We have performed two-photon ultraviolet direct frequency comb spectroscopy on the 1S-3S transition in atomic hydrogen to illuminate the so-called proton radius puzzle and to demonstrate the potential of this method. The proton radius puzzle is a significant discrepancy between data obtained with muonic hydrogen and regular atomic hydrogen that could not be explained within the framework of quantum

Changes in the growing-season lengths of temperate trees greatly affect biotic interactions and global carbon balance. Yet future growing-season trajectories remain highly uncertain because the environmental drivers of autumn leaf senescence are poorly understood. Using experiments and long-term observations, we show that increases in spring and summer productivity due to elevated carbon dioxide, temperature

Since the discovery of roaming as an alternative molecular dissociation pathway in formaldehyde (H2CO), it has been indirectly observed in numerous molecules. The phenomenon describes a frustrated dissociation with fragments roaming at relatively large interatomic distances rather than following conventional transition-state dissociation; incipient radicals from the parent molecule self-react to form

Branch-point singularities known as exceptional points (EPs), which carry a nonzero topological charge, can emerge in non-Hermitian systems. We demonstrate with both theory and acoustic experiments an “exceptional nexus” (EX), which is not only a higher-order EP but also the cusp singularity of multiple exceptional arcs (EAs). Because the parameter space is segmented by the EAs, the EX possesses a

Laser powder bed fusion is a dominant metal 3D printing technology. However, porosity defects remain a challenge for fatigue-sensitive applications. Some porosity is associated with deep and narrow vapor depressions called keyholes, which occur under high-power, low–scan speed laser melting conditions. High-speed x-ray imaging enables operando observation of the detailed formation process of pores

Anthropogenic environmental modification is placing as many as 1 million species at risk of extinction. One management action for reducing extinction risk is translocation of individuals to locations from which they have disappeared or to new locations where biologists hypothesize they have a good chance of surviving. To maximize this survival probability, the standard practice is to move animals from

Vaccine efforts to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. We performed cryo–election microscopy and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax

Unprecedented heatwave-drought concurrences in the past two decades have been reported over inner East Asia. Tree-ring–based reconstructions of heatwaves and soil moisture for the past 260 years reveal an abrupt shift to hotter and drier climate over this region. Enhanced land-atmosphere coupling, associated with persistent soil moisture deficit, appears to intensify surface warming and anticyclonic

Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by using synthetic Notch receptors to transcriptionally interconnect multiple molecular

The human mitochondrial ribosome (mitoribosome) and associated proteins regulate the synthesis of 13 essential subunits of the oxidative phosphorylation complexes. We report the discovery of a mitoribosome-associated quality control pathway that responds to interruptions during elongation, and we present structures at 3.1- to 3.3-angstrom resolution of mitoribosomal large subunits trapped during ribosome

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this

Various primary signals direct insect sex determination. In hymenopteran insects, the presence of a paternal genome is needed to initiate female development. When absent, uniparental haploid males develop. We molecularly and functionally identified the instructor sex-determination gene, wasp overruler of masculinization (wom), of the haplodiploid wasp Nasonia vitripennis. This gene contains a P53-like

Every protein has a story—how it folds, what it binds, its biological actions, and how it misbehaves in aging or disease. Stories are often inferred from a protein’s shape (i.e., its structure). But increasingly, stories are told using computational molecular physics (CMP). CMP is rooted in the principled physics of driving forces and reveals granular detail of conformational populations in space and

Understanding humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics, therapeutics, and vaccines. Deep serological profiling of 232 coronavirus disease 2019 (COVID-19) patients and 190 pre–COVID-19 era controls using VirScan revealed more than 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing

Epithelial structure is generated by the dynamic reorganization of cells in response to mechanical forces. Adherens junctions transmit forces between cells, but how cells sense and respond to these forces in vivo is not well understood. We identify a mechanotransduction pathway involving the Abl tyrosine kinase and Canoe/Afadin that stabilizes cell adhesion under tension at tricellular junctions in

The 14-subunit metazoan-specific Integrator contains an endonuclease that cleaves nascent RNA transcripts. Here, we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC. The 3.5-angstrom-resolution structure reveals that nine human Integrator subunits and PP2A-AC assemble into a cruciform-shaped central scaffold formed by the backbone and shoulder

The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in

Spliceosome remodeling, executed by conserved ATPase/helicases including Prp2, enables pre-mRNA splicing. However, the structural basis for the function of the ATPase/helicases remains poorly understood. Here, we report atomic structures of Prp2 in isolation, Prp2 complexed with its coactivator Spp2, and Prp2-loaded activated spliceosome, and results of structure-guided biochemical analysis. Prp2 weakly

Factor-dependent transcription termination mechanisms are poorly understood. We determined a series of cryo-electron microscopy structures portraying the hexameric ATPase ρ on path to terminating NusA/NusG-modified elongation complexes. An open ρ ring contacts NusA, NusG, and multiple regions of RNA polymerase, trapping and locally unwinding proximal upstream DNA. NusA wedges into the ρ ring, initially

Inflammasomes function as intracellular sensors of pathogen infection or cellular perturbation and thereby play a central role in numerous diseases. Given the high abundance of NLRP1 in epithelial barrier tissues, we screened a diverse panel of viruses for inflammasome activation in keratinocytes. We identified Semliki Forest virus (SFV), a positive-strand RNA virus, as a potent activator of human

Spliceosome activation involves extensive protein and RNA rearrangements that lead to formation of a catalytically-active U2/U6 RNA structure. At present, little is known about the assembly pathway of the latter and the mechanism whereby proteins aid its proper folding. Here we report the cryo-electron microscopy structures of two human pre-Bact complexes at core resolutions of 3.9-4.2 Å. These structures

A long-standing question in infectious disease dynamics concerns the role of transmission heterogeneities, driven by demography, behavior and interventions. Based on detailed patient and contact tracing data in Hunan, China we find 80% of secondary infections traced back to 15% of SARS-CoV-2 primary infections, indicating substantial transmission heterogeneities. Transmission risk scales positively

The advent of biocatalysts designed computationally and optimized by laboratory evolution provides an opportunity to explore molecular strategies for augmenting catalytic function. Applying a suite of NMR, crystallographic, and stopped-flow techniques to an enzyme designed for an elementary proton transfer reaction, we show how directed evolution gradually altered the conformational ensemble of the

Fire has been a source of global biodiversity for millions of years. However, interactions with anthropogenic drivers such as climate change, land use, and invasive species are changing the nature of fire activity and its impacts. We review how such changes are threatening species with extinction and transforming terrestrial ecosystems. Conservation of Earth’s biological diversity will be achieved

Loss-of-function (LOF) screens provide a powerful approach to identify regulators in biological processes. Pioneered in laboratory animals, LOF screens of human genes are currently restricted to two-dimensional cell cultures, which hinders the testing of gene functions requiring tissue context. Here, we present CRISPR–lineage tracing at cellular resolution in heterogeneous tissue (CRISPR-LICHT), which

Mast cells (MCs) are central effector cells in allergic reactions that are often mediated by immunoglobulin E (IgE). Allergies commonly start at an early age, and both MCs and IgE are detectable in fetuses. However, the origin of fetal IgE and whether fetal MCs can degranulate in response to IgE-dependent activation are presently unknown. Here, we show that human and mouse fetal MCs phenotypically

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo–electron microscopy structures

Spatial control over molecular movement is typically limited because motion at the atomic scale follows stochastic processes. We used scanning tunneling microscopy to bring single molecules into a stable orientation of high translational mobility where they moved along precisely defined tracks. Single dibromoterfluorene molecules moved over large distances of 150 nanometers with extremely high spatial

Human skin has different types of tactile receptors that can distinguish various mechanical stimuli from temperature. We present a deformable artificial multimodal ionic receptor that can differentiate thermal and mechanical information without signal interference. Two variables are derived from the analysis of the ion relaxation dynamics: the charge relaxation time as a strain-insensitive intrinsic

Monitoring of finger manipulation without disturbing the inherent functionalities is critical to understand the sense of natural touch. However, worn or attached sensors affect the natural feeling of the skin. We developed nanomesh pressure sensors that can monitor finger pressure without detectable effects on human sensation. The effect of the sensor on human sensation was quantitatively investigated

Globular clusters (GCs) are dense, gravitationally bound systems of thousands to millions of stars. They are preferentially associated with the oldest components of galaxies, so measurements of their composition can constrain the build-up of chemical elements in galaxies during the early Universe. We report a massive GC in the Andromeda Galaxy (M31), RBC EXT8, that is extremely depleted in heavy elements

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and

We prepared bulk samples of supercooled liquid water under pressure by isochoric heating of high-density amorphous ice to temperatures of 205 ± 10 kelvin, using an infrared femtosecond laser. Because the sample density is preserved during the ultrafast heating, we could estimate an initial internal pressure of 2.5 to 3.5 kilobar in the high-density liquid phase. After heating, the sample expanded rapidly

The Hawaiian-Emperor seamount chain that includes the Hawaiian volcanoes was created by the Hawaiian mantle plume. Although the mantle plume hypothesis predicts an oceanic plateau produced by massive decompression melting during the initiation stage of the Hawaiian hot spot, the fate of this plateau is unclear. We discovered a megameter-scale portion of thickened oceanic crust in the uppermost lower

Moving cells can sense and respond to physical features of the microenvironment; however, in vivo, the significance of tissue topography is mostly unknown. Here, we used Drosophila border cells, an established model for in vivo cell migration, to study how chemical and physical information influences path selection. Although chemical cues were thought to be sufficient, live imaging, genetics, modeling

The drivers and patterns of zoonotic virus emergence in the human population are poorly understood. The mosquito Aedes aegypti is a major arbovirus vector native to Africa that invaded most of the world’s tropical belt over the past four centuries, after the evolution of a “domestic” form that specialized in biting humans and breeding in water storage containers. Here, we show that human specialization

Disease outbreaks among wildlife have surged in recent decades alongside climate change, although it remains unclear how climate change alters disease dynamics across different geographic regions. We amassed a global, spatiotemporal dataset describing parasite prevalence across 7346 wildlife populations and 2021 host-parasite combinations, compiling local weather and climate records at each location

Rotavirus causes severe diarrheal disease in children by broadly dysregulating intestinal homeostasis. However, the underlying mechanism(s) of rotavirus-induced dysregulation remains unclear. We found that rotavirus-infected cells produce paracrine signals that manifested as intercellular calcium waves (ICWs), observed in cell lines and human intestinal enteroids. Rotavirus ICWs were caused by the

The photosynthetic apparatus of green sulfur bacteria (GSB) contains a peripheral antenna chlorosome, light-harvesting Fenna-Matthews-Olson proteins (FMO), and a reaction center (GsbRC). We used cryo–electron microscopy to determine a 2.7-angstrom structure of the FMO-GsbRC supercomplex from Chlorobaculum tepidum. The GsbRC binds considerably fewer (bacterio)chlorophylls [(B)Chls] than other known

Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick, and mice in response to different stimuli. We identified evolutionarily conserved and species-specific

Neurodegeneration in Alzheimer’s disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins—when expressed by simian-human immunodeficiency viruses in rhesus macaques—elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows

Palladium(II)-catalyzed C–H oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high Pd loading (e.g., 10 mol %) and a need for (super)stoichiometric quantities of undesirable oxidants, such as benzoquinone and silver(I) salts. The present study probes the

Plant roots and animal guts have evolved specialized cells layers to control mineral nutrient homeostasis that must tolerate the resident microbiota while keeping homeostatic integrity. Whether and how the root diffusion barriers in the endodermis, critical for the mineral nutrient balance of plants, coordinates with the microbiota, is unknown. We demonstrate that genes controlling endodermal function

Photonic materials designed at wavelength scales have enabled a range of emerging energy technologies, from solid-state lighting to efficient photovoltaics that have transformed global energy landscapes. Daytime passive radiative cooling materials shed heat from the ground to the cold universe by taking advantage of the terrestrial thermal radiation that is as large as the renewable solar energy. Newly

The high global warming potential of current refrigerants in cooling equipment based on the vapor-compression cycle has triggered a major effort to find and implement more environmentally benign alternatives. Here, we review the basics of the vapor-compression cycle together with the safety, environmental, and thermodynamic constraints that have led to the current and next generation of refrigerants

Magnetically driven thermal changes in magnetocaloric materials have, for several decades, been exploited to pump heat near room temperature. By contrast, their electrocaloric and mechanocaloric counterparts have only been intensively studied and exploited for little more than a decade. These different caloric strands have recently been unified to yield a single field of research that could help combat

The future trajectory of the coronavirus disease 2019 (COVID-19) pandemic hinges on the dynamics of adaptive immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, salient features of the immune response elicited by natural infection or vaccination are still uncertain. We use simple epidemiological models to explore estimates for the magnitude and timing of future COVID-19

In Arabidopsis thaliana, lateral roots initiate in a process preceded by periodic gene expression known as the root clock. We identified the vesicle-trafficking regulator GNOM and its suppressor, ADENOSINE PHOSPHATE RIBOSYLATION FACTOR GTPase ACTIVATION PROTEIN DOMAIN3, as root clock regulators. GNOM is required for the proper distribution of pectin, a mediator of intercellular adhesion, whereas the

Mars has lost most of its once-abundant water to space, leaving the planet cold and dry. In standard models, molecular hydrogen produced from water in the lower atmosphere diffuses into the upper atmosphere where it is dissociated, producing atomic hydrogen, which is lost. Using observations from the Neutral Gas and Ion Mass Spectrometer on the Mars Atmosphere and Volatile Evolution spacecraft, we

Metals usually exist in the form of polycrystalline solids, which are thermodynamically unstable because of the presence of disordered grain boundaries. Grain boundaries tend to be eliminated through coarsening when heated or by transforming into metastable amorphous states when the grains are small enough. Through experiments and molecular dynamics simulations, we discovered a different type of metastable

Calcium-aluminum–rich inclusions (CAIs) in meteorites are the first solids to have formed in the Solar System, defining the epoch of its birth on an absolute time scale. This provides a link between astronomical observations of star formation and cosmochemical studies of Solar System formation. We show that the distinct molybdenum isotopic compositions of CAIs cover almost the entire compositional

The energy damping time in a mechanical resonator is critical to many precision metrology applications, such as timekeeping and force measurements. We present measurements of the phonon lifetime of a microwave-frequency, nanoscale silicon acoustic cavity incorporating a phononic bandgap acoustic shield. Using pulsed laser light to excite a colocalized optical mode of the cavity, we measured the internal

The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and

Silica-based distributed fiber-optic sensor (DFOS) systems have been a powerful tool for sensing strain, pressure, vibration, acceleration, temperature, and humidity in inextensible structures. DFOS systems, however, are incompatible with the large strains associated with soft robotics and stretchable electronics. We develop a sensor composed of parallel assemblies of elastomeric lightguides that incorporate

Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by the induction of distinct gene programs tailored to each stress. Although the mechanisms driving repression of general protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here, we found

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which

Peptide biosynthesis is performed by ribosomes and several other classes of enzymes, but a simple chemical synthesis may have created the first peptides at the origins of life. α-Aminonitriles—prebiotic α–amino acid precursors—are generally produced by Strecker reactions. However, cysteine’s aminothiol is incompatible with nitriles. Consequently, cysteine nitrile is not stable, and cysteine has been