Ocular light drives a range of nonvisual responses in humans including suppression of melatonin secretion and circadian phase resetting. These responses are driven by intrinsically photosensitive ...retinal ganglion cells (ipRGCs) which combine intrinsic, melanopsin‐based, phototransduction with extrinsic rod/cone‐mediated signals. As a result of this arrangement, it has remained unclear how best to quantify light to predict its nonvisual effects. To address this, we analysed data from nineteen different laboratory studies that measured melatonin suppression, circadian phase resetting and/or alerting responses in humans to a wide array of stimulus types, intensities and durations with or without pupil dilation. Using newly established SI‐compliant metrics to quantify ipRGC‐influenced responses to light, we show that melanopic illuminance consistently provides the best available predictor for responses of the human circadian system. In almost all cases, melanopic illuminance is able to fully account for differences in sensitivity to stimuli of varying spectral composition, acting to drive responses that track variations in illumination characteristic of those encountered over civil twilight (~1‐1000 lux melanopic equivalent daylight illuminance). Collectively, our data demonstrate widespread utility of melanopic illuminance as a metric for predicting the circadian impact of environmental illumination. These data therefore provide strong support for the use of melanopic illuminance as the basis for guidelines that seek to regulate light exposure to benefit human health and to inform future lighting design.
This paper introduces a new empirical model for the rotational evolution of Sun-like stars-those with surface convection zones and non-convective interior regions. Previous models do not match the ...morphology of observed (rotation period)-color diagrams, notably the existence of a relatively long-lived "C-sequence" of fast rotators first identified by Barnes. This failure motivates the Metastable Dynamo Model (MDM) described here. The MDM posits that stars are born with their magnetic dynamos operating in a mode that couples very weakly to the stellar wind, so their (initially very short) rotation periods at first change little with time. At some point, this mode spontaneously and randomly changes to a strongly coupled mode, the transition occurring with a mass-dependent lifetime that is of the order of 100 Myr. I show that with this assumption, one can obtain good fits to observations of young clusters, particularly for ages of 150-200 Myr. Previous models and the MDM both give qualitative agreement with the morphology of the slower-rotating "I-sequence" stars, but none of them have been shown to accurately reproduce the stellar-mass-dependent evolution of the I-sequence stars, especially for clusters older than a few hundred million years. I discuss observational experiments that can test aspects of the MDM, and speculate that the physics underlying the MDM may be related to other situations described in the literature, in which stellar dynamos may have a multi-modal character.
Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over ...the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information. In this Review, I summarise these important recent advances, present hypotheses as to the functions and neural origins of these sensory signals, highlight key challenges for future research and discuss the implications of our current knowledge for animals and humans in the modern world.
A key task for the visual system is to combine spatially overlapping representations of the environment, viewed by either eye, into a coherent image. In cats and primates, this is accomplished in the ...cortex 1, with retinal outputs maintained as separate monocular maps en route through the lateral geniculate nucleus (LGN). While this arrangement is also believed to apply to rodents 2, 3, this has not been functionally confirmed. Accordingly, here we used multielectrode recordings to survey eye-specific visual responses across the mouse LGN. Surprisingly, while we find that regions of space visible to both eyes do indeed form part of a monocular representation of the contralateral visual field, we find no evidence for a corresponding ipsilateral representation. Instead, we find many cells that can be driven via either eye. These inputs combine to enhance the detection of weak stimuli, forming a binocular representation of frontal visual space. This extensive thalamic integration marks a fundamental distinction in mechanisms of binocular processing between mice and other mammals.
•The mouse LGN contains a binocular representation of frontal visual space•Uncrossed retinal projections do not support exclusively monocular representations•Nonlinear integration of binocular inputs enhances contrast detection
In cats and primates, binocular integration begins in the visual cortex. Howarth et al. show that in mice, eye-specific inputs are already extensively integrated by the level of the visual thalamus. This integration specifically enhances responses to weak stimuli within the frontal visual field.
Asteroseismology probes the internal structures of stars by using their natural pulsation frequencies
. It relies on identifying sequences of pulsation modes that can be compared with theoretical ...models, which has been done successfully for many classes of pulsators, including low-mass solar-type stars
, red giants
, high-mass stars
and white dwarfs
. However, a large group of pulsating stars of intermediate mass-the so-called δ Scuti stars-have rich pulsation spectra for which systematic mode identification has not hitherto been possible
. This arises because only a seemingly random subset of possible modes are excited and because rapid rotation tends to spoil regular patterns
. Here we report the detection of remarkably regular sequences of high-frequency pulsation modes in 60 intermediate-mass main-sequence stars, which enables definitive mode identification. The space motions of some of these stars indicate that they are members of known associations of young stars, as confirmed by modelling of their pulsation spectra.
Ocular light exposure has important influences on human health and well-being through modulation of circadian rhythms and sleep, as well as neuroendocrine and cognitive functions. Prevailing patterns ...of light exposure do not optimally engage these actions for many individuals, but advances in our understanding of the underpinning mechanisms and emerging lighting technologies now present opportunities to adjust lighting to promote optimal physical and mental health and performance. A newly developed, international standard provides a SI-compliant way of quantifying the influence of light on the intrinsically photosensitive, melanopsin-expressing, retinal neurons that mediate these effects. The present report provides recommendations for lighting, based on an expert scientific consensus and expressed in an easily measured quantity (melanopic equivalent daylight illuminance (melaponic EDI)) defined within this standard. The recommendations are supported by detailed analysis of the sensitivity of human circadian, neuroendocrine, and alerting responses to ocular light and provide a straightforward framework to inform lighting design and practice.
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and fourth leading cause of cancer-related death worldwide. Recent advances in systemic and locoregional therapies have led to ...changes in many guidelines regarding systemic therapy, as well as the possibility to downstage patients to undergo resection. This review examines the advances in surgical and medical therapies relative to multidisciplinary treatment strategies for HCC.
HCC is a major health problem worldwide. The obesity epidemic has made nonalcoholic fatty liver disease a major risk factor for the development of HCC. Multiple societies, such as the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of the Liver, and the National Comprehensive Cancer Network, provide guidelines for screening at-risk patients, as well as define staging systems to guide optimal treatment strategies. The Barcelona Clinic Liver Cancer staging system is widely accepted and has recently undergone updates with the introduction of new systemic therapies and stage migration.
The treatment of patients with HCC should involve a multidisciplinary approach with collaboration among surgeons, medical oncologists, radiation oncologists, and interventional radiologists to provide optimal care. Treatment paradigms must consider both tumor and patient-related factors such as extent of liver disease, which is a main driver of morbidity and mortality. The advent of more effective systemic and locoregional therapies has prolonged survival among patients with advanced disease and allowed some patients to undergo surgical intervention who would otherwise have disease considered unresectable.
Photoreception in the mammalian retina is not restricted to rods and cones but extends to a small number of intrinsically photoreceptive retinal ganglion cells (ipRGCs), expressing the photopigment ...melanopsin 1–4. ipRGCs are known to support various accessory visual functions including circadian photoentrainment and pupillary reflexes. However, despite anatomical and physiological evidence that they contribute to the thalamocortical visual projection 5–7, no aspect of visual discrimination has been shown to rely upon ipRGCs. Based on their currently known roles, we hypothesized that ipRGCs may contribute to distinguishing brightness. This percept is related to an object's luminance—a photometric measure of light intensity relevant for cone photoreceptors. However, the perceived brightness of different sources is not always predicted by their respective luminance 8–12. Here, we used parallel behavioral and electrophysiological experiments to first show that melanopsin contributes to brightness discrimination in both retinally degenerate and fully sighted mice. We continued to use comparable paradigms in psychophysical experiments to provide evidence for a similar role in healthy human subjects. These data represent the first direct evidence that an aspect of visual discrimination in normally sighted subjects can be supported by inner retinal photoreceptors.
► Melanopsin photoreception can be selectively modulated in an intact retina ► Melanopsin supports brightness discrimination in retinal degenerate and intact mice ► Melanopsin activation induces brightness percepts in healthy humans
Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction ...program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway.
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