The sequencing of the human genome has allowed the study of the genetic architecture of common diseases: the number of genomic variants that contribute to risk of disease and their joint frequency and effect size distribution. Common diseases are polygenic, with many loci contributing to phenotype, and the cumulative burden of risk alleles determines individual risk in conjunction with environmental

Recent advancements in DNA sequencing technologies and laboratory preparation protocols have rapidly expanded the scope of ancient DNA research over the past decade, both temporally and geographically. Discoveries include interactions between archaic and modern humans as well as modern human population dynamics, including those coinciding with the Last Glacial Maximum and the settlement history of

Cancer is a major cause of global mortality underpinned by genomic and epigenomic derangements. Here, we highlight the importance of multimodal data integration in understanding the molecular evolution of malignant cell states across the cancer life cycle. The widespread presence of driver mutations and epigenetic alterations in normal-appearing tissues is prompting a reassessment of how cancer initiation

Over the next decade, the primary challenge in human genetics will be to understand the biological mechanisms by which genetic variants influence phenotypes, including disease risk. Although the scale of this challenge is daunting, better methods for functional variant interpretation will have transformative consequences for disease diagnosis, risk prediction, and the development of new therapies.

Defects may display high reactivity because the specific arrangement of atoms differs from crystalline surfaces. We demonstrate that high-temperature steam pretreatment of palladium catalysts provides a 12-fold increase in the mass-specific reaction rate for carbon-hydrogen (C–H) activation in methane oxidation compared with conventional pretreatments. Through a combination of experimental and theoretical

Starches, a storage form of carbohydrates, are a major source of calories in the human diet and a primary feedstock for bioindustry. We report a chemical-biochemical hybrid pathway for starch synthesis from carbon dioxide (CO2) and hydrogen in a cell-free system. The artificial starch anabolic pathway (ASAP), consisting of 11 core reactions, was drafted by computational pathway design, established

Many human proteins contain domains that vary in size or copy number because of variable numbers of tandem repeats (VNTRs) in protein-coding exons. However, the relationships of VNTRs to most phenotypes are unknown because of difficulties in measuring such repetitive elements. We developed methods to estimate VNTR lengths from whole-exome sequencing data and impute VNTR alleles into single-nucleotide

The normal state of optimally doped cuprates is dominated by the “strange metal” phase that shows a linear temperature (T) dependence of the resistivity persisting down to the lowest T. For underdoped cuprates, this behavior is lost below the pseudogap temperature T*, where charge density waves (CDWs), together with other intertwined local orders, characterize the ground state. We found that the T-linear

Archaeologists and researchers in allied fields have long sought to understand human colonization of North America. Questions remain about when and how people migrated, where they originated, and how their arrival affected the established fauna and landscape. Here, we present evidence from excavated surfaces in White Sands National Park (New Mexico, United States), where multiple in situ human footprints

Topological insulator lasers are arrays of semiconductor lasers that exploit fundamental features of topology to force all emitters to act as a single coherent laser. In this study, we demonstrate a topological insulator vertical-cavity surface-emitting laser (VCSEL) array. Each VCSEL emits vertically, but the in-plane coupling between emitters in the topological-crystalline platform facilitates coherent

The development of silicon anodes for lithium-ion batteries has been largely impeded by poor interfacial stability against liquid electrolytes. Here, we enabled the stable operation of a 99.9 weight % microsilicon anode by using the interface passivating properties of sulfide solid electrolytes. Bulk and surface characterization, and quantification of interfacial components, showed that such an approach

Cardiomyocyte (CM) replacement is very slow in adult mammalian hearts, preventing regeneration of damaged myocardium. By contrast, fetal hearts display considerable regenerative potential owing to the presence of less mature CMs that still have the ability to proliferate. In this study, we demonstrate that heart-specific expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) induces adult CMs to dedifferentiate

Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Multiple mutations in SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover/spillback events between humans and animals. To develop prevention and therapeutic strategies, we

ATP-binding cassette (ABC) transporters couple ATP hydrolysis to substrate transport across biological membranes. Although many are promising drug targets, their mechanisms of modulation by small molecule inhibitors remain largely unknown. Intriguingly, two first-generation inhibitors of the MsbA transporter, TBT1 and G247, induce opposite effects on ATP hydrolysis. Using single-particle cryo-electron

Most multicomponent high-entropy alloys (HEAs) lose ductility with increasing strength, similar to conventional materials. We controllably introduced novel gradient nano-scaled dislocation-cell structures in one stable single-phase face-centered-cubic HEA, which result in enhanced strength without apparently losing ductility. The sample-level structural-gradient induces the progressive formation of

Zeolites are versatile catalysts and molecular sieves with large topological diversity, but managing phase competition in zeolite synthesis is an empirical, labor-intensive task. Here, we controlled phase selectivity in templated zeolite synthesis from first principles by combining high-throughput atomistic simulations, literature mining, human-computer interaction, synthesis, and characterization

Vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25-μg Moderna mRNA-1273 vaccine were examined over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing cross-reactive T cell memory impacts vaccine-generated immunity. Vaccine-generated spike-specific memory CD4+ T cells 6 months

Long-term, individual-based field studies, the application of genetic techniques, and phylogenetic reconstructions have led to substantial advances in our understanding of the diversity and evolution of mammalian breeding systems and their consequences. These studies show how differences in ecology, life histories, and phylogeny affect the distributions of breeding females and breeding males; how the

Morphological complexity is a notable feature of multicellular life, although whether it evolves gradually or in early bursts is unclear. Vascular plant reproductive structures, such as flowers, are familiar examples of complex morphology. In this study, we use a simple approach based on the number of part types to analyze changes in complexity over time. We find that reproductive complexity increased

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic

Conventional understanding has it that a liquid deposited on a surface tends to move along directions that reduce surface energy, which is mainly dictated by surface properties rather than liquid properties, such as surface tension. Achieving well-controlled directional steering remains challenging because the liquid-solid interaction mainly occurs in the two-dimensional (2D) domain. We show that the

During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting the genes involved in antigen processing and presentation or up-regulating inhibitory immune checkpoint genes. We performed in vivo CRISPR screens in syngeneic mouse tumor models to examine requirements for tumorigenesis both with and without adaptive immune selective pressure. In each tumor type tested, we

Vitamin A and its derivative retinol are essential for the development of intestinal adaptive immunity. Retinoic acid (RA)–producing myeloid cells are central to this process, but how myeloid cells acquire retinol for conversion to RA is unknown. Here, we show that serum amyloid A (SAA) proteins—retinol-binding proteins induced in intestinal epithelial cells by the microbiota—deliver retinol to myeloid

Microbial fuel cells (MFCs) can directly convert the chemical energy stored in organic matter to electricity and are of considerable interest for power generation and wastewater treatment. However, the current MFCs typically exhibit unsatisfactorily low power densities that are largely limited by the sluggish transmembrane and extracellular electron-transfer processes. Here, we report a rational strategy

Nanostructured metals are usually strong because the ultrahigh density of internal boundaries restricts the mean free path of dislocations. Usually, they are also more brittle because of their diminished work-hardening ability. Nanotwinned materials, with coherent interfaces of mirror symmetry, can overcome this inherent trade-off. We show a bulk nanostructuring method that produces a multiscale, hierarchical

Weakly interacting Bose gases usually form Bose-Einstein condensates in which most particles occupy the same single-particle state. However, when this state cannot realize a continuous symmetry of the many-body Hamiltonian, a fragmented condensate exhibiting the expected symmetry may emerge. Here, we produced a three-fragment condensate for a mesoscopic spin-1 gas of about 100 atoms, with anti-ferromagnetic

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SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, particularly as antibody titers wane over time. Here, we assess the impact of SARS-CoV-2 variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), and B.1.617.2 (Delta) on binding, neutralizing, and ACE2-competing antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive

The progression of the SARS-CoV-2 pandemic in Africa has so far been heterogeneous and the full impact is not yet well understood. Here, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations predominantly from Europe, which diminished following the early

IscB proteins are putative nucleases encoded in a distinct family of IS200/IS605 transposons and are likely ancestors of the RNA-guided endonuclease Cas9, but the functions of IscB and its interactions with any RNA remain uncharacterized. Using evolutionary analysis, RNA-seq, and biochemical experiments, we reconstruct the evolution of CRISPR-Cas9 systems from IS200/IS605 transposons. We show that

The functional relevance of pre-existing cross-immunity to SARS-CoV-2 is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)-reactive and SARS-CoV-2-cross-reactive CD4+ T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that pre-existing spike- and S816-830-reactive T cells

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of ‘vaccine nationalism’, we extend previous models to include simple scenarios of stockpiling between two regions. In general

Coupling Bose-Einstein condensates to optical cavities has enabled the study of many-body states with long-range interactions. However, equivalent experiments with ultracold Fermi gases have remained largely unexplored. Here we report an experimental realization of a superradiant quantum phase transition of a degenerate Fermi gas in a transversely pumped optical cavity. The self-ordering checkerboard

β-barrel outer membrane proteins (β-OMPs) play vital roles in mitochondria, chloroplasts, and Gram-negative bacteria. Evolutionarily conserved complexes such as the mitochondrial sorting and assembly machinery (SAM) mediate the assembly of β-OMPs. Here, we investigated the SAM-mediated assembly of the translocase of the outer membrane (TOM) core complex. Cryo-electron microscopy structures of SAM-fully

Type III CRISPR-Cas immunity is widespread in prokaryotes and is generally mediated by multi-subunit effector complexes. These complexes recognize complementary viral transcripts and can activate ancillary immune proteins. Here, we describe a type III-E effector from Candidatus “Scalindua brodae”, called Sb-gRAMP, which is natively encoded by a single gene with several type III domains fused together

The interaction between free electrons and light stands at the base of both classical and quantum physics, with applications in free-electron acceleration, radiation sources, and electron microscopy. Yet, to this day, all experiments involving free-electron–light interactions are fully explained by describing the light as a classical wave. Here, we observe quantum statistics effects of photons on free-electron–light

In Arabidopsis, de novo organogenesis of lateral roots is patterned by an oscillatory mechanism called the root clock, which is dependent on unidentified metabolites. To determine if retinoids regulate the root clock, we used a chemical reporter for retinaldehyde (retinal) binding proteins. We found that retinal binding precedes the root clock and predicts sites of lateral root organogenesis. Application

In neuromorphic hardware, peripheral circuits and memories based on heterogeneous devices are generally physically separated. Thus exploring homogeneous devices for these components is an important issue for improving module integration and resistance matching. Inspired by ferroelectric proximity effect on two-dimensional materials, we present a tungsten diselenide-on-LiNbO3 cascaded architecture as

Microbial ethylene-forming enzyme (EFE) converts the C3-C4 fragment of the ubiquitous primary metabolite, 2-oxoglutarate (2OG), to its namesake alkene product. This reaction is very different from the simple decarboxylation of 2OG to succinate promoted by related enzymes and has inspired disparate mechanistic hypotheses. We show that EFE produces stereochemically random (equal cis and trans) 1,2-[2H2]-ethylene

The realization of an efficient quantum optical interface for multi-qubit systems is an outstanding challenge in science and engineering. Using two atoms in individually-controlled optical tweezers coupled to a nanofabricated photonic crystal cavity, we demonstrate entanglement generation, fast non-destructive readout, and full quantum control of atomic qubits. The entangled state is verified in free

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of SARS-CoV-2 vaccine, mRNA-1273. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and

Conformational changes within biological macromolecules control a vast array of chemical reactions in living cells. Time-resolved crystallography can reveal time-dependent structural changes that occur within protein crystals, yielding chemical insights in unparalleled detail. Serial crystallography approaches developed at x-ray free-electron lasers are now routinely used for time-resolved diffraction

Protein kinase activity must be precisely regulated, but how a cell governs hyperactive kinases remains unclear. In this study, we generated a constitutively active mitogen-activated protein kinase DYF-5 (DYF-5CA) in Caenorhabditis elegans that disrupted sensory cilia. Genetic suppressor screens identified that mutations of ADR-2, an RNA adenosine deaminase, rescued ciliary phenotypes of dyf-5CA. We

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable

In eukaryotic cells, half of all proteins function as subunits within multiprotein complexes. Imbalanced synthesis of subunits leads to unassembled intermediates that must be degraded to minimize cellular toxicity. Here, we found that excess PSMC5, a subunit of the proteasome base, was targeted for degradation by the HERC1 ubiquitin ligase in mammalian cells. HERC1 identified unassembled PSMC5 by its

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible

Materials with multiple superconducting phases are rare. Here, we report the discovery of two-phase unconventional superconductivity in CeRh2As2. Using thermodynamic probes, we establish that the superconducting critical field of its high-field phase is as high as 14 tesla, even though the transition temperature is only 0.26 kelvin. Furthermore, a transition between two different superconducting phases