Autophagy maintains stemness by preventing senescenceGarcía-Prat, Laura; Martínez-Vicente, Marta; Perdiguero, Eusebio; Ortet, Laura; Rodríguez-Ubreva, Javier; Rebollo, Elena; Ruiz-Bonilla, Vanessa; Gutarra, Susana; Ballestar, Esteban; Serrano, Antonio L.; Sandri, Marco; Muñoz-Cánoves, Pura
doi: 10.1038/nature19415pmid: N/A
During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
Large anomalous Hall effect in a non-collinear antiferromagnet at room temperatureNakatsuji, S.; Kiyohara, N.; Higo, T.
doi: 10.1038/nature19416pmid: N/A
In ferromagnetic conductors, an electric current may induce a transverse voltage drop in zero applied magnetic field: this anomalous Hall effect is observed to be proportional to magnetization, and thus is not usually seen in antiferromagnets in zero field. Recent developments in theory and experiment have provided a framework for understanding the anomalous Hall effect using Berry-phase concepts, and this perspective has led to predictions that, under certain conditions, a large anomalous Hall effect may appear in spin liquids and antiferromagnets without net spin magnetization. Although such a spontaneous Hall effect has now been observed in a spin liquid state, a zero-field anomalous Hall effect has hitherto not been reported for antiferromagnets. Here we report empirical evidence for a large anomalous Hall effect in an antiferromagnet that has vanishingly small magnetization. In particular, we find that Mn3Sn, an antiferromagnet that has a non-collinear 120-degree spin order, exhibits a large anomalous Hall conductivity of around 20 per ohm per centimetre at room temperature and more than 100 per ohm per centimetre at low temperatures, reaching the same order of magnitude as in ferromagnetic metals. Notably, the chiral antiferromagnetic state has a very weak and soft ferromagnetic moment of about 0.002 Bohr magnetons per Mn atom, allowing us to switch the sign of the Hall effect with a small magnetic field of around a few hundred oersted. This soft response of the large anomalous Hall effect could be useful for various applications including spintronics—for example, to develop a memory device that produces almost no perturbing stray fields.
DNA-dependent formation of transcription factor pairs alters their binding specificityJolma, Arttu; Yin, Yimeng; Nitta, Kazuhiro R.; Dave, Kashyap; Popov, Alexander; Taipale, Minna; Enge, Martin; Kivioja, Teemu; Morgunova, Ekaterina; Taipale, Jussi
doi: 10.1038/nature18912pmid: N/A
Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs. Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs. However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF–TF–DNA interactions. This analysis revealed 315 TF–TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.
Controlling many-body states by the electric-field effect in a two-dimensional materialLi, L. J.; O'Farrell, E. C. T.; Loh, K. P.; Eda, G.; Özyilmaz, B.; Neto, A. H. Castro
doi: 10.1038/nature18453pmid: N/A
To understand the complex physics of a system with strong electron–electron interactions, the ideal is to control and monitor its properties while tuning an external electric field applied to the system (the electric-field effect). Indeed, complete electric-field control of many-body states in strongly correlated electron systems is fundamental to the next generation of condensed matter research and devices. However, the material must be thin enough to avoid shielding of the electric field in the bulk material. Two-dimensional materials do not experience electrical screening, and their charge-carrier density can be controlled by gating. Octahedral titanium diselenide (1T-TiSe2) is a prototypical two-dimensional material that reveals a charge-density wave (CDW) and superconductivity in its phase diagram, presenting several similarities with other layered systems such as copper oxides, iron pnictides, and crystals of rare-earth elements and actinide atoms. By studying 1T-TiSe2 single crystals with thicknesses of 10 nanometres or less, encapsulated in two-dimensional layers of hexagonal boron nitride, we achieve unprecedented control over the CDW transition temperature (tuned from 170 kelvin to 40 kelvin), and over the superconductivity transition temperature (tuned from a quantum critical point at 0 kelvin up to 3 kelvin). Electrically driving TiSe2 over different ordered electronic phases allows us to study the details of the phase transitions between many-body states. Observations of periodic oscillations of magnetoresistance induced by the Little–Parks effect show that the appearance of superconductivity is directly correlated with the spatial texturing of the amplitude and phase of the superconductivity order parameter, corresponding to a two-dimensional matrix of superconductivity. We infer that this superconductivity matrix is supported by a matrix of incommensurate CDW states embedded in the commensurate CDW states. Our results show that spatially modulated electronic states are fundamental to the appearance of two-dimensional superconductivity.
Foreign DNA capture during CRISPR–Cas adaptive immunityNuñez, James K.; Harrington, Lucas B.; Kranzusch, Philip J.; Engelman, Alan N.; Doudna, Jennifer A.
doi: 10.1038/nature18911pmid: N/A
Bacteria and archaea generate adaptive immunity against phages and plasmids by integrating foreign DNA of specific 30–40-base-pair lengths into clustered regularly interspaced short palindromic repeat (CRISPR) loci as spacer segments. The universally conserved Cas1–Cas2 integrase complex catalyses spacer acquisition using a direct nucleophilic integration mechanism similar to retroviral integrases and transposases. How the Cas1–Cas2 complex selects foreign DNA substrates for integration remains unknown. Here we present X-ray crystal structures of the Escherichia coli Cas1–Cas2 complex bound to cognate 33-nucleotide protospacer DNA substrates. The protein complex creates a curved binding surface spanning the length of the DNA and splays the ends of the protospacer to allow each terminal nucleophilic 3'-OH to enter a channel leading into the Cas1 active sites. Phosphodiester backbone interactions between the protospacer and the proteins explain the sequence-nonspecific substrate selection observed in vivo. Our results uncover the structural basis for foreign DNA capture and the mechanism by which Cas1–Cas2 functions as a molecular ruler to dictate the sequence architecture of CRISPR loci.
A comprehensive phylogeny of birds (Aves) using targeted next-generation DNA sequencingPrum, Richard O.; Berv, Jacob S.; Dornburg, Alex; Field, Daniel J.; Townsend, Jeffrey P.; Lemmon, Emily Moriarty; Lemmon, Alan R.
doi: 10.1038/nature19417pmid: N/A
Although reconstruction of the phylogeny of living birds has progressed tremendously in the last decade, the evolutionary history of Neoaves—a clade that encompasses nearly all living bird species—remains the greatest unresolved challenge in dinosaur systematics. Here we investigate avian phylogeny with an unprecedented scale of data: >390,000 bases of genomic sequence data from each of 198 species of living birds, representing all major avian lineages, and two crocodilian outgroups. Sequence data were collected using anchored hybrid enrichment, yielding 259 nuclear loci with an average length of 1,523 bases for a total data set of over 7.8 × 107 bases. Bayesian and maximum likelihood analyses yielded highly supported and nearly identical phylogenetic trees for all major avian lineages. Five major clades form successive sister groups to the rest of Neoaves: (1) a clade including nightjars, other caprimulgiforms, swifts, and hummingbirds; (2) a clade uniting cuckoos, bustards, and turacos with pigeons, mesites, and sandgrouse; (3) cranes and their relatives; (4) a comprehensive waterbird clade, including all diving, wading, and shorebirds; and (5) a comprehensive landbird clade with the enigmatic hoatzin (Opisthocomus hoazin) as the sister group to the rest. Neither of the two main, recently proposed Neoavian clades—Columbea and Passerea—were supported as monophyletic. The results of our divergence time analyses are congruent with the palaeontological record, supporting a major radiation of crown birds in the wake of the Cretaceous–Palaeogene (K–Pg) mass extinction.
Critical insolation-CO2 relation for diagnosing past and future glacial inceptionGanopolski, Andrey; Winkelmann, Ricarda; Schellnhuber, Hans Joachim
doi: 10.1038/nature18452pmid: N/A
The past rapid growth of Northern Hemisphere continental ice sheets, which terminated warm and stable climate periods, is generally attributed to reduced summer insolation in boreal latitudes. Yet such summer insolation is near to its minimum at present, and there are no signs of a new ice age. This challenges our understanding of the mechanisms driving glacial cycles and our ability to predict the next glacial inception. Here we propose a critical functional relationship between boreal summer insolation and global carbon dioxide (CO2) concentration, which explains the beginning of the past eight glacial cycles and might anticipate future periods of glacial inception. Using an ensemble of simulations generated by an Earth system model of intermediate complexity constrained by palaeoclimatic data, we suggest that glacial inception was narrowly missed before the beginning of the Industrial Revolution. The missed inception can be accounted for by the combined effect of relatively high late-Holocene CO2 concentrations and the low orbital eccentricity of the Earth. Additionally, our analysis suggests that even in the absence of human perturbations no substantial build-up of ice sheets would occur within the next several thousand years and that the current interglacial would probably last for another 50,000 years. However, moderate anthropogenic cumulative CO2 emissions of 1,000 to 1,500 gigatonnes of carbon will postpone the next glacial inception by at least 100,000 years. Our simulations demonstrate that under natural conditions alone the Earth system would be expected to remain in the present delicately balanced interglacial climate state, steering clear of both large-scale glaciation of the Northern Hemisphere and its complete deglaciation, for an unusually long time.