Four-dimensional (4D) printing relies on multimaterial printing, reinforcement patterns, or micro/nanofibrous additives as programmable tools to achieve desired shape reconfigurations. However, existing programming approaches still follow the so-called origami design principle to generate reconfigurable structures by self-folding stacked 2D materials, particularly at small scales. Here, we propose a programmable modular design that directly constructs 3D reconfigurable microstructures capable of sophisticated 3D-to-3D shape transformations by assembling 4D micro-building blocks. 4D direct laser writing is used to print two-photon polymerizable, stimuli-responsive hydrogels to construct building blocks at micrometer scales. Denavit-Hartenberg (DH) parameters, used to define robotic arm kinematics, are introduced as guidelines for how to assemble the micro-building blocks and plan the 3D motion of assembled chain blocks. Last, a 3D-printed microscaled transformer capable of changing its shape from a race car to a humanoid robot is devised and fabricated using the DH parameters to guide the motion of various assembled compartments.

Despite the enormous interest in superhydrophobicity for self-cleaning, a clear picture of contaminant removal is missing, in particular, on a single-particle level. Here, we monitor the removal of individual contaminant particles on the micrometer scale by confocal microscopy. We correlate this space- and time-resolved information with measurements of the friction force. The balance of capillary and adhesion force between the drop and the contamination on the substrate determines the friction force of drops during self-cleaning. These friction forces are in the range of micro-Newtons. We show that hydrophilic and hydrophobic particles hardly influence superhydrophobicity provided that the particle size exceeds the pore size or the thickness of the contamination falls below the height of the protrusions. These detailed insights into self-cleaning allow the rational design of superhydrophobic surfaces that resist contamination as demonstrated by outdoor environmental (>200 days) and industrial standardized contamination experiments.

Anisotropic dynamics on the colloidal length scale is ubiquitous in nature. Of particular interest is the dynamics of systems approaching a kinetically arrested state. The failure of classical techniques for investigating the dynamics of highly turbid suspensions has contributed toward the limited experimental information available up until now. Exploiting the recent developments in the technique of differential dynamic microscopy (DDM), we report the first experimental study of the anisotropic collective dynamics of colloidal ellipsoids with a magnetic hematite core over a wide concentration range approaching kinetic arrest. In addition, we have investigated the effect of an external magnetic field on the resulting anisotropic collective diffusion. We combine DDM with small-angle x-ray scattering and rheological measurements to locate the glass transition and to relate the collective short- and long-time diffusion coefficients to the structural correlations and the evolution of the zero shear viscosity as the system approaches an arrested state.

Melting is a fundamental process of matter that is still not fully understood at the microscopic level. Here, we use time-resolved x-ray diffraction to examine the ultrafast melting of polycrystalline gold thin films using an optical laser pump followed by a delayed hard x-ray probe pulse. We observe the formation of an intermediate new diffraction peak, which we attribute to material trapped between the solid and melted states, that forms 50 ps after laser excitation and persists beyond 500 ps. The peak width grows rapidly for 50 ps and then narrows distinctly at longer time scales. We attribute this to a melting band originating from the grain boundaries and propagating into the grains. Our observation of this intermediate state has implications for the use of ultrafast lasers for ablation during pulsed laser deposition.

This work establishes a means to exploit genetic networks to create living synthetic composites that change shape in response to specific biochemical or physical stimuli. Baker’s yeast embedded in a hydrogel forms a responsive material where cellular proliferation leads to a controllable increase in the composite volume of up to 400%. Genetic manipulation of the yeast enables composites where volume change on exposure to l-histidine is 14× higher than volume change when exposed to d-histidine or other amino acids. By encoding an optogenetic switch into the yeast, spatiotemporally controlled shape change is induced with pulses of dim blue light (2.7 mW/cm2). These living, shape-changing materials may enable sensors or medical devices that respond to highly specific cues found within a biological milieu.

Triggerable materials capable of being degraded by selective stimuli stand to transform our capacity to precisely control biomedical device activity and performance while reducing the need for invasive interventions. Here, we describe the development of a modular and tunable light-triggerable hydrogel system capable of interfacing with implantable devices. We apply these materials to two applications in the gastrointestinal (GI) tract: a bariatric balloon and an esophageal stent. We demonstrate biocompatibility and on-demand triggering of the material in vitro, ex vivo, and in vivo. Moreover, we characterize performance of the system in a porcine large animal model with an accompanying ingestible LED. Light-triggerable hydrogels have the potential to be applied broadly throughout the GI tract and other anatomic areas. By demonstrating the first use of light-degradable hydrogels in vivo, we provide biomedical engineers and clinicians with a previously unavailable, safe, dynamically deliverable, and precise tool to design dynamically actuated implantable devices.

The never-ending pursuits for exploring aromatic molecular architectures result in the large libraries of aromatics with fascinating structures, which have greatly broadened the scope of aromaticity. Despite extensive efforts that have been paid to develop aromatic frameworks, the construction of polycyclic aromatics that share a bridgehead atom with more than three rings has never been accomplished. Here, an unprecedented family of aromatics, in which a metal center shared by 4 five-membered aromatic rings, has been achieved by using the metalla-click reactions with excellent yields and remarkable regioselectivity. The distinctive tetracyclic aromatics exhibit a broad absorption in the ultraviolet-visible near-infrared region and excellent thermal stability in air, enabling their potential applications in photoelectric materials and biomedicine. This study now makes it possible to incorporate four aromatic rings with one common sharing metal center by a straightforward strategy that would promote further development of previously unknown polycyclic complex motifs in aromatic chemistry.

Monolithic strong magnetic induction at the mtesla to tesla level provides essential functionalities to physical, chemical, and medical systems. Current design options are constrained by existing capabilities in three-dimensional (3D) structure construction, current handling, and magnetic material integration. We report here geometric transformation of large-area and relatively thick (~100 to 250 nm) 2D nanomembranes into multiturn 3D air-core microtubes by a vapor-phase self-rolled-up membrane (S-RuM) nanotechnology, combined with postrolling integration of ferrofluid magnetic materials by capillary force. Hundreds of S-RuM power inductors on sapphire are designed and tested, with maximum operating frequency exceeding 500 MHz. An inductance of 1.24 μH at 10 kHz has been achieved for a single microtube inductor, with corresponding areal and volumetric inductance densities of 3 μH/mm2 and 23 μH/mm3, respectively. The simulated intensity of the magnetic induction reaches tens of mtesla in fabricated devices at 10 MHz.

Metallic bonds remain one of the most important and least understood of the chemical bonds. In this study, we generated Re2 molecules in which the Re–Re core is unsupported by ligands. Real-time imaging of the atomic-scale dynamics of Re2 adsorbed on a graphitic lattice allows direct measurement of Re–Re bond lengths for individual molecules that changes in discrete steps correlating with bond order from one to four. Direct imaging of the Re–Re bond breaking process reveals a new bonding state with the bond order less than one and a high-amplitude vibrational stretch, preceding the bond dissociation. The methodology, based on aberration-corrected transmission electron microscopy imaging, is shown to be a powerful analytical tool for the investigation of dynamics of metallic bonding at the atomic level.

With the growing interest in the optical imaging of ultrafast phenomena in transparent objects, from shock wave to neuronal action potentials, high contrast imaging at high frame rates has become desirable. While phase sensitivity provides the contrast, the frame rates and sequence depths are highly limited by the detectors. Here, we present phase-sensitive compressed ultrafast photography (pCUP) for single-shot real-time ultrafast imaging of transparent objects by combining the contrast of dark-field imaging with the speed and the sequence depth of CUP. By imaging the optical Kerr effect and shock wave propagation, we demonstrate that pCUP can image light-speed phase signals in a single shot with up to 350 frames captured at up to 1 trillion frames per second. We expect pCUP to be broadly used for a vast range of fundamental and applied sciences.

Microcirculatory obstruction is a hallmark of severe malaria, but mechanisms of parasite sequestration are only partially understood. Here, we developed a robust three-dimensional microvessel model that mimics the arteriole-capillary-venule (ACV) transition consisting of a narrow 5- to 10-μm-diameter capillary region flanked by arteriole- or venule-sized vessels. Using this platform, we investigated red blood cell (RBC) transit at the single cell and at physiological hematocrits. We showed normal RBCs deformed via in vivo–like stretching and tumbling with negligible interactions with the vessel wall. By comparison, Plasmodium falciparum–infected RBCs exhibited virtually no deformation and rapidly accumulated in the capillary-sized region. Comparison of wild-type parasites to those lacking either cytoadhesion ligands or membrane-stiffening knobs showed highly distinctive spatial and temporal kinetics of accumulation, linked to velocity transition in ACVs. Our findings shed light on mechanisms of microcirculatory obstruction in malaria and establish a new platform to study hematologic and microvascular diseases.

The vision of using light to manipulate electronic and spin excitations in materials on their fundamental time and length scales requires new approaches in experiment and theory to observe and understand these excitations. The ultimate speed limit for all-optical manipulation requires control schemes for which the electronic or magnetic subsystems of the materials are coherently manipulated on the time scale of the laser excitation pulse. In our work, we provide experimental evidence of such a direct, ultrafast, and coherent spin transfer between two magnetic subsystems of an alloy of Fe and Ni. Our experimental findings are fully supported by time-dependent density functional theory simulations and, hence, suggest the possibility of coherently controlling spin dynamics on subfemtosecond time scales, i.e., the birth of the research area of attomagnetism.

In spintronics, two-dimensional van der Waals crystals constitute a most promising material class for long-distance spin transport or effective spin manipulation at room temperature. To realize all-vdW-material–based spintronic devices, however, vdW materials with itinerant ferromagnetism at room temperature are needed for spin current generation and thereby serve as an effective spin source. We report theoretical design and experimental realization of a iron-based vdW material, Fe4GeTe2, showing a nearly room temperature ferromagnetic order, together with a large magnetization and high conductivity. These properties are well retained even in cleaved crystals down to seven layers, with notable improvement in perpendicular magnetic anisotropy. Our findings highlight Fe4GeTe2 and its nanometer-thick crystals as a promising candidate for spin source operation at nearly room temperature and hold promise to further increase Tc in vdW ferromagnets by theory-guided material discovery.

The dominant pathway of radiation damage begins with the ionization of water. Thus far, however, the underlying primary processes could not be conclusively elucidated. Here, we directly study the earliest steps of extreme ultraviolet (XUV)–induced water radiolysis through one-photon excitation of large water clusters using time-resolved photoelectron imaging. Results are presented for H2O and D2O clusters using femtosecond pump pulses centered at 133 or 80 nm. In both excitation schemes, hydrogen or proton transfer is observed to yield a prehydrated electron within 30 to 60 fs, followed by its solvation in 0.3 to 1.0 ps and its decay through geminate recombination on a ∼10-ps time scale. These results are interpreted by comparison with detailed multiconfigurational non-adiabatic ab-initio molecular dynamics calculations. Our results provide the first comprehensive picture of the primary steps of radiation chemistry and radiation damage and demonstrate new approaches for their study with unprecedented time resolution.

Heusler compounds are exciting materials for future spintronics applications because they display a wide range of tunable electronic and magnetic interactions. Here, we use a femtosecond laser to directly transfer spin polarization from one element to another in a half-metallic Heusler material, Co2MnGe. This spin transfer initiates as soon as light is incident on the material, demonstrating spatial transfer of angular momentum between neighboring atomic sites on time scales < 10 fs. Using ultrafast high harmonic pulses to simultaneously and independently probe the magnetic state of two elements during laser excitation, we find that the magnetization of Co is enhanced, while that of Mn rapidly quenches. Density functional theory calculations show that the optical excitation directly transfers spin from one magnetic sublattice to another through preferred spin-polarized excitation pathways. This direct manipulation of spins via light provides a path toward spintronic devices that can operate on few-femtosecond or faster time scales.

In rare cases, fossils function like snapshots, capturing key moments of evolution. One of these rare cases is Origolestes lii, a stem therian mammal from the Yixian Formation (China) described by Mao et al. (1) on page 305 of this issue. The study provides a glimpse of a fundamental moment in mammalian evolution—the separation of middle ear elements from the Meckelian cartilage of the lower jaw, which provided freedom to the system to improve both chewing function and hearing ability.

When cells take up extracellular fluid by endocytosis, they internalize a considerable proportion of the cell volume quickly and yet maintain their volume and ionic composition. This is particularly striking in the case of macropinocytosis, which is the bulk uptake of extracellular fluid. Through this pathway, macrophages can be stimulated to internalize ∼25% of their cellular volume per hour into large vacuoles known as macropinosomes. An intriguing question is how cells and organelles are able to maintain their size while internalizing such large volumes. On page 301 of this issue, Freeman et al. (1) reveal a molecular mechanism underpinning homeostatic regulation of cell size. They demonstrate that newly formed macropinosomes rapidly lose volume by osmosis driven by two-pore channel (TPC)–mediated outflow of sodium ions. This reduces hydrostatic pressure within the macropinosome, facilitating the extension of tubules from the macropinosome surface and recycling of membrane lipids and proteins back to the cell surface.

The adaptive immune system, with T and B lymphocytes being its two principal cell types, enables efficient protection from countless pathogens. T lymphocytes emerge from the thymus as quiescent (noncycling) naïve cells and display an immense repertoire of clonally distributed T cell receptors (TCRs) that detect antigens and are generated as the result of a largely random process of somatic gene rearrangement in thymic precursor cells. On page 264 of this issue, ElTanbouly et al. (1) show that naïve T cell quiescence is actively regulated upon their egress from the thymus and that this may be critical for constraining self-reactive T cells and preventing autoimmunity.

Discussions about the quality of the fossil record frequently focus on completeness—that is, the proportion of species that existed for which scientists have fossil samples. An equally important aspect of quality is how finely the ages of fossils and durations of major evolutionary events can be resolved. Paleontologists and other biologists typically date fossils using the general ages of the chronostratigraphic units assigned to the rock strata yielding the fossils. For example, if a fossiliferous bed comes from the Rhuddanian Gasworks Sandstone, then the ages assigned to the fossils are usually 443.8 to 440.8 million years. On page 272 of this issue, Fan et al. (1) report on their use of constrained optimization (CONOP) (2) in biochronological analyses of fossil-bearing layers containing 11,000+ marine invertebrate species from 3000+ sections of sedimentary rocks, which constrain ages to a fraction of that range.

A new agreement is being negotiated under the 1982 United Nations Convention on the Law of the Sea (UNCLOS) to provide legally binding mechanisms to protect the marine environment and to conserve and ensure the sustainable use of marine biodiversity on the high seas (international waters in areas beyond national jurisdiction) (1). One of the suggested objectives in the current draft text is to “apply an approach that builds ecosystem resilience to the adverse effects of climate change” when applying area-based management tools (ABMTs), including marine protected areas (MPAs). Yet even though climate change is resulting in shifts in species' ranges (2) and in the behavior of the human users of mobile, commercially valuable species (3), protection of highly mobile species and the dynamic habitats on which they depend is not currently a focus of negotiations. With the final language to be determined as early as 2020 (1), we urge negotiators to include new dynamic management tools, including mobile MPAs (mMPAs), whose boundaries shift across space and time, that could help to safeguard marine life and build ecosystem resilience by protecting dynamic habitats as well as migratory marine species in a changing ocean.

Astrology was the first art to capitalize on "the powerful storytelling possibilities inherent in numerical data," writes Alexander Boxer in his new book, A Scheme of Heaven. In that regard, it was the predecessor of all modern big data disciplines. A Scheme of Heaven is an introduction to astrology that offers a handsome primer of the structures and concepts with which astrologers have tried to make our world of data manageable.

Can science save humanity? In the face of runaway climate change and massive species extinction, some say that we already know all we need to know to fix these problems: Further research is a distraction and what we need now is action. Others anticipate a feat of technical ingenuity that will catapult us out of our current crisis. Into this fray comes Jürgen Renn, a polymath historian of science, whose research has careened from ancient Chinese mechanics to Einstein's theory of gravitation to contemporary energy systems. What links these projects is Renn's fascination with the dynamics by which science changes and changes hands. His new tour de force, The Evolution of Knowledge, addresses all those concerned with science's fate.

The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism.

One great challenge in understanding the history of life is resolving the influence of environmental change on biodiversity. Simulated annealing and genetic algorithms were used to synthesize data from 11,000 marine fossil species, collected from more than 3000 stratigraphic sections, to generate a new Cambrian to Triassic biodiversity curve with an imputed temporal resolution of 26 ± 14.9 thousand years. This increased resolution clarifies the timing of known diversification and extinction events. Comparative analysis suggests that partial pressure of carbon dioxide (Pco2) is the only environmental factor that seems to display a secular pattern similar to that of biodiversity, but this similarity was not confirmed when autocorrelation within that time series was analyzed by detrending. These results demonstrate that fossil data can provide the temporal and taxonomic resolutions necessary to test (paleo)biological hypotheses at a level of detail approaching those of long-term ecological analyses.

Solar flares are powered by a rapid release of energy in the solar corona, thought to be produced by the decay of the coronal magnetic field strength. Direct quantitative measurements of the evolving magnetic field strength are required to test this. We report microwave observations of a solar flare, showing spatial and temporal changes in the coronal magnetic field. The field decays at a rate of ~5 Gauss per second for 2 minutes, as measured within a flare subvolume of ~1028 cubic centimeters. This fast rate of decay implies a sufficiently strong electric field to account for the particle acceleration that produces the microwave emission. The decrease in stored magnetic energy is enough to power the solar flare, including the associated eruption, particle acceleration, and plasma heating.

The Schmidt reaction has been an efficient and widely used synthetic approach to amides and nitriles since its discovery in 1923. However, its application often entails the use of volatile, potentially explosive, and highly toxic azide reagents. Here, we report a sequence whereby triflic anhydride and formic and acetic acids activate the bulk chemical nitromethane to serve as a nitrogen donor in place of azides in Schmidt-like reactions. This protocol further expands the substrate scope to alkynes and simple alkyl benzenes for the preparation of amides and nitriles.

Strange metal behavior is ubiquitous in correlated materials, ranging from cuprate superconductors to bilayer graphene, and may arise from physics beyond the quantum fluctuations of a Landau order parameter. In quantum-critical heavy-fermion antiferromagnets, such physics may be realized as critical Kondo entanglement of spin and charge and probed with optical conductivity. We present terahertz time-domain transmission spectroscopy on molecular beam epitaxy–grown thin films of YbRh2Si2, a model strange-metal compound. We observed frequency over temperature scaling of the optical conductivity as a hallmark of beyond-Landau quantum criticality. Our discovery suggests that critical charge fluctuations play a central role in the strange metal behavior, elucidating one of the long-standing mysteries of correlated quantum matter.

Subwavelength optical resonators made of high-index dielectric materials provide efficient ways to manipulate light at the nanoscale through mode interferences and enhancement of both electric and magnetic fields. Such Mie-resonant dielectric structures have low absorption, and their functionalities are limited predominantly by radiative losses. We implement a new physical mechanism for suppressing radiative losses of individual nanoscale resonators to engineer special modes with high quality factors: optical bound states in the continuum (BICs). We demonstrate that an individual subwavelength dielectric resonator hosting a BIC mode can boost nonlinear effects increasing second-harmonic generation efficiency. Our work suggests a route to use subwavelength high-index dielectric resonators for a strong enhancement of light–matter interactions with applications to nonlinear optics, nanoscale lasers, quantum photonics, and sensors.

Variable feather overlap enables birds to morph their wings, unlike aircraft. They accomplish this feat by means of elastic compliance of connective tissue, which passively redistributes the overlapping flight feathers when the skeleton moves to morph the wing planform. Distinctive microstructures form “directional Velcro,” such that when adjacent feathers slide apart during extension, thousands of lobate cilia on the underlapping feathers lock probabilistically with hooked rami of overlapping feathers to prevent gaps. These structures unlock automatically during flexion. Using a feathered biohybrid aerial robot, we demonstrate how both passive mechanisms make morphing wings robust to turbulence. We found that the hooked microstructures fasten feathers across bird species except silent fliers, whose feathers also lack the associated Velcro-like noise. These findings could inspire innovative directional fasteners and morphing aircraft.

The loss of water from Mars to space is thought to result from the transport of water to the upper atmosphere, where it is dissociated to hydrogen and escapes the planet. Recent observations have suggested large, rapid seasonal intrusions of water into the upper atmosphere, boosting the hydrogen abundance. We use the Atmospheric Chemistry Suite on the ExoMars Trace Gas Orbiter to characterize the water distribution by altitude. Water profiles during the 2018–2019 southern spring and summer stormy seasons show that high-altitude water is preferentially supplied close to perihelion, and supersaturation occurs even when clouds are present. This implies that the potential for water to escape from Mars is higher than previously thought.

Despite ongoing (macro)pinocytosis of extracellular fluid, the volume of the endocytic pathway remains unchanged. To investigate the underlying mechanism, we used high-resolution video imaging to analyze the fate of macropinosomes formed by macrophages in vitro and in situ. Na+, the primary cationic osmolyte internalized, exited endocytic vacuoles via two-pore channels, accompanied by parallel efflux of Cl− and osmotically coupled water. The resulting shrinkage caused crenation of the membrane, which fostered recruitment of curvature-sensing proteins. These proteins stabilized tubules and promoted their elongation, driving vacuolar remodeling, receptor recycling, and resolution of the organelles. Failure to resolve internalized fluid impairs the tissue surveillance activity of resident macrophages. Thus, osmotically driven increases in the surface-to-volume ratio of endomembranes promote traffic between compartments and help to ensure tissue homeostasis.

On the basis of multiple skeletal specimens from Liaoning, China, we report a new genus and species of Cretaceous stem therian mammal that displays decoupling of hearing and chewing apparatuses and functions. The auditory bones, including the surangular, have no bone contact with the ossified Meckel’s cartilage; the latter is loosely lodged on the medial rear of the dentary. This configuration probably represents the initial morphological stage of the definitive mammalian middle ear. Evidence shows that hearing and chewing apparatuses have evolved in a modular fashion. Starting as an integrated complex in non-mammaliaform cynodonts, the two modules, regulated by similar developmental and genetic mechanisms, eventually decoupled during the evolution of mammals, allowing further improvement for more efficient hearing and mastication.

Allotropes of carbon, such as diamond and graphene, are among the best conductors of heat. We monitored the evolution of thermal conductivity in thin graphite as a function of temperature and thickness and found an intimate link between high conductivity, thickness, and phonon hydrodynamics. The room-temperature in-plane thermal conductivity of 8.5-micrometer-thick graphite was 4300 watts per meter-kelvin—a value well above that for diamond and slightly larger than in isotopically purified graphene. Warming enhances thermal diffusivity across a wide temperature range, supporting partially hydrodynamic phonon flow. The enhancement of thermal conductivity that we observed with decreasing thickness points to a correlation between the out-of-plane momentum of phonons and the fraction of momentum-relaxing collisions. We argue that this is due to the extreme phonon dispersion anisotropy in graphite.

Bismuth catalysis has traditionally relied on the Lewis acidic properties of the element in a fixed oxidation state. In this paper, we report a series of bismuth complexes that can undergo oxidative addition, reductive elimination, and transmetallation in a manner akin to transition metals. Rational ligand optimization featuring a sulfoximine moiety produced an active catalyst for the fluorination of aryl boronic esters through a bismuth (III)/bismuth (V) redox cycle. Crystallographic characterization of the different bismuth species involved, together with a mechanistic investigation of the carbon-fluorine bond-forming event, identified the crucial features that were combined to implement the full catalytic cycle.

This issue of Science includes the program of the 2020 AAAS Annual Meeting. The theme of the AAAS Annual Meeting in Seattle,Washington, 13 to 16 February 2020, is Envisioning Tomorrow's Earth. A PDF of the program as it appears in this issue is available here; for more information on the meeting (including registration forms and information on accommodations), please visit www.aaas.org/meetings/.

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

Spin liquids are quantum phases of matter with a variety of unusual features arising from their topological character, including “fractionalization”—elementary excitations that behave as fractions of an electron. Although there is not yet universally accepted experimental evidence that establishes that any single material has a spin liquid ground state, in the past few years a number of materials have been shown to exhibit distinctive properties that are expected of a quantum spin liquid. Here, we review theoretical and experimental progress in this area.

Within cells, the spatial compartmentalization of thousands of distinct proteins serves a multitude of diverse biochemical needs. Correlative super-resolution (SR) fluorescence and electron microscopy (EM) can elucidate protein spatial relationships to global ultrastructure, but has suffered from tradeoffs of structure preservation, fluorescence retention, resolution, and field of view. We developed a platform for three-dimensional cryogenic SR and focused ion beam–milled block-face EM across entire vitreously frozen cells. The approach preserves ultrastructure while enabling independent SR and EM workflow optimization. We discovered unexpected protein-ultrastructure relationships in mammalian cells including intranuclear vesicles containing endoplasmic reticulum–associated proteins, web-like adhesions between cultured neurons, and chromatin domains subclassified on the basis of transcriptional activity. Our findings illustrate the value of a comprehensive multimodal view of ultrastructural variability across whole cells.

N6-methyladenosine (m6A) regulates stability and translation of messenger RNA (mRNA) in various biological processes. Here, we showed that knockout of the m6A writer Mettl3 or a nuclear reader Ythdc1 in mouse embryonic stem cells increases chromatin accessibility and activates transcription in an m6A-dependent manner. We found that METTL3 deposits m6A modifications on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs and repeats RNAs. YTHDC1 facilitates decay of a subset of these m6A-modified RNAs, especially LINE1 elements, through the NEXT-mediated nuclear degradation. Reducing m6A methylation by METTL3 depletion or site-specific m6A demethylation of selected carRNAs elevates the levels of carRNAs and promotes open chromatin state and downstream transcription. Collectively, our results revealed that m6A on carRNAs can globally tune chromatin state and transcription.

Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP) are vital for cell function in all organisms and form cofactors to a host of enzymes in catabolic and anabolic processes. NAD(P) transhydrogenases (NTHs) catalyse hydride ion transfer between NAD(H) and NADP(H). Membrane‐bound NTH isoforms reside in the cytoplasmic membrane of bacteria, and the inner membrane of mitochondria in metazoans, where they generate NADPH. Here, we show that malaria parasites encode a single membrane‐bound NTH that localises to the crystalloid, an organelle required for sporozoite transmission from mosquitos to vertebrates. We demonstrate that NTH has an essential structural role in crystalloid biogenesis, whilst its enzymatic activity is required for sporozoite development. This pinpoints an essential function in sporogony to the activity of a single crystalloid protein. Its additional presence in the apicoplast of sporozoites identifies NTH as a likely supplier of NADPH for this organelle during liver infection. Our findings reveal that Plasmodium species have co‐opted NTH to a variety of non‐mitochondrial organelles to provide a critical source of NADPH reducing power.

NMR sensitivity-enhancement methods involving hyperpolarized water could be of importance for solution-state biophysical investigations. Hyperpolarized water (HyperW) can enhance the 1H NMR signals of exchangeable sites by orders of magnitude over their thermal counterparts, while providing insight into chemical exchange and solvent accessibility at a site-resolved level. As HyperW’s enhancements are achieved by exploiting fast solvent exchanges associated with minimal interscan delays, possibilities for the rapid monitoring of chemical reactions and biomolecular (re)folding are opened. HyperW NMR can also accommodate heteronuclear transfers, facilitating the rapid acquisition of 2-dimensional (2D) 15N-1H NMR correlations, and thereby combining an enhanced spectral resolution with speed and sensitivity. This work demonstrates how these qualities can come together for the study of nucleic acids. HyperW injections were used to target the guanine-sensing riboswitch aptamer domain (GSRapt) of the xpt-pbuX operon in Bacillus subtilis. Unlike what had been observed in proteins, where residues benefited of HyperW NMR only if/when sufficiently exposed to water, these enhancements applied to every imino resonance throughout the RNA. The >300-fold enhancements observed in the resulting 1H NMR spectra allowed us to monitor in real time the changes that GSRapt undergoes upon binding hypoxanthine, a high-affinity interaction leading to conformational refolding on a ∼1-s timescale at 36 °C. Structural responses could be identified for several nucleotides by 1-dimensional (1D) imino 1H NMR as well as by 2D HyperW NMR spectra acquired upon simultaneous injection of hyperpolarized water and hypoxanthine. The folding landscape revealed by this HyperW strategy for GSRapt, is briefly discussed.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The locus of the human proprotein convertase subtilisin‐kexin type‐7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene‐cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglycerides (TG), and exome sequencing of African‐Americans revealed the association of a low‐frequency coding variant of PC7 (R504H; SNP rs142953140) with a ~30% TG‐reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter‐variant of the liver‐derived apolipoprotein A‐V (apoA‐V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG‐levels. We thus hypothesized that PC7 regulates the levels/activity of apoA‐V. Studies in the human hepatic cell line HuH7 revealed that wild‐type (WT) PC7 and its endoplasmic reticulum (ER)‐retained forms bind to and enhance the degradation of human apoA‐V in acidic lysosomes in a non‐enzymatic fashion. PC7‐induced degradation of apoA‐V is inhibited by bafilomycin‐A1, and the alkalinizing agents: chloroquine and NH4Cl. Thus, the PC7‐induced apoA‐V degradation implicates an ER‐lysosomal communication inhibited by bafilomycin‐A1. In vitro, the natural R504H mutant enhances PC7 Ser505‐phosphorylation at the structurally‐exposed Ser‐X‐Glu507 motif recognized by the secretory kinase Fam20C. Co‐expression of the phosphomimetic PC7‐S505E with apoA‐V resulted in lower degradation compared to WT, suggesting that Ser505 phosphorylation of PC7 lowers TG levels via reduced apoA‐V degradation. In agreement, in Pcsk7‐/‐ mice fed high‐fat diet, plasma apoA‐V levels and adipocyte LpL activity are increased, providing an in vivo mechanistic link for a role of liver PC7 in enhanced TG storage in adipocytes.