Cell division and differentiation depend on massive and rapid organelle remodeling. The mitotic oscillator, centered on the cyclin-dependent kinase 1–anaphase-promoting complex/cyclosome (CDK1-APC/C) axis, spatiotemporally coordinates this reorganization in dividing cells. Here we discovered that nondividing cells could also implement this mitotic clocklike regulatory circuit to orchestrate subcellular reorganization associated with differentiation. We probed centriole amplification in differentiating mouse-brain multiciliated cells. These postmitotic progenitors fine-tuned mitotic oscillator activity to drive the orderly progression of centriole production, maturation, and motile ciliation while avoiding the mitosis commitment threshold. Insufficient CDK1 activity hindered differentiation, whereas excessive activity accelerated differentiation yet drove postmitotic progenitors into mitosis. Thus, postmitotic cells can redeploy and calibrate the mitotic oscillator to uncouple cytoplasmic from nuclear dynamics for organelle remodeling associated with differentiation.

The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are in rapid exchange with those in the cytosol. Loss of lysosomal acidification through inhibition of the vacuolar H⁺–adenosine triphosphatase (V-ATPase) increased the luminal concentrations of most metabolites but had no effect on those of the majority of essential amino acids. Instead, nutrient starvation regulates the lysosomal concentrations of these amino acids, an effect we traced to regulation of the mechanistic target of rapamycin (mTOR) pathway. Inhibition of mTOR strongly reduced the lysosomal efflux of most essential amino acids, converting the lysosome into a cellular depot for them. These results reveal the dynamic nature of lysosomal metabolites and that V-ATPase- and mTOR-dependent mechanisms exist for controlling lysosomal amino acid efflux.

mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

De la Cruz et al. question the reliability of our results, claiming that we do not refer to the most appropriate spatial extent of drylands. In our response, we explain why we chose an existing and internationally recognized delineation of drylands among several options, and why our findings are due to a difference of remote sensing technique and not to the definition of drylands we have selected.

We present an atomic model of a substrate-bound inner mitochondrial membrane AAA+ quality control protease in yeast, YME1. Our ~3.4-angstrom cryo–electron microscopy structure reveals how the adenosine triphosphatases (ATPases) form a closed spiral staircase encircling an unfolded substrate, directing it toward the flat, symmetric protease ring. Three coexisting nucleotide states allosterically induce distinct positioning of tyrosines in the central channel, resulting in substrate engagement and translocation to the negatively charged proteolytic chamber. This tight coordination by a network of conserved residues defines a sequential, around-the-ring adenosine triphosphate hydrolysis cycle that results in stepwise substrate translocation. A hingelike linker accommodates the large-scale nucleotide-driven motions of the ATPase spiral relative to the planar proteolytic base. The translocation mechanism is likely conserved for other AAA+ ATPases.

The mammalian neocortex contains many cell types, but whether they organize into repeated structures has been unclear. We discovered that major cell types in neocortical layer 5 form a lattice structure in many brain areas. Large-scale three-dimensional imaging revealed that distinct types of excitatory and inhibitory neurons form cell type–specific radial clusters termed microcolumns. Thousands of microcolumns, in turn, are patterned into a hexagonal mosaic tessellating diverse regions of the neocortex. Microcolumn neurons demonstrate synchronized in vivo activity and visual responses with similar orientation preference and ocular dominance. In early postnatal development, microcolumns are coupled by cell type–specific gap junctions and later serve as hubs for convergent synaptic inputs. Thus, layer 5 neurons organize into a brainwide modular system, providing a template for cortical processing.

Insects and mammals share similarities of neural organization underlying the perception of odors, taste, vision, sound, and gravity. We observed that insect somatosensation also corresponds to that of mammals. In Drosophila, the projections of all the somatosensory neuron types to the insect’s equivalent of the spinal cord segregated into modality-specific layers comparable to those in mammals. Some sensory neurons innervate the ventral brain directly to form modality-specific and topological somatosensory maps. Ascending interneurons with dendrites in matching layers of the nerve cord send axons that converge to respective brain regions. Pathways arising from leg somatosensory neurons encode distinct qualities of leg movement information and play different roles in ground detection. Establishment of the ground pattern and genetic tools for neuronal manipulation should provide the basis for elucidating the mechanisms underlying somatosensation.

Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)–mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (Ca²⁺) uptake by mitochondria after synaptically induced Ca²⁺-release from ER and thereby regulated cytoplasmic Ca²⁺ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic Ca²⁺ dynamics in mammalian neurons.

Plasmonics provides a possible route to overcome both the speed limitations of electronics and the critical dimensions of photonics. We present an all-plasmonic 116–gigabits per second electro-optical modulator in which all the elements—the vertical grating couplers, splitters, polarization rotators, and active section with phase shifters—are included in a single metal layer. The device can be realized on any smooth substrate surface and operates with low energy consumption. Our results show that plasmonics is indeed a viable path to an ultracompact, highest-speed, and low-cost technology that might find many applications in a wide range of fields of sensing and communications because it is compatible with and can be placed on a wide variety of materials.

Although stereochemistry has been a central focus of the molecular sciences since Pasteur, its province has previously been restricted to the nanometric scale. We have programmed the self-assembly of micron-sized colloidal clusters with structural information stemming from a nanometric arrangement. This was done by combining DNA nanotechnology with colloidal science. Using the functional flexibility of DNA origami in conjunction with the structural rigidity of colloidal particles, we demonstrate the parallel self-assembly of three-dimensional microconstructs, evincing highly specific geometry that includes control over position, dihedral angles, and cluster chirality.

Resonant cavities are essential building blocks governing many wave-based phenomena, but their geometry and reciprocity fundamentally limit the integration of optical devices. We report, at telecommunication wavelengths, geometry-independent and integrated nonreciprocal topological cavities that couple stimulated emission from one-way photonic edge states to a selected waveguide output with an isolation ratio in excess of 10 decibels. Nonreciprocity originates from unidirectional edge states at the boundary between photonic structures with distinct topological invariants. Our experimental demonstration of lasing from topological cavities provides the opportunity to develop complex topological circuitry of arbitrary geometries for the integrated and robust generation and transport of photons in classical and quantum regimes.

The irradiation of gold nanorod colloids with a femtosecond laser can be tuned to induce controlled nanorod reshaping, yielding colloids with exceptionally narrow localized surface plasmon resonance bands. The process relies on a regime characterized by a gentle multishot reduction of the aspect ratio, whereas the rod shape and volume are barely affected. Successful reshaping can only occur within a narrow window of the heat dissipation rate: Low cooling rates lead to drastic morphological changes, and fast cooling has nearly no effect. Hence, a delicate balance must be achieved between irradiation fluence and surface density of the surfactant on the nanorods. This perfection process is appealing because it provides a simple, fast, reproducible, and scalable route toward gold nanorods with an optical response of exceptional quality, near the theoretical limit.

Ultracold molecules represent a fascinating research frontier in physics and chemistry, but it has proven challenging to prepare dense samples at low velocities. Here, we present a solution to this goal by means of a nonconventional approach dubbed cryofuge. It uses centrifugal force to bring cryogenically cooled molecules to kinetic energies below 1 K x k_B in the laboratory frame, where k_B is the Boltzmann constant, with corresponding fluxes exceeding 10¹⁰ per second at velocities below 20 meters per second. By attaining densities higher than 10⁹ per cubic centimeter and interaction times longer than 25 milliseconds in samples of fluoromethane as well as deuterated ammonia, we observed cold dipolar collisions between molecules and determined their collision cross sections.

The distinct Landau level spectrum of bilayer graphene (BLG) is predicted to support a non-abelian even-denominator fractional quantum Hall (FQH) state similar to the 52 state first identified in GaAs. However, the nature of this state has remained difficult to characterize. Here, we report transport measurements of a robust sequence of even-denominator FQH in dual-gated BLG devices. Parallel field measurement confirms the spin-polarized nature of the ground state, which is consistent with the Pfaffian/anti-Pfaffian description. The sensitivity of the even-denominator states to both filling fraction and transverse displacement field provides new opportunities for tunability. Our results suggest that BLG is a platform in which topological ground states with possible non-abelian excitations can be manipulated and controlled.

Southern Africa is consistently placed as a potential region for the evolution of Homo sapiens. We present genome sequences, up to 13x coverage, from seven ancient individuals from KwaZulu-Natal, South Africa. The remains of three Stone Age hunter-gatherers (about 2000 years old) were genetically similar to current-day southern San groups, and those of four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. We estimate that all modern-day Khoe-San groups have been influenced by 9 to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, we estimate the first modern human population divergence time to between 350,000 and 260,000 years ago. This estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.

To date, the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50,000 years ago from Vindija Cave, Croatia, to ~30-fold genomic coverage. She carried 1.6 differences per 10,000 base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10 to 20% more Neandertal DNA to be identified in present-day humans, including variants involved in low-density lipoprotein cholesterol concentrations, schizophrenia, and other diseases.

Present-day hunter-gatherers (HGs) live in multilevel social groups essential to sustain a population structure characterized by limited levels of within-band relatedness and inbreeding. When these wider social networks evolved among HGs is unknown. To investigate whether the contemporary HG strategy was already present in the Upper Paleolithic, we used complete genome sequences from Sunghir, a site dated to ~34,000 years before the present, containing multiple anatomically modern human individuals. We show that individuals at Sunghir derive from a population of small effective size, with limited kinship and levels of inbreeding similar to HG populations. Our findings suggest that Upper Paleolithic social organization was similar to that of living HGs, with limited relatedness within residential groups embedded in a larger mating network.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.

Condensin plays crucial roles in chromosome organization and compaction, but the mechanistic basis for its functions remains obscure. We used single-molecule imaging to demonstrate that Saccharomyces cerevisiae condensin is a molecular motor capable of adenosine triphosphate hydrolysis–dependent translocation along double-stranded DNA. Condensin’s translocation activity is rapid and highly processive, with individual complexes traveling an average distance of ≥10 kilobases at a velocity of ~60 base pairs per second. Our results suggest that condensin may take steps comparable in length to its ~50-nanometer coiled-coil subunits, indicative of a translocation mechanism that is distinct from any reported for a DNA motor protein. The finding that condensin is a mechanochemical motor has important implications for understanding the mechanisms of chromosome organization and condensation.

Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA–specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.

Our planet is an increasingly urbanized landscape, with over half of the human population residing in cities. Despite advances in urban ecology, we do not adequately understand how urbanization affects the evolution of organisms, nor how this evolution may affect ecosystems and human health. Here, we review evidence for the effects of urbanization on the evolution of microbes, plants, and animals that inhabit cities. Urbanization affects adaptive and nonadaptive evolutionary processes that shape the genetic diversity within and between populations. Rapid adaptation has facilitated the success of some native species in urban areas, but it has also allowed human pests and disease to spread more rapidly. The nascent field of urban evolution brings together efforts to understand evolution in response to environmental change while developing new hypotheses concerning adaptation to urban infrastructure and human socioeconomic activity. The next generation of research on urban evolution will provide critical insight into the importance of evolution for sustainable interactions between humans and our city environments.

Bastin et al. (Reports, 12 May 2017, p. 635) claim to have discovered 467 million hectares of new dryland forest. We would argue that these additional areas are not completely "new" and that some have been reported before. A second shortcoming is that not all sources of uncertainty are considered; the uncertainty could be much higher than the reported value of 3.5%.

The neuroscience field is steaming ahead, fueled by a revolution in cutting-edge technologies. Concurrently, another revolution has been underway—the diversity of species utilized for neuroscience research is sharply declining, as the field converges on a few selected model organisms. Here, from the perspective of a young scientist, I naively ask: Is the great diversity of questions in neuroscience best studied in only a handful of animal models? I review some of the limitations the field is facing following this convergence and how these can be rectified by increasing the diversity of appropriate model species. I propose that at this exciting time of revolution in genetics and device technologies, neuroscience might be ready to diversify again, if provided the appropriate support.

New technologies in neuroscience generate reams of data at an exponentially increasing rate, spurring the design of very-large-scale data-mining initiatives. Several supranational ventures are contemplating the possibility of achieving, within the next decade(s), full simulation of the human brain.

During evolution, the prefrontal region grew in size relative to the rest of the cortex. It reached its largest extent in the human brain, where it constitutes 30% of the total cortical area. This growth was accompanied by phylogenetic differentiation of the cortical areas. It has been argued that the human brain holds prefrontal regions that are both qualitatively and functionally unique. Present-day neuroscientists studying the prefrontal cortex increasingly use mice. An important goal is to reveal how the prefrontal cortex enables complex behavior. However, the prefrontal cortex still lacks a conclusive definition. The structure and function of this brain area across species remain unresolved. This state of affairs is often overlooked, warranting renewed focus on what the prefrontal cortex is and does.

Nothing is more intuitive, yet more complex, than the concepts of space and time. In contrast to spacetime in physics, space and time in neuroscience remain separate coordinates to which we attach our observations. Investigators of navigation and memory relate neuronal activity to position, distance, time point, and duration and compare these parameters to units of measuring instruments. Although spatial-temporal sequences of brain activity often correlate with distance and duration measures, these correlations may not correspond to neuronal representations of space or time. Neither instruments nor brains sense space or time. Neuronal activity can be described as a succession of events without resorting to the concepts of space or time. Instead of searching for brain representations of our preconceived ideas, we suggest investigating how brain mechanisms give rise to inferential, model-building explanations.

The controversial question of whether machines may ever be conscious must be based on a careful consideration of how consciousness arises in the only physical system that undoubtedly possesses it: the human brain. We suggest that the word "consciousness" conflates two different types of information-processing computations in the brain: the selection of information for global broadcasting, thus making it flexibly available for computation and report (C1, consciousness in the first sense), and the self-monitoring of those computations, leading to a subjective sense of certainty or error (C2, consciousness in the second sense). We argue that despite their recent successes, current machines are still mostly implementing computations that reflect unconscious processing (C0) in the human brain. We review the psychological and neural science of unconscious (C0) and conscious computations (C1 and C2) and outline how they may inspire novel machine architectures.

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

Materials often exhibit a trade-off between stiffness and extensibility; for example, strengthening elastomers by increasing their cross-link density leads to embrittlement and decreased toughness. Inspired by cuticles of marine mussel byssi, we circumvent this inherent trade-off by incorporating sacrificial, reversible iron-catechol cross-links into a dry, loosely cross-linked epoxy network. The iron-containing network exhibits two to three orders of magnitude increases in stiffness, tensile strength, and tensile toughness compared to its iron-free precursor while gaining recoverable hysteretic energy dissipation and maintaining its original extensibility. Compared to previous realizations of this chemistry in hydrogels, the dry nature of the network enables larger property enhancement owing to the cooperative effects of both the increased cross-link density given by the reversible iron-catecholate complexes and the chain-restricting ionomeric nanodomains that they form.