Science

Programmable RNA editing enables reversible recoding of RNA information for research and disease treatment. Previously, we developed a programmable A to I RNA editing approach by fusing catalytically inactivated RNA-targeting CRISPR-Cas13 (dCas13) with the adenine deaminase domain of ADAR2. Here, we report a C to U RNA editor, referred to as RNA Editing for Specific C to U Exchange (RESCUE), by directly evolving ADAR2 into a cytidine deaminase. RESCUE doubles the number of pathogenic mutations targetable by RNA editing and enables modulation of phospho-signaling-relevant residues...

In recent years there have been great strides in artificial intelligence (AI), with games often serving as challenge problems, benchmarks, and milestones for progress. Poker has served for decades as such a challenge problem. Past successes in such benchmarks, including poker, have been limited to two-player games. However, poker in particular is traditionally played with more than two players. Multiplayer games present fundamental additional issues beyond those in two-player games, and multiplayer poker is a recognized AI milestone...

The nuclear proteome is rich in stress-sensitive proteins, suggesting that effective protein quality control mechanisms are in place to ensure conformational maintenance. Here we investigated the role of the nucleolus in this process. In mammalian tissue culture cells, under stress conditions misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation...

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals, or tissue-specific deletion in the liver, and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets...

Histone modifications regulate gene expression and development. To address how they are reprogrammed in human early development, we investigated key histone marks in human oocytes and early embryos. Unlike that in mouse, the permissive mark H3K4me3 largely exhibits canonical patterns at promoters in human oocytes. After fertilization, pre-zygotic genome activation (ZGA) embryos acquire permissive chromatin and widespread H3K4me3 in CpG-rich regulatory regions. By contrast, the repressive mark H3K27me3 undergoes global depletion...

Fast Radio Bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Non-repeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single pulse FRB 180924 to a position 4 kpc from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from the only other accurately localized FRB source...

The Cdc48 ATPase (p97 or VCP in mammals) and its cofactor Ufd1/Npl4 extract poly-ubiquitinated proteins from membranes or macromolecular complexes for subsequent degradation by the proteasome. How Cdc48 processes its diverse and often well-folded substrates is unclear. Here, we report cryo-EM structures of the Cdc48 ATPase in complex with Ufd1/Npl4 and poly-ubiquitinated substrate. The structures show that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings...

The cellular machine Cdc48 functions in multiple biological pathways by segregating its protein substrates from a variety of stable environments such as organelles or multi-subunit complexes. Despite extensive studies, the mechanism of Cdc48 has remained obscure, and its reported structures are inconsistent with models of substrate translocation proposed for other AAA+ ATPases. Here, we report a 3.7 Å resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings...

Cerebral blood flow is reduced early in Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors...

Transport coefficients of correlated electron systems are often useful for mapping hidden phases with distinct symmetries. Here we report a transport signature of spontaneous symmetry breaking in the magnetic Weyl semimetal CeAlGe system in the form of singular angular magnetoresistance (SAMR). This angular response exceeding 1000% radian-1 is confined along the high symmetry axes with a full width at half maximum reaching to less than 1° and is tunable via isoelectronic Ge/Si substitution. The SAMR phenomena is explained theoretically as a consequence of controllable high resistance domain walls, arising from the breaking of magnetic point group symmetry strongly coupled to a nearly nodal electronic structure...

Altruism and self-image, not selfishness, drive surprising findings.

Civic honesty is essential to social capital and economic development, but is often in conflict with material self-interest. We examine the trade-off between honesty and self-interest using field experiments in 355 cities spanning 40 countries around the globe. We turned in over 17,000 lost wallets with varying amounts of money at public and private institutions, and measured whether recipients contacted the owner to return the wallets. In virtually all countries citizens were more likely to return wallets that contained more money...

Superconducting proximity pairing in helical edge modes, such as those of topological insulators (TI), is predicted to provide a unique platform for realizing Majorana zero modes (MZMs). We use scanning tunneling microscopy measurements to probe the influence of proximity induced superconductivity and magnetism on the helical hinge states of Bi(111) films, grown on a superconducting Nb substrate and decorated with magnetic Fe clusters. Consistent with model calculations, our measurements reveal the emergence of a localized MZM at the interface between the superconducting helical edge channel and the Fe clusters with strong magnetization component along the edge...

Neural circuits emerge through the interplay of genetic programming and activity-dependent process. During the development of mouse olfactory map, axons segregate into distinct glomeruli in an olfactory receptor (OR)-dependent manner. ORs generate a combinatorial code of axon-sorting molecules, whose expression is regulated by neural activity. However, how neural activity induces OR-specific expression patterns of axon-sorting molecules remains unclear. Here we revealed that the temporal patterns of spontaneous neuronal spikes were not spatially-organized, but were correlated with the OR types...

How food production first entered eastern Africa ~5000 years ago and the extent to which people moved with livestock is unclear. We present genome-wide data from 41 individuals associated with Later Stone Age, Pastoral Neolithic (PN), and Iron Age contexts in what are now Kenya and Tanzania to examine the genetic impacts of the spreads of herding and farming. Our results support a multi-phase model in which admixture between northeastern African-related peoples and eastern African foragers formed multiple pastoralist groups, including a genetically homogeneous PN cluster...

Tight binding and high selectivity are hallmarks of biomolecular recognition. Achieving these behaviors with synthetic receptors has usually been associated with OH and NH hydrogen bonding. Contrary to this conventional wisdom, we designed a chloride-selective receptor in the form of a cryptand-like cage using only CH hydrogen bonding. Crystallography showed chloride stabilized by six short 2.7-Å hydrogen bonds originating from the cage's six 1,2,3-triazoles. Atto-molar affinity (1017 M-1 ) was determined using liquid-liquid extractions of chloride from water into nonpolar dichloromethane solvents...

How coral reefs survive as oases of life in low-productivity oceans has puzzled scientists for centuries. The answer may lie in internal nutrient cycling and/or input from the pelagic zone. Integrating meta-analysis, field data, and population modelling, we show that the ocean's smallest vertebrates, cryptobenthic reef fishes, promote internal reef-fish biomass production through exceptional larval supply from the pelagic environment. Specifically, cryptobenthics account for two-thirds of reef-fish larvae in the near-reef pelagic zone, despite limited adult reproductive outputs...

We introduce the optical ruler, an electromagnetic analog of a physical ruler, for nanoscale displacement metrology. The optical ruler is a complex electromagnetic field in which singularities serve as the marks on the scale. It is created by the diffraction of light on a metasurface, with singularity marks then revealed by high-magnification interferometric observation. Using a Pancharatnam-Berry phase metasurface, we demonstrate a displacement resolving power of better than 1 nm (λ/800) at a wavelength of 800 nm...

G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists compared to when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β1 -adrenoceptor (β1 AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β1 AR bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site...

The mammalian brain's somatosensory cortex is a topographic map of the body's sensory experience. In mice, cortical barrels reflect whisker input. We asked whether these cortical structures require sensory input to develop or are driven by intrinsic activity. Indeed, thalamocortical columns, connecting thalamus to cortex, emerge before sensory input and concur with calcium waves in the embryonic thalamus. We show here that the columnar organization of the thalamocortical somatotopic map exists in the mouse embryo before sensory input, thus linking spontaneous embryonic thalamic activity to somatosensory map formation...