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The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT 1 and MT 2 . Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light–dark cycle 1 – 4 . The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep 5 , 6 and depression 1 – 4 , 7 – 9 . Despite their importance, few in vivo active MT 1 -selective ligands have been reported 2 , 8 , 10 – 12 , hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT 1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT 1 inverse agonists—which were topologically unrelated to previously explored chemotypes—that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT 1 -selective inverse agonists advanced the phase of the mouse circadian clock by 1.3–1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT 1 - but not in MT 2 -knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT 1 -selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries. A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT 1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.

Coal mine pollution is a serious threat to the mine safe production and occupational health of miners. Chemical dust suppression can effectively reduce the concentration of coal dust and suppress the re-entrainment of dust. This paper discusses the research progress of three kinds of traditional dust suppressants: the wetting-type, cohesive type, and condensed type. In order to meet dust suppression and environmental protection requirements, 7 kinds of new type dust suppressants, such as compound, ecological environmental protection, polymer, functional, microbes, and enzymes, have been developed by the predecessors. And all kinds of dust suppressant mechanism and main performance index have been summarized. Through the analysis of the research results from 1985 to 2021, it is found that the compound and environment-friendly dust suppressants have gradually become the research focus in this field, accounting for 17.93% and 26.21% of the total number of achievements. In the recent 5 years, new materials, such as microbe suppressant, urease suppressant, and nanomaterials, have gradually emerged. Because of their natural and environmental protection characteristics, it could be predicted that they will become the future development trend in this field. However, there are still some problems to be improved, such as expensive price and complex preparation technology. Graphical Abstract

A substantial fraction of the deep ocean is ventilated in the high-latitude North Atlantic. Consequently, the region plays a crucial role in transient climate change through the uptake of carbon dioxide and heat. However, owing to the Lagrangian nature of the process, many aspects of deep Atlantic Ocean ventilation and its representation in climate simulations remain obscure. We investigate the nature of ventilation in the high-latitude North Atlantic in an eddy-permitting numerical ocean circulation model using a comprehensive set of Lagrangian trajectory experiments. Backward-in-time trajectories from a model-defined North Atlantic Deep Water (NADW) reveal the locations of subduction from the surface mixed layer at high spatial resolution. The major fraction of NADW ventilation results from subduction in the Labrador Sea, predominantly within the boundary current (∼60% of ventilated NADW volume) and a smaller fraction arising from open ocean deep convection (∼25%). Subsurface transformations—due in part to the model’s parameterization of bottom-intensified mixing—facilitate NADW ventilation, such that water subducted in the boundary current ventilates all of NADW, not just the lighter density classes. There is a notable absence of ventilation arising from subduction in the Greenland–Iceland–Norwegian Seas, due to the re-entrainment of those waters as they move southward. Taken together, our results emphasize an important distinction between ventilation and dense water formation in terms of the location where each takes place, and their concurrent sensitivities. These features of NADW ventilation are explored to understand how the representation of high-latitude processes impacts properties of the deep ocean in a state-of-the-science numerical simulation.

The separation dynamics of a sphere released from the surface of a ramp into a hypersonic flow is investigated, focusing on the influence of the ramp boundary layer on the sphere behaviour. First, numerical simulations are conducted of a sphere interacting with an isolated high-speed boundary layer to determine the influence on the sphere force coefficients as the sphere diameter and wall-normal location are varied. It is found that the lift coefficient is strongly affected by the near-wall interactions, becoming increasingly negative as the ratio of the sphere radius to boundary-layer thickness, $r/\\delta$, is decreased. These results are combined with force coefficients derived from simulations of the sphere interacting with the ramp-generated oblique shock to enable numerical predictions of the sphere trajectories for a $10^{\\circ }$ ramp at Mach 6 (using a similar decoupled approach to Part 1 of this work). It is found that the three trajectory types of the inviscid situation – shock surfing, ejection followed by re-entrainment within the shock layer and direct entrainment – also characterize the sphere behaviour here. Their relative prevalence, however, is influenced by the sphere size: for smaller values of $r/\\delta$, direct entrainment dominates because of the wall suction, while shock surfing and then ejection/re-entrainment become increasingly likely at larger values of $r/\\delta$. Increasing the ramp angle and/or the free-stream Mach number reduces the relative influence of the boundary-layer interactions. Finally, experiments are conducted using free-flying spheres released from a ramp surface in a hypersonic shock tunnel, confirming the major trends predicted numerically.

We use idealized large-eddy simulations (LES) and a simple analytical theory to study the influence of submesoscales on the concentration and export of sinking particles from the mixed layer. We find that restratification of the mixed layer following the development of submesoscales reduces the rate of vertical mixing which, in turn, enhances the export rate associated with gravitational settling. For a neutral tracer initially confined to the mixed layer, subinertial (submesoscale) motions enhance the downward tracer flux, consistent with previous studies. However, the sign of the advective flux associated with the concentration of sinking particles reverses, indicating reentrainment into the mixed layer. A new theory is developed to model the gravitational settling flux when the particle concentration is nonuniform. The theory broadly agrees with the LES results and allows us to extend the analysis to a wider range of parameters.

The Cryptochrome 1 (Cry1)—deficient duper mutant hamster has a short free-running period in constant darkness (τDD) and shows large phase shifts in response to brief light pulses. We tested whether this measure of the lability of the circadian phase is a general characteristic of Cry1-null animals and whether it indicates resistance to jet lag. Upon advance of the light:dark (LD) cycle, both duper hamsters and Cry1 -/- mice re-entrained locomotor rhythms three times as fast as wild types. However, accelerated re-entrainment was dissociated from the amplified phase-response curve (PRC): unlike duper hamsters, Cry1 -/- mice show no amplification of the phase response to 15’ light pulses. Neither the amplified acute shifts nor the increased rate of re-entrainment in duper mutants is due to acceleration of the circadian clock: when mutants drank heavy water to lengthen the period, these aspects of the phenotype persisted. In light of the health consequences of circadian misalignment, we examined effects of duper and phase shifts on a hamster model of heart disease previously shown to be aggravated by repeated phase shifts. The mutation shortened the lifespan of cardiomyopathic hamsters relative to wild types, but this effect was eliminated when mutants experienced 8-h phase shifts every second week, to which they rapidly re-entrained. Our results reveal previously unsuspected roles of Cry1 in phase shifting and longevity in the face of heart disease. The duper mutant offers new opportunities to understand the basis of circadian disruption and jet lag.

Aiming to further improve the dust suppression performance of the dust suppressant, the present study independently develops a new type of biodegradable environmentally-friendly dust suppressant. Specifically, the naturally occurring biodegradable soybean protein isolate (SPI) is selected as the main material, which is subject to an anionic surfactant, i.e., sodium dodecyl sulfonate (SDS) for modification with the presence of additives including carboxymethylcellulose sodium and methanesiliconic acid sodium. As a result, the SDS-SPI cementing dust suppressant is produced. The present study experimentally tests solutions with eight different dust suppressant concentrations under the same experimental condition, so as to evaluate their dust suppression performances. Key metrics considered include water retention capability, cementing power and dust suppression efficiency. The optimal concentration of dust suppressant solution is determined by collectively comparing these metrics. The experiments indicate that the optimal dust suppressant concentration is 3%, at which level the newly developed environmentally-friendly dust suppressant solution exhibits a decent dust suppression characteristic, with the water retention power reaching its peak level, and the corresponding viscosity being 12.96 mPa·s. This performance can generally meet the requirements imposed by coal mines. The peak efficiency of dust suppression can reach 92.13%. Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were used to analyze the dust suppression mechanism of the developed dust suppressant. It was observed that a dense hardened shell formed on the surface of the pulverized coal particles sprayed with the dust suppressant. There is strong cementation between coal dust particles, and the cementation effect is better. This can effectively inhibit the re-entrainment of coal dust and reduce environmental pollution.

Visual system function depends upon the elaboration of precise connections between retinal ganglion cell (RGC) axons and their central targets in the brain. Though some progress has been made in defining the molecules that regulate RGC connectivity required for the assembly and function of image-forming circuitry, surprisingly little is known about factors required for intrinsically photosensitive RGCs (ipRGCs) to target a principal component of the non-image-forming circuitry: the suprachiasmatic nucleus (SCN). Furthermore, the molecules required for forming circuits critical for circadian behaviors within the SCN are not known. We observe here that the adhesion molecule teneurin-3 (Tenm3) is highly expressed in vasoactive intestinal peptide (VIP) neurons located in the core region of the SCN. Since Tenm3 is required for other aspects of mammalian visual system development, we investigate roles for Tenm3 in regulating ipRGC-SCN connectivity and function. Our results show that Tenm3 negatively regulates association between VIP and arginine vasopressin (AVP) neurons within the SCN and is essential for M1 ipRGC axon innervation to the SCN. Specifically, in Tenm3 -/- mice, we find a reduction in ventro-medial innervation to the SCN. Despite this reduction, Tenm3 -/- mice have higher sensitivity to light and faster re-entrainment to phase advances, probably due to the increased association between VIP and AVP neurons. These data show that Tenm3 plays key roles in elaborating non-image-forming visual system circuitry and that it influences murine responses to phase-advancing light stimuli.

Numerical simulations are employed to investigate the dynamical separation of an initially stationary sphere from the surface of a two-dimensional ramp in hypersonic flow. We consider the inviscid limit, which is equivalent to assuming the sphere radius to be much larger than the ramp boundary-layer thickness; this assumption allows a range of Mach numbers and ramp angles to be explored efficiently. Of particular interest is determining how the shock-surfing phenomenon discovered by Laurence & Deiterding (J. Fluid Mech., vol. 676, 2011, pp. 396–431), in which a spherical body can stably oscillate about an oblique shock as it moves downstream, manifests itself in such a situation. First, the isolated interactions between a sphere and an oblique shock, and then between a sphere and an inviscid wall, are examined independently to elucidate relevant trends. Full trajectory predictions are subsequently performed using a decoupled model in which the shock and wall interactions are assumed to contribute independently to the aerodynamic forces. Three types of trajectories are found to be possible: surfing of the spherical body; initial expulsion outside the shock layer followed by re-entry and entrainment; or direct entrainment. At relatively low hypersonic Mach numbers, the latter two types of trajectories are predominant, but at higher Mach numbers ($M\\gtrsim 10$), surfing becomes possible over an increasingly wide range of ramp angles and downstream release locations. By reparameterizing the release location as the initial lateral distance of the sphere from the shock, good collapse of the transition boundary delineating surfing from ejection/re-entrainment over various Mach numbers and ramp angles is obtained.

The composition of road dust is influenced by emissions from local industry as well as by traffic emissions. Thus, the composition of urban road dust can be used as an indicator for environmental pollution. Pollutants contained in road dust also are transferred into the atmosphere by resuspension and into the aquatic system by wash-off. In this transfer, the particle size of the road dust particles is of extreme importance. Therefore, information about the composition of road dust in dependence of the particle size is crucial. In this study, road dust samples were separated by air classification into size fractions down to 2 µm. The chemical analysis of the size fractions also revealed a significant size dependence of the metal concentrations in the finest size fractions. The least polluted size fraction was generally the fraction 200–500 µm, whereas the highest concentrations were measured in the finest size fraction < 2 µm. These results are important for the assessment of the mass fraction of the various pollutants in the mobile size fractions in re-entrainment as well as in run-off during rainfall.