资源环境科技发展态势分析平台

Massive disk galaxies like the Milky Way are expected to form at late times in traditional models of galaxy formation(1,2), but recent numerical simulations suggest that such galaxies could form as early as a billion years after the Big Bang through the accretion of cold material and mergers(3,4). Observationally, it has been difficult to identify disk galaxies in emission at high redshift(5,6) in order to discern between competing models of galaxy formation. Here we report imaging, with a resolution of about 1.3 kiloparsecs, of the 158-micrometre emission line from singly ionized carbon, the far-infrared dust continuum and the near-ultraviolet continuum emission from a galaxy at a redshift of 4.2603, identified by detecting its absorption of quasar light. These observations show that the emission arises from gas inside a cold, dusty, rotating disk with a rotational velocity of about 272 kilometres per second. The detection of emission from carbon monoxide in the galaxy yields a molecular mass that is consistent with the estimate from the ionized carbon emission of about 72 billion solar masses. The existence of such a massive, rotationally supported, cold disk galaxy when the Universe was only 1.5 billion years old favours formation through either cold-mode accretion or mergers, although its large rotational velocity and large content of cold gas remain challenging to reproduce with most numerical simulations(7,8).

A massive rotating disk galaxy was formed a mere 1.5 billion years after the Big Bang, a surprisingly short time after the origin of the Universe.

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. 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 MT1-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 MT1 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 MT1 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 MT1-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 MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-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 MT1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.

The transverse tarsal arch, acting through the inter-metatarsal tissues, is important for the longitudinal stiffness of the foot and its appearance is a key step in the evolution of human bipedalism.

The stiff human foot enables an efficient push-off when walking or running, and was critical for the evolution of bipedalism(1-6). The uniquely arched morphology of the human midfoot is thought to stiffen it(5-9), whereas other primates have flat feet that bend severely in the midfoot(7,10,11). However, the relationship between midfoot geometry and stiffness remains debated in foot biomechanics(12,13), podiatry(14,15) and palaeontology(4-6). These debates centre on the medial longitudinal arch(5,6) and have not considered whether stiffness is affected by the second, transverse tarsal arch of the human foot(16). Here we show that the transverse tarsal arch, acting through the inter-metatarsal tissues, is responsible for more than 40% of the longitudinal stiffness of the foot. The underlying principle resembles a floppy currency note that stiffens considerably when it curls transversally. We derive a dimensionless curvature parameter that governs the stiffness contribution of the transverse tarsal arch, demonstrate its predictive power using mechanical models of the foot and find its skeletal correlate in hominin feet. In the foot, the material properties of the inter-metatarsal tissues and the mobility of the metatarsals may additionally influence the longitudinal stiffness of the foot and thus the curvature-stiffness relationship of the transverse tarsal arch. By analysing fossils, we track the evolution of the curvature parameter among extinct hominins and show that a human-like transverse arch was a key step in the evolution of human bipedalism that predates the genus Homo by at least 1.5 million years. This renewed understanding of the foot may improve the clinical treatment of flatfoot disorders, the design of robotic feet and the study of foot function in locomotion.