The target landscape of clinical kinase drugs

<p>Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD&ndash;positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.</p>

Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils

<p>Bone marrow&ndash;derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (<I>n</I> = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn<sup>+</sup>) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF<sup>high</sup> neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn<sup>+</sup> cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF<sup>high</sup> neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.</p>

Metalenses: Versatile multifunctional photonic components

<p>Recent progress in metasurface designs fueled by advanced-fabrication techniques has led to the realization of ultrathin, lightweight, and flat lenses (metalenses) with unprecedented functionalities. Owing to straightforward fabrication, generally requiring a single-step lithography, and the possibility of vertical integration, these planar lenses can potentially replace or complement their conventional refractive and diffractive counterparts, leading to further miniaturization of high-performance optical devices and systems. Here we provide a brief overview of the evolution of metalenses, with an emphasis on the visible and near-infrared spectrum, and summarize their important features: diffraction-limited focusing, high-quality imaging, and multifunctionalities. We discuss impending challenges, including aberration correction, and also examine current issues and solutions. We conclude by providing an outlook of this technology platform and identifying promising directions for future research.</p>

Comment on "Water harvesting from air with metal-organic frameworks powered by natural sunlight"

<p>Kim <I>et al</I>. (Reports, 28 April 2017, p. 430) describe a method for harvesting water from air, using a metal-organic framework (MOF) as the adsorbent. The process as described in the paper is, however, inadequate, and the system cannot deliver the claimed amount of liquid water in an arid climate. A modification of the process design and the use of more suitable MOFs may be more likely to achieve the goals targeted by Kim <I>et al</I>.</p>

Response to Comment on "Water harvesting from air with metal-organic frameworks powered by natural sunlight"

<p>The Comment by Meunier states that the process we described in our report cannot deliver the claimed amount of liquid water in an arid climate. This statement is not valid because the parameters presented in our study were inappropriately combined to draw misguided conclusions.</p>

RNA editing with CRISPR-Cas13

<p>Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided ribonuclease Cas13. We profiled type VI systems in order to engineer a Cas13 ortholog capable of robust knockdown and demonstrated RNA editing by using catalytically inactive Cas13 (dCas13) to direct adenosine-to-inosine deaminase activity by ADAR2 (adenosine deaminase acting on RNA type 2) to transcripts in mammalian cells. This system, referred to as RNA Editing for Programmable A to I Replacement (REPAIR), which has no strict sequence constraints, can be used to edit full-length transcripts containing pathogenic mutations. We further engineered this system to create a high-specificity variant and minimized the system to facilitate viral delivery. REPAIR presents a promising RNA-editing platform with broad applicability for research, therapeutics, and biotechnology.</p>

Molecular and cellular reorganization of neural circuits in the human lineage

<p>To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type&ndash;specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.</p>

Structure-property relationships from universal signatures of plasticity in disordered solids

<p>When deformed beyond their elastic limits, crystalline solids flow plastically via particle rearrangements localized around structural defects. Disordered solids also flow, but without obvious structural defects. We link structure to plasticity in disordered solids via a microscopic structural quantity, "softness," designed by machine learning to be maximally predictive of rearrangements. Experimental results and computations enabled us to measure the spatial correlations and strain response of softness, as well as two measures of plasticity: the size of rearrangements and the yield strain. All four quantities maintained remarkable commonality in their values for disordered packings of objects ranging from atoms to grains, spanning seven orders of magnitude in diameter and 13 orders of magnitude in elastic modulus. These commonalities link the spatial correlations and strain response of softness to rearrangement size and yield strain, respectively.</p>

Ten-month-old infants infer the value of goals from the costs of actions

<p>Infants understand that people pursue goals, but how do they learn which goals people prefer? We tested whether infants solve this problem by inverting a mental model of action planning, trading off the costs of acting against the rewards actions bring. After seeing an agent attain two goals equally often at varying costs, infants expected the agent to prefer the goal it attained through costlier actions. These expectations held across three experiments that conveyed cost through different physical path features (height, width, and incline angle), suggesting that an abstract variable&mdash;such as "force," "work," or "effort"&mdash;supported infants&rsquo; inferences. We modeled infants&rsquo; expectations as Bayesian inferences over utility-theoretic calculations, providing a bridge to recent quantitative accounts of action understanding in older children and adults.</p>

The fundamental advantages of temporal networks

<p>Most networked systems of scientific interest are characterized by temporal links, meaning the network&rsquo;s structure changes over time. Link temporality has been shown to hinder many dynamical processes, from information spreading to accessibility, by disrupting network paths. Considering the ubiquity of temporal networks in nature, we ask: Are there any advantages of the networks&rsquo; temporality? We use an analytical framework to show that temporal networks can, compared to their static counterparts, reach controllability faster, demand orders of magnitude less control energy, and have control trajectories, that are considerably more compact than those characterizing static networks. Thus, temporality ensures a degree of flexibility that would be unattainable in static networks, enhancing our ability to control them.</p>

Major role of nitrite-oxidizing bacteria in dark ocean carbon fixation

<p>Carbon fixation by chemoautotrophic microorganisms in the dark ocean has a major impact on global carbon cycling and ecological relationships in the ocean&rsquo;s interior, but the relevant taxa and energy sources remain enigmatic. We show evidence that nitrite-oxidizing bacteria affiliated with the Nitrospinae phylum are important in dark ocean chemoautotrophy. Single-cell genomics and community metagenomics revealed that Nitrospinae are the most abundant and globally distributed nitrite-oxidizing bacteria in the ocean. Metaproteomics and metatranscriptomics analyses suggest that nitrite oxidation is the main pathway of energy production in Nitrospinae. Microautoradiography, linked with catalyzed reporter deposition fluorescence in situ hybridization, indicated that Nitrospinae fix 15 to 45% of inorganic carbon in the mesopelagic western North Atlantic. Nitrite oxidation may have a greater impact on the carbon cycle than previously assumed.</p>

An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism

<p>Viruses regulate host metabolic networks to improve their survival. The molecules that are responsive to viral infection and regulate such metabolic changes are hardly known, but are essential for understanding viral infection. Here we identify a long noncoding RNA (lncRNA) that is induced by multiple viruses, but not by type I interferon (IFN-I), and facilitates viral replication in mouse and human cells. In vivo deficiency of lncRNA-ACOD1 (a lncRNA identified by its nearest coding gene <I>Acod1</I>, aconitate decarboxylase 1) significantly attenuates viral infection through IFN-I&ndash;IRF3 (interferon regulatory factor 3)&ndash;independent pathways. Cytoplasmic lncRNA-ACOD1 directly binds the metabolic enzyme glutamic-oxaloacetic transaminase (GOT2) near the substrate niche, enhancing its catalytic activity. Recombinant GOT2 protein and its metabolites could rescue viral replication upon lncRNA-ACOD1 deficiency and increase lethality. This work reveals a feedback mechanism of virus-induced lncRNA-mediated metabolic promotion of viral infection and a potential target for developing broad-acting antiviral therapeutics.</p>

Architecture of eukaryotic mRNA 3'-end processing machinery

<p>Newly transcribed eukaryotic precursor messenger RNAs (pre-mRNAs) are processed at their 3' ends by the ~1-megadalton multiprotein cleavage and polyadenylation factor (CPF). CPF cleaves pre-mRNAs, adds a polyadenylate tail, and triggers transcription termination, but it is unclear how its various enzymes are coordinated and assembled. Here, we show that the nuclease, polymerase, and phosphatase activities of yeast CPF are organized into three modules. Using electron cryomicroscopy, we determined a 3.5-angstrom-resolution structure of the ~200-kilodalton polymerase module. This revealed four &beta; propellers, in an assembly markedly similar to those of other protein complexes that bind nucleic acid. Combined with in vitro reconstitution experiments, our data show that the polymerase module brings together factors required for specific and efficient polyadenylation, to help coordinate mRNA 3'-end processing.</p>

Structure of the TAPBPR-MHC I complex defines the mechanism of peptide loading and editing

<p>Adaptive immunity is shaped by a selection of peptides presented on major histocompatibility complex class I (MHC I) molecules. The chaperones Tapasin (Tsn) and TAP-binding protein&ndash;related (TAPBPR) facilitate MHC I peptide loading and high-affinity epitope selection. Despite the pivotal role of Tsn and TAPBPR in controlling the hierarchical immune response, their catalytic mechanism remains unknown. Here, we present the x-ray structure of the TAPBPR&ndash;MHC I complex, which delineates the central step of catalysis. TAPBPR functions as peptide selector by remodeling the MHC I &alpha;2-1-helix region, stabilizing the empty binding groove, and inserting a loop into the groove that interferes with peptide binding. The complex explains how mutations in MHC I&ndash;specific chaperones cause defects in antigen processing and suggests a unifying mechanism of peptide proofreading.</p>

Crystal structure of a TAPBPR-MHC I complex reveals the mechanism of peptide editing in antigen presentation

<p>Central to CD8<sup>+</sup> T cell&ndash;mediated immunity is the recognition of peptide&ndash;major histocompatibility complex class I (p&ndash;MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein&ndash;related), a tapasin homolog. TAPBPR remodels the peptide-binding groove of MHC I, resulting in the release of low-affinity peptide. Changes include groove relaxation, modifications of key binding pockets, and domain adjustments. This structure captures a peptide-receptive state of MHC I and provides insights into the mechanism of peptide editing by TAPBPR and, by analogy, tapasin.</p>

Control of zeolite framework flexibility and pore topology for separation of ethane and ethylene

<p>The discovery of new materials for separating ethylene from ethane by adsorption, instead of using cryogenic distillation, is a key milestone for molecular separations because of the multiple and widely extended uses of these molecules in industry. This technique has the potential to provide tremendous energy savings when compared with the currently used cryogenic distillation process for ethylene produced through steam cracking. Here we describe the synthesis and structural determination of a flexible pure silica zeolite (ITQ-55). This material can kinetically separate ethylene from ethane with an unprecedented selectivity of ~100, owing to its distinctive pore topology with large heart-shaped cages and framework flexibility. Control of such properties extends the boundaries for applicability of zeolites to challenging separations.</p>

Three-dimensional mechanical metamaterials with a twist

<p>Rationally designed artificial materials enable mechanical properties that are inaccessible with ordinary materials. Pushing on an ordinary linearly elastic bar can cause it to be deformed in many ways. However, a twist, the counterpart of optical activity in the static case, is strictly zero. The unavailability of this degree of freedom hinders applications in terms of mode conversion and the realization of advanced mechanical designs using coordinate transformations. Here, we aim at realizing microstructured three-dimensional elastic chiral mechanical metamaterials that overcome this limitation. On overall millimeter-sized samples, we measure twists per axial strain exceeding 2&deg;/%. Scaling up the number of unit cells for fixed sample dimensions, the twist is robust due to metamaterial stiffening, indicating a characteristic length scale and bringing the aforementioned applications into reach.</p>

Topological origin of equatorial waves

<p>Topology sheds new light on the emergence of unidirectional edge waves in a variety of physical systems, from condensed matter to artificial lattices. Waves observed in geophysical flows are also robust to perturbations, which suggests a role for topology. We show a topological origin for two well-known equatorially trapped waves, the Kelvin and Yanai modes, owing to the breaking of time-reversal symmetry by Earth&rsquo;s rotation. The nontrivial structure of the bulk Poincar&eacute; wave modes encoded through the first Chern number of value 2 guarantees the existence of these waves. This invariant demonstrates that ocean and atmospheric waves share fundamental properties with topological insulators and that topology plays an unexpected role in Earth&rsquo;s climate system.</p>

Creation of a Bose-condensed gas of 87Rb by laser cooling

<p>Protocols for attaining quantum degeneracy in atomic gases almost exclusively rely on evaporative cooling, a time-consuming final step associated with substantial atom loss. We demonstrate direct laser cooling of a gas of rubidium-87 (<sup>87</sup>Rb) atoms to quantum degeneracy. The method is fast and induces little atom loss. The atoms are trapped in a two-dimensional optical lattice that enables cycles of compression to increase the density, followed by Raman sideband cooling to decrease the temperature. From a starting number of 2000 atoms, 1400 atoms reach quantum degeneracy in 300 milliseconds, as confirmed by a bimodal velocity distribution. The method should be broadly applicable to many bosonic and fermionic species and to systems where evaporative cooling is not possible.</p>

Double-trap measurement of the proton magnetic moment at 0.3 parts per billion precision

<p>Precise knowledge of the fundamental properties of the proton is essential for our understanding of atomic structure as well as for precise tests of fundamental symmetries. We report on a direct high-precision measurement of the magnetic moment &mu;<SUB>p</SUB> of the proton in units of the nuclear magneton &mu;<SUB>N</SUB>. The result, &mu;<SUB>p</SUB> = 2.79284734462 (&plusmn;0.00000000082) &mu;<SUB>N</SUB>, has a fractional precision of 0.3 parts per billion, improves the previous best measurement by a factor of 11, and is consistent with the currently accepted value. This was achieved with the use of an optimized double&ndash;Penning trap technique. Provided a similar measurement of the antiproton magnetic moment can be performed, this result will enable a test of the fundamental symmetry between matter and antimatter in the baryonic sector at the 10<sup>&ndash;10</sup> level.</p>

Current-induced strong diamagnetism in the Mott insulator Ca2RuO4

<p>Mott insulators can host a surprisingly diverse set of quantum phenomena when their frozen electrons are perturbed by various stimuli. Superconductivity, metal-insulator transition, and colossal magnetoresistance induced by element substitution, pressure, and magnetic field are prominent examples. Here we report strong diamagnetism in the Mott insulator calcium ruthenate (Ca<SUB>2</SUB>RuO<SUB>4</SUB>) induced by dc electric current. The application of a current density of merely 1 ampere per centimeter squared induces diamagnetism stronger than that in other nonsuperconducting materials. This change is coincident with changes in the transport properties as the system becomes semimetallic. These findings suggest that dc current may be a means to control the properties of materials in the vicinity of a Mott insulating transition.</p>

Structural insights into ion conduction by channelrhodopsin 2

<p>The light-gated ion channel channelrhodopsin 2 (ChR2) from <I>Chlamydomonas reinhardtii</I> is a major optogenetic tool. Photon absorption starts a well-characterized photocycle, but the structural basis for the regulation of channel opening remains unclear. We present high-resolution structures of ChR2 and the C128T mutant, which has a markedly increased open-state lifetime. The structure reveals two cavities on the intracellular side and two cavities on the extracellular side. They are connected by extended hydrogen-bonding networks involving water molecules and side-chain residues. Central is the retinal Schiff base that controls and synchronizes three gates that separate the cavities. Separate from this network is the DC gate that comprises a water-mediated bond between C128 and D156 and interacts directly with the retinal Schiff base. Comparison with the C128T structure reveals a direct connection of the DC gate to the central gate and suggests how the gating mechanism is affected by subtle tuning of the Schiff base&rsquo;s interactions.</p>

Response to Comment on "The extent of forest in dryland biomes"

<p>Griffith <I>et al</I>. do not question the quality of our analysis, but they question our results with respect to the definition of forest we employed. In our response, we explain why the differences we report result from a difference of technique and not of definition, and how anyone can adapt&mdash;as we did&mdash;our data set to any forest definition and tree cover threshold of interest.</p>

The structural basis of flagellin detection by NAIP5: A strategy to limit pathogen immune evasion

<p>Robust innate immune detection of rapidly evolving pathogens is critical for host defense. Nucleotide-binding domain leucine-rich repeat (NLR) proteins function as cytosolic innate immune sensors in plants and animals. However, the structural basis for ligand-induced NLR activation has so far remained unknown. NAIP5 (NLR family, apoptosis inhibitory protein 5) binds the bacterial protein flagellin and assembles with NLRC4 to form a multiprotein complex called an inflammasome. Here we report the cryo&ndash;electron microscopy structure of the assembled ~1.4-megadalton flagellin-NAIP5-NLRC4 inflammasome, revealing how a ligand activates an NLR. Six distinct NAIP5 domains contact multiple conserved regions of flagellin, prying NAIP5 into an open and active conformation. We show that innate immune recognition of multiple ligand surfaces is a generalizable strategy that limits pathogen evolution and immune escape.</p>

Photoionization in the time and frequency domain

<p>Ultrafast processes in matter, such as the electron emission after light absorption, can now be studied using ultrashort light pulses of attosecond duration (10<sup>&ndash;18</sup> seconds) in the extreme ultraviolet spectral range. The lack of spectral resolution due to the use of short light pulses has raised issues in the interpretation of the experimental results and the comparison with theoretical calculations. We determine photoionization time delays in neon atoms over a 40&ndash;electron volt energy range with an interferometric technique combining high temporal and spectral resolution. We spectrally disentangle direct ionization from ionization with shake-up, in which a second electron is left in an excited state, and obtain excellent agreement with theoretical calculations, thereby solving a puzzle raised by 7-year-old measurements.</p>

Arbitrary spin-to-orbital angular momentum conversion of light

<p>Optical elements that convert the spin angular momentum (SAM) of light into vortex beams have found applications in classical and quantum optics. These elements&mdash;SAM-to&ndash;orbital angular momentum (OAM) converters&mdash;are based on the geometric phase and only permit the conversion of left- and right-circular polarizations (spin states) into states with opposite OAM. We present a method for converting arbitrary SAM states into total angular momentum states characterized by a superposition of independent OAM. We designed a metasurface that converts left- and right-circular polarizations into states with independent values of OAM and designed another device that performs this operation for elliptically polarized states. These results illustrate a general material-mediated connection between SAM and OAM of light and may find applications in producing complex structured light and in optical communication.</p>

Full momentum- and energy-resolved spectral function of a 2D electronic system

<p>The single-particle spectral function measures the density of electronic states in a material as a function of both momentum and energy, providing central insights into strongly correlated electron phenomena. Here we demonstrate a high-resolution method for measuring the full momentum- and energy-resolved electronic spectral function of a two-dimensional (2D) electronic system embedded in a semiconductor. The technique remains operational in the presence of large externally applied magnetic fields and functions even for electronic systems with zero electrical conductivity or with zero electron density. Using the technique on a prototypical 2D system, a GaAs quantum well, we uncover signatures of many-body effects involving electron-phonon interactions, plasmons, polarons, and a phonon analog of the vacuum Rabi splitting in atomic systems.</p>

Tunable excitons in bilayer graphene

<p>Excitons, the bound states of an electron and a hole in a solid material, play a key role in the optical properties of insulators and semiconductors. Here, we report the observation of excitons in bilayer graphene (BLG) using photocurrent spectroscopy of high-quality BLG encapsulated in hexagonal boron nitride. We observed two prominent excitonic resonances with narrow line widths that are tunable from the mid-infrared to the terahertz range. These excitons obey optical selection rules distinct from those in conventional semiconductors and feature an electron pseudospin winding number of 2. An external magnetic field induces a large splitting of the valley excitons, corresponding to a <I>g</I>-factor of about 20. These findings open up opportunities to explore exciton physics with pseudospin texture in electrically tunable graphene systems.</p>

Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth

<p>The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera&ndash;electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera&ndash;electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin.</p>

Compacted dimensions and singular plasmonic surfaces

<p>In advanced field theories, there can be more than four dimensions to space, the excess dimensions described as compacted and unobservable on everyday length scales. We report a simple model, unconnected to field theory, for a compacted dimension realized in a metallic metasurface periodically structured in the form of a grating comprising a series of singularities. An extra dimension of the grating is hidden, and the surface plasmon excitations, though localized at the surface, are characterized by three wave vectors rather than the two of typical two-dimensional metal grating. We propose an experimental realization in a doped graphene layer.</p>