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Background Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF. Objective We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP. Methods A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex. Results Among 1544 AP subjects, there was a sex‐dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04–1.15) but not in females (OR 0.98, 95% CI 0.90–1.1). Male subjects with AP, whose BMIs were 30–34 and >35 kg/m2, had odds ratios of 3.78 (95% CI 1.62–8.83) and 3.44 (95% CI 1.08–9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non‐alcohol etiologies (OR 4.17, 95% CI 2.16–8.05). Conclusion Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP.

Haematopoietic stem cells (HSCs) circulate in the bloodstream under steady-state conditions, but the mechanisms controlling their physiological trafficking are unknown. Here we show that circulating HSCs and their progenitors exhibit robust circadian fluctuations, peaking 5 h after the initiation of light and reaching a nadir 5 h after darkness. Circadian oscillations are markedly altered when mice are subjected to continuous light or to a ‘jet lag’ (defined as a shift of 12 h). Circulating HSCs and their progenitors fluctuate in antiphase with the expression of the chemokine CXCL12 in the bone marrow microenvironment. The cyclical release of HSCs and expression of Cxcl12 are regulated by core genes of the molecular clock through circadian noradrenaline secretion by the sympathetic nervous system. These adrenergic signals are locally delivered by nerves in the bone marrow, transmitted to stromal cells by the β 3 -adrenergic receptor, leading to a decreased nuclear content of Sp1 transcription factor and the rapid downregulation of Cxcl12 . These data indicate that a circadian, neurally driven release of HSC during the animal’s resting period may promote the regeneration of the stem cell niche and possibly other tissues. Stem cells got rhythm Haematopoietic stem cells (HSCs) circulate in the blood, where they can home to sites throughout the body. The release of these cells into the blood stream has now been found to be regulated by circadian rhythms. In mice, HSCs undergo pronounced fluctuations corresponding to circadian oscillations induced by continuous light or by a 12-hour time-shift or 'jet lag'. Timing of the expression of the chemokine CXCL12 in the stem cell niche was also in step with the oscillations in response to adrenergic signals delivered locally by nerves in the bone marrow. The rhythmic release of stem cells into the blood during the animal's resting period suggests a possible role in regeneration. Circulating haematopoetic stem cells and their progenitors exhibit robust circadian fluctuations, peaking 5 hours after the initiation of light and reaching a nadir 5 hours after darkness. Circadian oscillations are markedly altered when mice are subjected to continuous light or to a 'jet lag' (defined as a shift of 12 h). Data also suggests that circadian, neurally driven haematopoetic stem cells release during the animal's resting period may promote regeneration of the stem cell niche, and possibly of other tissues.

Various systemic metabolic diseases arise from prolonged crosstalk across multiple organs, triggering serious impairments in various physiological systems. These diseases are intricate systemic pathologies characterized by complex mechanisms and an unclear etiology, making the treatment challenging. Efforts have been made to develop in vitro models to understand these diseases and devise new treatments. However, there are limitations in reconstructing the causal relationships between diseases and interorgan crosstalk, including the tissue‐specific microenvironment. Alternatively, multi‐organ microphysiological systems (MOMPS) present new possibilities for capturing the complexity of systemic metabolic diseases by replicating human microphysiology and simulating diverse interorgan crosstalk. Controlled interactions and scalable representations of biological complexity in MOMPS offer a more accurate portrayal of organ interactions, enabling the identification of novel relationships between organ crosstalk, metabolism, and immunity. This, in turn, can yield valuable insights into disease mechanisms and drug development research and enhance the efficiency of preclinical studies. In this review, the examples and technical capabilities of MOMPS pathological modeling for various diseases are discussed, leveraging state‐of‐the‐art biofabrication technology of MOMPS. It evaluates the current opportunities and challenges in this field. Multi‐organ microphysiological systems (MOMPS) replicate human microphysiology and interorgan crosstalk. The precise fabrication of MOMPS requires various elements, including biomaterials, cell sources, accurate organ crosstalk, biofabrication techniques, and humanized design. The MOMPS enhances the understanding of systemic metabolic disease mechanisms, improves drug development, and increases the efficiency of preclinical studies by capturing the complexity of organ interactions and tissue‐specific microenvironments..

Circadian co-regulators cryptochrome 1 and 2 are shown to alter globally the transcriptional response to glucocorticoids in mouse embryonic fibroblasts. Glucocorticoids take their tempo from cryptochromes Mammalian metabolism follows a regular 24-hour or circadian pattern. The major hormonal circuits, including that of the glucocorticoids, are linked to the circadian clock, but the nature of the linkage is poorly understood. This study shows that two clock co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent manner to influence gene expression and normal metabolic homeostasis, and thus change the transcriptional response to glucocorticoids. Glucocorticoids are used clinically to suppress inflammation, but their nonspecific mode of action has been linked with various undesirable side effects. Altering the timing of treatment, or combining it with agents that specifically target the cryptochromes, may help to alleviate these side effects. Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling 1 , 2 . However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic–pituitary–adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.

Mice subjected to an aberrant daily light cycle that still maintain the circadian timing system are shown to exhibit increased depression-like behaviours and disruptions in synaptic plasticity and cognitive function. Disrupted light–dark cycles cause depression Disruption of the body's circadian clock by exposure to irregular light cycles can affect sleep–wake patterns and cause sleep deprivation, both of which are often associated with mood alterations and cognitive disruptions. This study in mice shows that irregular light schedules can directly affect mood and cognitive function, independent of sleep and circadian rhythms. The aberrant light effects are dependent on melanopsin-containing retinal ganglion cells, and administration of antidepressant drugs restores learning ability, suggesting that the depressive effect precedes learning impairment. The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep–wake cycles to the correct temporal niche 1 . Changes in day-length, shift-work, and transmeridian travel lead to mood alterations and cognitive function deficits 2 . Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules 2 . Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling. A system employing liquid-handling robotics and an integrated mobile microscope enables the automated culture, sample collection and in situ microscopy imaging of up to ten fluidically coupled organ chips within a standard tissue-culture incubator.

Key Points Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. We have a good conceptual understanding of the cell-autonomous molecular clockwork that regulates the generation of circadian rhythms in gene expression, but there is a lack of a mechanistic understanding of how this molecular feedback loop interacts with the membrane to produce physiological circadian rhythms. A hallmark feature of the SCN population is that these neurons are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Individual SCN neurons exhibit variability in their firing patterns and are best thought of as weakly coupled oscillators. Sets of currents are responsible for this daily rhythm in spontaneous activity. During the day, SCN neurons are much more depolarized than neurons that do not show spontaneous activity. A set of currents (persistent sodium, hyperpolarization-activated, cyclic nucleotide-gated (HCN) and T- and L-type calcium currents) provide the excitatory drive that is necessary for any spontaneously active neurons. The excitatory drive in SCN neurons seems to be relatively constant throughout the daily cycle. Another set of currents translate this excitatory drive into a regular pattern of action potentials. In the SCN, the fast delayed rectifier (FDR) current, subthreshold-operating A-type K + current (I A current) and BK potassium current all seem to play a part in the regulation of spontaneous action potential firing in SCN neurons during the day. The biophysical properties of these currents suggest that these three currents will also be critically involved in determining how SCN neurons respond to synaptic stimulation from other regions. These currents are mostly active during the day. There are currents that hyperpolarize the membrane and thereby underlie the nightly silencing of firing. We know the least about these night-active currents but two-pore domain potassium channels (K2P, TASK and TREK) are the most likely candidates. There is evidence that membrane excitability and/or synaptic transmission may be required for the generation of molecular oscillations in SCN neurons. The hypothesis that dysregulated neural activity and synaptic transmission weakens basal Ca 2+ and cyclic AMP-responsive element (CRE) activity to a level that is insufficient to drive the expression of period ( PER ) or cryptochrome ( CRY ) genes. This evidence is discussed but it is premature to form a conclusion. Certainly, many cell types without electrical activity can generate circadian oscillations. There is strong evidence that membrane excitability can alter clock gene expression. The cellular and molecular mechanisms by which light regulates the expression of PER1 in the SCN have been the subject of much analysis and provide a clear example of how electrical activity can adaptively alter gene expression in this system. Several studies that have explored the impact of mutations in the core clockwork on electrical activity rhythms that are recorded in the SCN have provided strong evidence that the molecular clockwork in the SCN can drive the rhythms in electrical activity. Unfortunately, we can only speculate about the likely mechanisms (rhythmic transcription and translation, ion channel trafficking, and post-translational modifications) by which the molecular clockwork alters membrane properties of SCN neurons. Lastly, evidence is presented that raises the possibility that a decline in neural activity in the SCN may be a crucial mechanism by which ageing and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health. Neurons in the suprachiasmatic nucleus (SCN) show circadian patterns, not only in gene transcription and protein translation but also in neural activity. Christopher Colwell describes the mechanisms that drive the rhythmic firing patterns of SCN neurons, including the contribution of ion channels, and discusses the mutual regulation of neural activity and the molecular clock. Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na + currents, L-type Ca 2+ currents, hyperpolarization-activated currents (I H ), large-conductance Ca 2+ activated K + (BK) currents and fast delayed rectifier (FDR) K + currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.

Environmental temperature cycles are a universal entraining cue for all circadian systems at the organismal level with the exception of homeothermic vertebrates. We report here that resistance to temperature entrainment is a property of the suprachiasmatic nucleus (SCN) network and is not a cell-autonomous property of mammalian clocks. This differential sensitivity to temperature allows the SCN to drive circadian rhythms in body temperature, which can then act as a universal cue for the entrainment of cell-autonomous oscillators throughout the body. Pharmacological experiments show that network interactions in the SCN are required for temperature resistance and that the heat shock pathway is integral to temperature resetting and temperature compensation in mammalian cells. These results suggest that the evolutionarily ancient temperature resetting response can be used in homeothermic animals to enhance internal circadian synchronization.

The human thymus is the site of T‐cell maturation and induction of central tolerance. Hematopoietic stem cell (HSC)‐derived progenitors are recruited to the thymus from the fetal liver during early prenatal development and from bone marrow at later stages and postnatal life. The mechanism by which HSCs are recruited to the thymus is poorly understood in humans, though mouse models have indicated the critical role of thymic stromal cells (TSC). Here, we developed a 3D microfluidic assay based on human cells to model HSC extravasation across the endothelium into the extracellular matrix. We found that the presence of human TSC consisting of cultured thymic epithelial cells (TEC) and interstitial cells (TIC) increases the HSC extravasation rates by 3‐fold. Strikingly, incorporating TEC or TIC alone is insufficient to perturb HSC extravasation rates. Furthermore, we identified complex gene expressions from interactions between endothelial cells, TEC and TIC modulates the HSCs extravasation. Our results suggest that comprehensive signaling from the complex thymic microenvironment is crucial for thymus seeding and that our system will allow manipulation of these signals with the potential to increase thymocyte migration in a therapeutic setting.

The interrelationship between circadian and sleep rhythm abnormalities and neurological disease has long been recognized. Foster and colleagues now provide a conceptual framework regarding common mechanisms of neurological disease and circadian and sleep physiology, and propose new approaches for the treatment of neuropsychiatric and neurodegenerative diseases. Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep–wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of — and permit early intervention of — psychiatric and neurodegenerative disease.