Prognostic thresholds of outcome predictors in severe accidental hypothermia.

Hemodynamically unstable patients with severe hypothermia and preserved circulation should be transported to dedicated extracorporeal life support (ECLS) centers, but not all are eligible for extracorporeal therapy. In this group of patients, the outcome of rewarming may sometimes be unfavorable. It is, therefore, crucial to identify potential risk factors for death. Furthermore, it is unclear what criterion for hemodynamic stability should be adopted for patients with severe hypothermia. The aim of this study is to identify pre-rewarming predictors of death and their threshold values in hypothermic patients with core temperature ≤ 28 °C and preserved circulation, who were treated without extracorporeal rewarming. We conducted a multicenter retrospective study involving patients in accidental hypothermia with core temperature 28 °C or lower, and preserved spontaneous circulation on rewarming initiation. The data were collected from the International Hypothermia Registry, HELP Registry, and additional hospital data. The primary outcome was survival to hospital discharge. We conducted a multivariable logistic regression and receiver operating characteristic curve (ROC) analysis. In the multivariate analysis of laboratory tests and vital signs, systolic blood pressure (SBP) adjusted for cooling circumstances and base excess (BE) were identified as the best predictor of death (OR 0.974 95% CI 0.952-0.996), AUC ROC 0.79 (0.70-0.88). The clinically relevant cutoff for SBP was identified at 90 mmHg with a sensitivity of 0.74 (0.54-0.89) and a specificity of 0.70 (0.60-0.79). The increased risk of death among hypothermic patients with preserved circulation occurs among those with an SBP below 90 mmHg and in those who developed hypothermia in their homes.

Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks.

Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3ß axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily oscillations in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

Macromolecular condensation buffers intracellular water potential.

Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions1. Reciprocally, macromolecules restrict the movement of 'structured' water molecules within their hydration layers, reducing the available 'free' bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Here, within concentrated macromolecular solutions such as the cytosol, we found that modest changes in temperature greatly affect the water potential, and are counteracted by opposing changes in osmotic strength. This duality of temperature and osmotic strength enables simple manipulations of solvent thermodynamics to prevent cell death after extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength, which impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales2,3; we therefore postulated the existence of a rapid compensatory response. We find that this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically disordered proteins. The formation and dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which is consequently robustly buffered in the cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest that preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

Vimentin intermediate filaments provide structural stability to the mammalian Golgi complex.

The Golgi complex comprises a connected ribbon of stacked cisternal membranes localized to the perinuclear region in most vertebrate cells. The position and morphology of this organelle depends upon interactions with microtubules and the actin cytoskeleton. In contrast, we know relatively little about the relationship of the Golgi complex with intermediate filaments (IFs). In this study, we show that the Golgi is in close physical proximity to vimentin IFs in cultured mouse and human cells. We also show that the trans-Golgi network coiled-coil protein GORAB can physically associate with vimentin IFs. Loss of vimentin and/or GORAB had a modest effect upon Golgi structure at the steady state. The Golgi underwent more rapid disassembly upon chemical disruption with brefeldin A or nocodazole, and slower reassembly upon drug washout, in vimentin knockout cells. Moreover, loss of vimentin caused reduced Golgi ribbon integrity when cells were cultured on high-stiffness hydrogels, which was exacerbated by loss of GORAB. These results indicate that vimentin IFs contribute to the structural stability of the Golgi complex and suggest a role for GORAB in this process.

The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc.

The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes in their environment. Chronic disruption to circadian rhythms (e.g., through ageing or shift work) is thought to contribute to a multitude of diseases, including degeneration of the musculoskeletal system. The intervertebral disc (IVD) in the spine contains circadian clocks which control ∼6% of the transcriptome in a rhythmic manner, including key genes involved in extracellular matrix (ECM) homeostasis. However, it remains largely unknown to what extent the local IVD molecular clock is required to drive rhythmic gene transcription and IVD physiology. In this work, we identified profound age-related changes of ECM microarchitecture and an endochondral ossification-like phenotype in the annulus fibrosus (AF) region of the IVD in the Col2a1-Bmal1 knockout mice. Circadian time series RNA-Seq of the whole IVD in Bmal1 knockout revealed loss of circadian patterns in gene expression, with an unexpected emergence of 12 h ultradian rhythms, including FOXO transcription factors. Further RNA sequencing of the AF tissue identified region-specific changes in gene expression, evidencing a loss of AF phenotype markers and a dysregulation of ECM and FOXO pathways in Bmal1 knockout mice. Consistent with an up-regulation of FOXO1 mRNA and protein levels in Bmal1 knockout IVDs, inhibition of FOXO1 in AF cells suppressed their osteogenic differentiation. Collectively, these data highlight the importance of the local molecular clock mechanism in the maintenance of the cell fate and ECM homeostasis of the IVD. Further studies may identify potential new molecular targets for alleviating IVD degeneration.

The circadian clock and extracellular matrix homeostasis in aging and age-related diseases.

The extracellular matrix (ECM) is the noncellular scaffolding component present within all tissues and organs. It provides crucial biochemical and biomechanical cues to instruct cellular behavior and has been shown to be under circadian clock regulation, a highly conserved cell-intrinsic timekeeping mechanism that has evolved with the 24-hour rhythmic environment. Aging is a major risk factor for many diseases, including cancer, fibrosis, and neurodegenerative disorders. Both aging and our modern 24/7 society disrupt circadian rhythms, which could contribute to altered ECM homeostasis. Understanding the daily dynamics of ECM and how this mechanism changes with age will have a profound impact on tissue health, disease prevention, and improving treatments. Maintaining rhythmic oscillations has been proposed as a hallmark of health. On the other hand, many hallmarks of aging turn out to be key regulators of circadian timekeeping mechanisms. In this review, we summarize new work linking the ECM with circadian clocks and tissue aging. We discuss how the changes in the biomechanical and biochemical properties of ECM during aging may contribute to circadian clock dysregulation. We also consider how the dampening of clocks with age could compromise the daily dynamic regulation of ECM homeostasis in matrix-rich tissues. This review aims to encourage new concepts and testable hypotheses about the two-way interactions between circadian clocks and ECM in the context of aging.

Extracorporeal Rewarming Is Associated With Increased Survival Rate in Severely Hypothermic Patients With Preserved Spontaneous Circulation.

Treatment recommendations for rewarming patients in severe accidental hypothermia with preserved spontaneous circulation have a weak evidence due to the absence of randomized clinical trials. We aimed to compare the outcomes of extracorporeal versus less-invasive rewarming of severely hypothermic patients with preserved spontaneous circulation. We conducted a multicenter retrospective study. The patient population was compiled based on data from the HELP Registry, the International Hypothermia Registry, and a literature review. Adult patients with a core temperature <28°C and preserved spontaneous circulation were included. Patients who underwent extracorporeal rewarming were compared with patients rewarmed with less-invasive methods, using a matched-pair analysis. The study population consisted of 50 patients rewarmed extracorporeally and 85 patients rewarmed with other, less-invasive methods. Variables significantly associated with survival included: lower age; outdoor cooling circumstances; higher blood pressure; higher PaCO 2 ; higher BE; higher HCO 3 ; and the absence of comorbidities. The survival rate was higher in patients rewarmed extracorporeally ( p = 0.049). The relative risk of death was twice as high in patients rewarmed less invasively. Based on our data, we conclude that patients in severe accidental hypothermia with circulatory instability can benefit from extracorporeal rewarming without an increased risk of complications.

Post-Processing of Raw Data Recorded Continuously Using a FORS-Fibre-Optic Rotational Seismograph.

Modern optoelectronic devices use the advantage of digital systems for data processing aimed at delivering reliable information. However, since commonly used DACs have limited accuracy, some artefacts can be observed in data streams, especially in systems designed for continuous, long-term process monitoring. In this paper, the authors' experience with data enhancement using a fibre-optic rotational seismograph (FORS) operating in a closed-loop mode is presented and discussed. Generally, two kinds of enhancement are described. The first one uses suitable filtering techniques adequate for FORS noise investigation, as well as a suitable data resampling method for transmitted data file size reduction. The second one relates to the artefacts observed during data recording in real time. The recording starting point is triggered when the detected signal exceeds a middle signal level and, therefore, the existence of artefacts generally disturbs the recording process. Although the artefacts are easily recognised by human eyes even at first sight, their automatic elimination is not so easy. In this paper, the authors propose a new concept of signal filtering to solve the above problem.

Active control of dielectric singularities in indium-tin-oxides hyperbolic metamaterials.

Dielectric singularities (DSs) constitute one of the most exotic features occurring in the effective permittivity of artificial multilayers called hyperbolic metamaterials (HMMs). Associated to DSs, a rich phenomenology arises that justifies the ever-increasing interest profuse by the photonic community in achieving an active control of their properties. As an example, the possibility to "canalize" light down to the nanoscale as well as the capability of HMMs to interact with quantum emitters, placed in their proximity, enhancing their emission rate (Purcell effect), are worth mentioning. HMMs, however, suffer of an intrinsic lack of tunability of its DSs. Several architectures have been proposed to overcome this limit and, among them, the use of graphene outstands. Graphene-based HMMs recently shown outstanding canalization capabilities achieving λ/1660 light collimation. Despite the exceptional performances promised by these structures, stacking graphene/oxide multilayers is still an experimental challenge, especially envisioning electrical gating of all the graphene layers. In this paper, we propose a valid alternative in which indium-tin-oxide (ITO) is used as an electrically tunable metal. Here we have numerically designed and analyzed an ITO/SiO2 based HMM with a tunable canalization wavelength within the range between 1.57 and 2.74 µm. The structure feature light confinement of λ/8.8 (resolution of about 178 nm), self-focusing of the light down to 0.26 µm and Purcell factor of approximately 700. The proposed HMM nanoarchitecture could be potentially used in many applications, such as ultra-fast signal processing, high harmonic generation, lab-on-a-chip nanodevices, bulk plasmonic waveguides in integrated photonic circuits and laser diode collimators.

Synthetic gene circuits for preventing disruption of the circadian clock due to interleukin-1-induced inflammation.

The circadian clock regulates tissue homeostasis through temporal control of tissue-specific clock-controlled genes. In articular cartilage, disruptions in the circadian clock are linked to a procatabolic state. In the presence of inflammation, the cartilage circadian clock is disrupted, which further contributes to the pathogenesis of diseases such as osteoarthritis. Using synthetic biology and tissue engineering, we developed and tested genetically engineered cartilage from murine induced pluripotent stem cells (miPSCs) capable of preserving the circadian clock in the presence of inflammation. We found that circadian rhythms arise following chondrogenic differentiation of miPSCs. Exposure of tissue-engineered cartilage to the inflammatory cytokine interleukin-1 (IL-1) disrupted circadian rhythms and degraded the cartilage matrix. All three inflammation-resistant approaches showed protection against IL-1-induced degradation and loss of circadian rhythms. These synthetic gene circuits reveal a unique approach to support daily rhythms in cartilage and provide a strategy for creating cell-based therapies to preserve the circadian clock.

Detection of Organosulfur and Organophosphorus Compounds Using a Hexafluorobutyl Acrylate-Coated Tapered Optical Fibers.

This paper presents the results of a study on the possibility of detecting organosulfur and organophosphorus compounds by means of polymer-assisted optical fiber technology. The detection of the aforementioned compounds can be realized by fabricating a polymer-coated tapered optical fiber (TOF), where the polymer works as an absorber, which changes the light propagation conditions in the TOF. The TOFs were manufactured based on a standard single-mode fiber for telecommunication purposes and, as an absorbing polymer, hexafluorobutyl acrylate was used, which is sensitive to organosulfur and organophosphorus compounds. The spectral measurements were conducted in a wide optical range-500-1800 nm-covering the visible part of the spectrum as well as near infrared part in order to show the versatility of the proposed solution. Additionally, detailed absorption dynamics measurements were provided for a single wavelength of 1310 nm. The analyses were conducted for two concentrations of evaporating compounds, 10 µL and 100 µL, in a volume of 150 mL. Additionally, a temperature dependency analysis and tests with distilled water were carried out to eliminate the influence of external factors. The results presented in this article confirmed the possibility to provide low-cost sensors for dangerous and harmful chemical compounds using optical fiber technology and polymers as sensitive materials.

Restoring the dampened expression of the core clock molecule BMAL1 protects against compression-induced intervertebral disc degeneration.

The circadian clock participates in maintaining homeostasis in peripheral tissues, including intervertebral discs (IVDs). Abnormal mechanical loading is a known risk factor for intervertebral disc degeneration (IDD). Based on the rhythmic daily loading pattern of rest and activity, we hypothesized that abnormal mechanical loading could dampen the IVD clock, contributing to IDD. Here, we investigated the effects of abnormal loading on the IVD clock and aimed to inhibit compression-induced IDD by targeting the core clock molecule brain and muscle Arnt-like protein-1 (BMAL1). In this study, we showed that BMAL1 KO mice exhibit radiographic features similar to those of human IDD and that BMAL1 expression was negatively correlated with IDD severity by systematic analysis based on 149 human IVD samples. The intrinsic circadian clock in the IVD was dampened by excessive loading, and BMAL1 overexpression by lentivirus attenuated compression-induced IDD. Inhibition of the RhoA/ROCK pathway by Y-27632 or melatonin attenuated the compression-induced decrease in BMAL1 expression. Finally, the two drugs partially restored BMAL1 expression and alleviated IDD in a diurnal compression model. Our results first show that excessive loading dampens the circadian clock of nucleus pulposus tissues via the RhoA/ROCK pathway, the inhibition of which potentially protects against compression-induced IDD by preserving BMAL1 expression. These findings underline the importance of the circadian clock for IVD homeostasis and provide a potentially effective therapeutic strategy for IDD.

Study of Rotational Motions Caused by Multiple Mining Blasts Recorded by Different Types of Rotational Seismometers.

Digging two vertical shafts with the multiple blasts technique gave the opportunity to measure the induced angular motions in a horizontal plane with well-defined positions of sources. Three kinds of rotation rate sensors, sharing an underground location, were used. Two of them-a Fiber-Optic System for Rotational Events & phenomena Monitoring (FOSREM) and a prototypical seismometer housing the liquid-filled torus-sensed the rotation, while a microarray of two double-pendulum seismometers sensed both the rotation and symmetric strain. The FOSREM was sampled at 656.168 Hz, while all the others were only sampled at 100 Hz. There were considerable differences within the results gathered from the mining blasts, which should be attributed to two causes. The first one is the difference in principles of the operation and sampling rates of the devices used, while the other is the complex and spatially variable character of the studied wave fields. Additionally, we established that the liquid-filled sensor, due to its relatively low sensitivity, proved to be viable only during a registration of strong ground motions. Overall, a comparative study of three different rotational seismometers was performed during mining-induced strong ground motions with well-localized sources.

The Impact of COVID-19 on Admissions and Management of Patients with Atrial Fibrillation Episodes in the Emergency Department.

BACKGROUND: During the COVID-19 pandemic, the number of admissions to the emergency department (ED) due to a primary diagnosis of atrial fibrillation (AF) has decreased when compared to pre-pandemic times. The principal aim of the study was to assess the frequency of SARS-CoV-2 infections and sinus rhythm restoration among patients who arrived at the ED with AF. Secondary aims included determining whether patients arriving at the ED principally due to AF delayed their presentations and whether the frequency of successful cardioversion for AF was decreased during the pandemic period. MATERIALS AND METHODS: A retrospective analysis of medical records of patients admitted to two hospital EDs due to AF during July-December 2019 (pre-pandemic period) versus July-December 2020 (pandemic period) was performed. RESULTS: During the study periods, 601 ED visits by 497 patients were made due to the primary diagnosis of AF. The patients were aged 71.2+/-13.5 years and 51.3% were male. The duration of an AF episode before the ED admission was 10 h (4.5-30 h) during the pandemic period vs. 5 h (3-24 h) during the non-pandemic period (p = 0.001). A shorter duration of the AF episode before ED admission was associated with the successful restoration of the sinus rhythm. During the pandemic period, among patients with short-lasting AF who were not treated with Phenazolinum, the restoration of the sinus rhythm was more frequent in the Copernicus Memorial Hospital than in the University Hospital (p = 0.026). A positive SARS-CoV-2 test was found in 5 (1%) patients, while 2 other patients (0.5%) had a prior diagnosis of COVID-19 disease noted in their medical history. CONCLUSIONS: 1. The number of AF episodes treated in these two EDs was lower during the pandemic than non-pandemic period. 2. The patients with AF appeared at the ED later after AF onset in the pandemic period. 3. Successful cardioversion of atrial fibrillation was more frequent during the pre-pandemic period in one of the two hospitals. 4. A difference of approaches to the treatment of short-lasting AF episodes between EDs during the pandemic period may exist between these two EDs. 5. The patients with SARS-CoV-2 infection during the second wave of the COVID-19 pandemic constituted a small percentage of the patients admitted to EDs due to an AF episode.

Graphene-based tunable hyperbolic microcavity.

Graphene-based hyperbolic metamaterials provide a unique scaffold for designing nanophotonic devices with active functionalities. In this work, we have theoretically demonstrated that the characteristics of a polarization-dependent tunable hyperbolic microcavity in the mid-infrared frequencies could be realized by modulating the thickness of the dielectric layers, and thus breaking periodicity in a graphene-based hyperbolic metamaterial stack. Transmission of the tunable microcavity shows a Fabry-Perot resonant mode with a Q-factor > 20, and a sixfold local enhancement of electric field intensity. It was found that by varying the gating voltage of graphene from 2 to 8 V, the device could be self-regulated with respect to both the intensity (up to 30%) and spectrum (up to 2.1 µm). In addition, the switching of the device was considered over a wide range of incident angles for both the transverse electric and transverse magnetic modes. Finally, numerical analysis indicated that a topological transition between elliptic and type II hyperbolic dispersion could be actively switched. The proposed scheme represents a remarkably versatile platform for the mid-infrared wave manipulation and may find applications in many multi-functional architectures, including ultra-sensitive filters, low-threshold lasers, and photonic chips.

Tissue physiology revolving around the clock: circadian rhythms as exemplified by the intervertebral disc.

Circadian clocks in the brain and peripheral tissues temporally coordinate local physiology to align with the 24 hours rhythmic environment through light/darkness, rest/activity and feeding/fasting cycles. Circadian disruptions (during ageing, shift work and jet-lag) have been proposed as a risk factor for degeneration and disease of tissues, including the musculoskeletal system. The intervertebral disc (IVD) in the spine separates the bony vertebrae and permits movement of the spinal column. IVD degeneration is highly prevalent among the ageing population and is a leading cause of lower back pain. The IVD is known to experience diurnal changes in loading patterns driven by the circadian rhythm in rest/activity cycles. In recent years, emerging evidence indicates the existence of molecular circadian clocks within the IVD, disruption to which accelerates tissue ageing and predispose animals to IVD degeneration. The cell-intrinsic circadian clocks in the IVD control key aspects of physiology and pathophysiology by rhythmically regulating the expression of ~3.5% of the IVD transcriptome, allowing cells to cope with the drastic biomechanical and chemical changes that occur throughout the day. Indeed, epidemiological studies on long-term shift workers have shown an increased incidence of lower back pain. In this review, we summarise recent findings of circadian rhythms in health and disease, with the IVD as an exemplar tissue system. We focus on rhythmic IVD functions and discuss implications of utilising biological timing mechanisms to improve tissue health and mitigate degeneration. These findings may have broader implications in chronic rheumatic conditions, given the recent findings of musculoskeletal circadian clocks.

Rotation, Strain, and Translation Sensors Performance Tests with Active Seismic Sources.

Interest in measuring displacement gradients, such as rotation and strain, is growing in many areas of geophysical research. This results in an urgent demand for reliable and field-deployable instruments measuring these quantities. In order to further establish a high-quality standard for rotation and strain measurements in seismology, we organized a comparative sensor test experiment that took place in November 2019 at the Geophysical Observatory of the Ludwig-Maximilians University Munich in Fürstenfeldbruck, Germany. More than 24 different sensors, including three-component and single-component broadband rotational seismometers, six-component strong-motion sensors and Rotaphone systems, as well as the large ring laser gyroscopes ROMY and a Distributed Acoustic Sensing system, were involved in addition to 14 classical broadband seismometers and a 160 channel, 4.5 Hz geophone chain. The experiment consisted of two parts: during the first part, the sensors were co-located in a huddle test recording self-noise and signals from small, nearby explosions. In a second part, the sensors were distributed into the field in various array configurations recording seismic signals that were generated by small amounts of explosive and a Vibroseis truck. This paper presents details on the experimental setup and a first sensor performance comparison focusing on sensor self-noise, signal-to-noise ratios, and waveform similarities for the rotation rate sensors. Most of the sensors show a high level of coherency and waveform similarity within a narrow frequency range between 10 Hz and 20 Hz for recordings from a nearby explosion signal. Sensor as well as experiment design are critically accessed revealing the great need for reliable reference sensors.

Measurements of Rotational Events Generated by Artificial Explosions and External Excitations Using the Optical Fiber Sensors Network.

Measurements of artificial events can substantially confirm the data validity of constructed rotational sensors, as well as provide methods for simplifying the measurement process. The above task, especially with international cooperation, can provide full-field measurement results of the target object, which can deliver more significant data and sensor properties. The paper presents vertical rotational velocity recordings gathered during an international experiment that took place at the Geophysical Observatory of the Ludwig Maximilian University of Munich in Fürstenfeldbruck, Germany. Data were obtained during artificial explosions, as well as external excitations induced by a VibroSeis truck. The authors present data recorded by two prototypes of optical fiber rotational sensors. They have been specially designed for rotational seismology needs and are characterized by a theoretical sensitivity equal to 2 × 10-8 rad/s/√Hz and a wide measuring range both in amplitude even up to 10 rad/s, and a frequency from DC to 1000 Hz. Their self-noise investigation during the aforementioned experiment showed that both sensors have precision no worse than 2 × 10-6 rad/s/sqrt (Hz) in all desired frequency range from 0.01 to 100 Hz. A down-sampling and a spectral analysis of the recorded signals are also presented. The recorded data and their analysis confirmed the performance and reliability of the applied optical fiber rotational sensors. Moreover, the presented international experiment underlines a special necessity for specifying the sensors' performance test methodologies in the rotational seismology.

Quantitative live imaging of Venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator.

Evolutionarily conserved circadian clocks generate 24-hour rhythms in physiology and behaviour that adapt organisms to their daily and seasonal environments. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the principal co-ordinator of the cell-autonomous clocks distributed across all major tissues. The importance of robust daily rhythms is highlighted by experimental and epidemiological associations between circadian disruption and human diseases. BMAL1 (a bHLH-PAS domain-containing transcription factor) is the master positive regulator within the transcriptional-translational feedback loops (TTFLs) that cell-autonomously define circadian time. It drives transcription of the negative regulators Period and Cryptochrome alongside numerous clock output genes, and thereby powers circadian time-keeping. Because deletion of Bmal1 alone is sufficient to eliminate circadian rhythms in cells and the whole animal it has been widely used as a model for molecular disruption of circadian rhythms, revealing essential, tissue-specific roles of BMAL1 in, for example, the brain, liver and the musculoskeletal system. Moreover, BMAL1 has clock-independent functions that influence ageing and protein translation. Despite the essential role of BMAL1 in circadian time-keeping, direct measures of its intra-cellular behaviour are still lacking. To fill this knowledge-gap, we used CRISPR Cas9 to generate a mouse expressing a knock-in fluorescent fusion of endogenous BMAL1 protein (Venus::BMAL1) for quantitative live imaging in physiological settings. The Bmal1Venus mouse model enabled us to visualise and quantify the daily behaviour of this core clock factor in central (SCN) and peripheral clocks, with single-cell resolution that revealed its circadian expression, anti-phasic to negative regulators, nuclear-cytoplasmic mobility and molecular abundance.