lesson extracts emerge a number of ways in which teachers can improve their teacher talk to facilitate and optimize learner contributions. The conclusion, that teachers’ ability to control their use of language is at least as important as their ability to select appropriate methodologies, has implications for both teacher education and classroom practices.

Background: We tested the hypothesis that cycle length-dependent cardiac contractility in atrial fibrillation is primarily governed by the negative interval-force relation in patients with normal and depressed systolic function. Methods and Results: We performed two-dimensional guided M-mode echocardiography in 41 patients (mean age, 69 ± 4 years; range, 48 to 92 years; 19 men, 11 women). Twelve patients had objective evidence of left ventricular systolic dysfunction (CMP; mean ejection fraction, 37% ± 7%) in the absence of coronary artery disease (CAD), 13 patients had documented CAD (mean ejection fraction, 43% ± 6%), and 16 patients had normal resting left ventricular systolic function (mean ejection fraction, 58% ± 7%). Simultaneous beat-to-beat blood pressure, end-systolic and end-diastolic dimension, circumferential velocity of fiber shortening (Vcf), and end-systolic wall stress (ESWS) were calculated for all patients. All three groups showed a significant linear relation between beat-to-beat Vcf and Vcf corrected for afterload (represented as the Vcf/ESWS ratio) and preceding cycle length. There was, however, no significant difference in the relation between either of these variables and cycle length among the three groups. There was also no difference in the rate of change in either Vcf or Vcf corrected for afterload (Vcf/ESWS ratio) from beat-to-beat among the three groups. Control patients with normal systolic function showed greater Vcf at any given cycle length compared with patients with CMP or CAD. Conclusion: Our data show that, for each beat in atrial fibrillation, Vcf and Vcf/ESWS ratio are decreased after shorter cycle lengths and increased after long cycles, but there is no significant attenuation of this effect in patients with systolic dysfunction with or without coronary disease compared with controls. Thus, the negative interval-force relation, the predominant determinant of beat-to-beat variation in contractility in atrial fibrillation, is preserved in patients with CAD or reduced left ventricular systolic function.

By combining a riboswitch with a cell-permeable photocaged small molecule ligand, an optochemical gene control element was constructed, enabling spatial and temporal control of gene expression in bacterial cells. Because of the simplicity of this strategy, coupled with the ability to create synthetic riboswitches with tailored ligand specificities and output in a variety of microorganisms, plants, and fungi, this approach may afford a general strategy to photo-control gene expression in vivo. The ability to activate riboswitches using light enables the interrogation and manipulation of a wide range of biological processes with high precision, and will have broad utility in regulation of artificial genetic circuits.

In this chapter, the second language classroom is characterized by the ways in which teachers and learners jointly construct meanings through the ‘talk’ that they produce. Understanding and language acquisition do not simply ‘happen’; they are negotiated in the give-and- take of classroom interaction. In order to gain an understanding of classroom discourse, a variable approach is proposed, which views any lesson as a series of complex, dynamic and inter-related micro-contexts. There are three reasons for adopting a variable stance. Firstly, all L2 classroom discourse is goal-oriented and related to teachers’ unfolding pedagogic goals; secondly, the prime responsibility for establishing and shaping the interaction lies with the teacher; thirdly, pedagogic goals and language use are inextricably linked.

Despite the many wireless scheduling algorithms that have been proposed to date, there are a number of practical wireless scheduling issues which have yet to be provided for. This paper asserts that an intelligent wireless scheduler must be knowledge-based. To make practical decisions on which flows should receive what degree of compensation when links experience channel errors, it is essential to have knowledge of two individual metrics; a bandwidth metric and traffic metric. The current aggregate system bandwidth changes continuously according to the 'atmospheric conditions experienced and adaptive methods employed on a per channel basis. The traffic profile of each flow also changes depending on the burstiness of individual channels. These two parameters have a significant impact on how compensation should be issued. Also, a wireless scheduling algorithm should be realizable on existing hardware technology. It is the aim of this research to present an algorithm which schedules IP packets at the network layer using current state-of-the-art fair queuing techniques and a weight based method of compensation for lagging flows. The proposed algorithm is highly adaptable taking into account the current traffic profile as well as the constantly varying channel conditions and system bandwidth capacity in order to compensate lagging flow's. Results presented in this paper show how compensation is provided to error channels on a knowledge-based principle.

In the very near future wireless LAN and UMTS technologies will have to co-exist in many populated areas. Since UMTS radio cells are more limited in capacity than WLAN access points (AP), this technology integration gives operators the opportunity to perform internetwork load balancing by transferring services to WLAN hotspots. By doing so, UMTS cell congestion can be alleviated and capacity can be freed for future real time connections. Several scenarios arise depending on the level of congestion of both networks. This research studies such scenarios by assessing the impact of performing internetwork load balancing when transferring non-real time traffic. Promising results show how light and intermediate loaded neighboring WLAN hotspots can absorb up to 50% of the load of a congested UMTS cell, enhancing the throughput for switched non-real time applications and freeing 50% capacity of for future real time UMTS calls. This is achieved without degrading the service of existing applications in the WLAN hotspot.

Despite the many wireline and wireless scheduling algorithms in existence today, there is no emphasis on implementing a practical scheduling algorithm, which can be realised on existing hardware architectures. It is the aim of this paper to present an algorithm which schedules IP packets at the network layer using current state-of-the-art fair queuing techniques and a weight based method of compensation for lagging flows. Furthermore, the wireless fair scheduling algorithms that have been published to date have failed to consider the influence of traffic patterns on compensating channels, which have lost service due to channel errors. This paper highlights the importance of these traffic patterns and presents a new framework for a traffic-profile based wireless fair queuing (TBWFQ) algorithm. This algorithm is implemented using Xilinx FPGA design techniques.