ALBERT

Description: Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace tests with juvenile fish. Hundreds of thousands of fish at this developmental stage are annually used to assess the influence of chemicals on growth. Juveniles are more sensitive than adult fish, and their growth can affect their chances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical impact on fish growth based on in vitro data. Our model predicts reduced fish growth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration.

Description: Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis b (Le b ) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Le b antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Le b at 2.0- and 2.1-Å resolutions, respectively. BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Le b binding site at its tip within a β-strand motif. No conformational change occurs in BabA upon binding of Le b , which is characterized by low affinity under acidic [ K D (dissociation constant) of ~227 μM] and neutral ( K D of ~252 μM) conditions. Binding is mediated by a network of hydrogen bonds between Le b Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Le b , respectively. Knowledge of the molecular basis of Le b recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa.

Description: In the absence of sensory stimulation or motor output, the brain exhibits complex spatiotemporal patterns of intrinsically generated neural activity. Analysis of ongoing brain dynamics has identified the prevailing modes of cortico-cortical interaction; however, little is known about how such patterns of intrinsically generated activity are correlated between cortical and subcortical brain areas. We investigate the correlation structure of ongoing cortical and superior colliculus (SC) activity across multiple spatial and temporal scales. Ongoing cortico-tectal interaction was characterized by correlated fluctuations in the amplitude of delta, spindle, low gamma, and high-frequency oscillations (〉100 Hz). Of these identified coupling modes, topographical patterns of high-frequency coupling were the most consistent with patterns of anatomical connectivity, reflecting synchronized spiking within cortico-tectal networks. Cortico-tectal coupling at high frequencies was temporally parcellated by the phase of slow cortical oscillations and was strongest for SC-cortex channel pairs that displayed overlapping visual spatial receptive fields. Despite displaying a high degree of spatial specificity, cortico-tectal coupling in lower-frequency bands did not match patterns of cortex-to-SC anatomical connectivity. Collectively, our findings demonstrate that neural activity is spontaneously coupled between cortex and SC, with high- and low-frequency modes of coupling reflecting direct and indirect cortico-tectal interactions, respectively.

Description: There is a striking correlation between terrestrial species’ pupil shape and ecological niche (that is, foraging mode and time of day they are active). Species with vertically elongated pupils are very likely to be ambush predators and active day and night. Species with horizontally elongated pupils are very likely to be prey and to have laterally placed eyes. Vertically elongated pupils create astigmatic depth of field such that images of vertical contours nearer or farther than the distance to which the eye is focused are sharp, whereas images of horizontal contours at different distances are blurred. This is advantageous for ambush predators to use stereopsis to estimate distances of vertical contours and defocus blur to estimate distances of horizontal contours. Horizontally elongated pupils create sharp images of horizontal contours ahead and behind, creating a horizontally panoramic view that facilitates detection of predators from various directions and forward locomotion across uneven terrain.

Description: Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase Pc Cel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium . Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the "Newton’s cradle"–like proton relay pathway of the catalytic cycle. Amide–imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions.

Description: A unique functional electrode made of hierarchal Ni-Mo-S nanosheets with abundant exposed edges anchored on conductive and flexible carbon fiber cloth, referred to as Ni-Mo-S/C, has been developed through a facile biomolecule-assisted hydrothermal method. The incorporation of Ni atoms in Mo-S plays a crucial role in tuning its intrinsic catalytic property by creating substantial defect sites as well as modifying the morphology of Ni-Mo-S network at atomic scale, resulting in an impressive enhancement in the catalytic activity. The Ni-Mo-S/C electrode exhibits a large cathodic current and a low onset potential for hydrogen evolution reaction in neutral electrolyte (pH ~7), for example, current density of 10 mA/cm 2 at a very small overpotential of 200 mV. Furthermore, the Ni-Mo-S/C electrode has excellent electrocatalytic stability over an extended period, much better than those of MoS 2 /C and Pt plate electrodes. Scanning and transmission electron microscopy, Raman spectroscopy, x-ray diffraction, x-ray photoelectron spectroscopy, and x-ray absorption spectroscopy were used to understand the formation process and electrocatalytic properties of Ni-Mo-S/C. The intuitive comparison test was designed to reveal the superior gas-evolving profile of Ni-Mo-S/C over that of MoS 2 /C, and a laboratory-scale hydrogen generator was further assembled to demonstrate its potential application in practical appliances.

Description: The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others. The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces. More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine–Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed.

Description: Alkali-doped fullerides A 3 C 60 ( A = K, Rb, Cs) are surprising materials where conventional phonon-mediated superconductivity and unconventional Mott physics meet, leading to a remarkable phase diagram as a function of volume per C 60 molecule. We address these materials with a state-of-the-art calculation, where we construct a realistic low-energy model from first principles without using a priori information other than the crystal structure and solve it with an accurate many-body theory. Remarkably, our scheme comprehensively reproduces the experimental phase diagram including the low-spin Mott-insulating phase next to the superconducting phase. More remarkably, the critical temperatures T c ’s calculated from first principles quantitatively reproduce the experimental values. The driving force behind the surprising phase diagram of A 3 C 60 is a subtle competition between Hund’s coupling and Jahn-Teller phonons, which leads to an effectively inverted Hund’s coupling. Our results establish that the fullerides are the first members of a novel class of molecular superconductors in which the multiorbital electronic correlations and phonons cooperate to reach high T c s -wave superconductivity.

Description: Nitrogen oxides, released from fossil fuel use and other combustion processes, affect air quality and climate. From the mid-1990s onward, nitrogen dioxide (NO 2 ) has been monitored from space, and since 2004 with relatively high spatial resolution by the Ozone Monitoring Instrument. Strong upward NO 2 trends have been observed over South and East Asia and the Middle East, in particular over major cities. We show, however, that a combination of air quality control and political factors, including economical crisis and armed conflict, has drastically altered the emission landscape of nitrogen oxides in the Middle East. Large changes, including trend reversals, have occurred since about 2010 that could not have been predicted and therefore are at odds with emission scenarios used in projections of air pollution and climate change in the early 21st century.

Description: Cluster analysis is one of the most popular data analysis tools in a wide range of applied disciplines. We propose and justify a computationally efficient and straightforward-to-implement way of imposing the available information from networks/graphs (a priori available in many application areas) on a broad family of clustering methods. The introduced approach is illustrated on the problem of a noninvasive unsupervised brain signal classification. This task is faced with several challenging difficulties such as nonstationary noisy signals and a small sample size, combined with a high-dimensional feature space and huge noise-to-signal ratios. Applying this approach results in an exact unsupervised classification of very short signals, opening new possibilities for clustering methods in the area of a noninvasive brain-computer interface.

Description: The CRISPR (clustered regularly interspaced short palindromic repeats)–Cas (CRISPR-associated) nuclease system represents an efficient tool for genome editing and gene function analysis. It consists of two components: single-guide RNA (sgRNA) and the enzyme Cas9. Typical sgRNA and Cas9 intracellular delivery techniques are limited by their reliance on cell type and exogenous materials as well as their toxic effects on cells (for example, electroporation). We introduce and optimize a microfluidic membrane deformation method to deliver sgRNA and Cas9 into different cell types and achieve successful genome editing. This approach uses rapid cell mechanical deformation to generate transient membrane holes to enable delivery of biomaterials in the medium. We achieved high delivery efficiency of different macromolecules into different cell types, including hard-to-transfect lymphoma cells and embryonic stem cells, while maintaining high cell viability. With the advantages of broad applicability across different cell types, particularly hard-to-transfect cells, and flexibility of application, this method could potentially enable new avenues of biomedical research and gene targeting therapy such as mutation correction of disease genes through combination of the CRISPR-Cas9–mediated knockin system.

Description: Ocean acidification threatens the survival of coral reef ecosystems worldwide. The negative effects of ocean acidification observed in many laboratory experiments have been seen in studies of naturally low-pH reefs, with little evidence to date for adaptation. Recently, we reported initial data suggesting that low-pH coral communities of the Palau Rock Islands appear healthy despite the extreme conditions in which they live. Here, we build on that observation with a comprehensive statistical analysis of benthic communities across Palau’s natural acidification gradient. Our analysis revealed a shift in coral community composition but no impact of acidification on coral richness, coralline algae abundance, macroalgae cover, coral calcification, or skeletal density. However, coral bioerosion increased 11-fold as pH decreased from the barrier reefs to the Rock Island bays. Indeed, a comparison of the naturally low-pH coral reef systems studied so far revealed increased bioerosion to be the only consistent feature among them, as responses varied across other indices of ecosystem health. Our results imply that whereas community responses may vary, escalation of coral reef bioerosion and acceleration of a shift from net accreting to net eroding reef structures will likely be a global signature of ocean acidification.

Description: Eukaryotic replication disrupts each nucleosome as the fork passes, followed by reassembly of disrupted nucleosomes and incorporation of newly synthesized histones into nucleosomes in the daughter genomes. In this review, we examine this process of replication-coupled nucleosome assembly to understand how characteristic steady-state nucleosome landscapes are attained. Recent studies have begun to elucidate mechanisms involved in histone transfer during replication and maturation of the nucleosome landscape after disruption by replication. A fuller understanding of replication-coupled nucleosome assembly will be needed to explain how epigenetic information is replicated at every cell division.

Description: The structure effect is widely present in the catalysis of alloy systems. However, the surface structure of this system is still ambiguous because of the limitations of the current surface characterization tools. We reported the x-ray crystallographic structure of the first and the largest AgAu alloy nanocluster with a doping shell formulated as [Ag 46 Au 24 (SR) 32 ](BPh 4 ) 2 . This nanocluster consists of an achiral bimetallic Ag 2 @Au 18 @Ag 20 core protected by a chiral Ag 24 Au 6 (SR) 32 shell. The catalysis experiments further revealed that the surface structure affects the selectivity of products significantly. This is the first case to find the structure effect in atomically precise alloy nanoclusters. Our work will benefit the basic understanding of bimetal distribution, as well as the structure-related catalytic property of alloy nanoclusters at the atomic level.

Description: The accumulation of amyloid fibrils is the hallmark of several major human diseases. Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties. Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies. We determine that several other metabolites that accumulate in metabolic disorders form ordered amyloid-like ultrastructures, which induce apoptotic cell death, as observed for amyloid structures. The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases.

Description: The developmental costs and benefits of early locomotor play are a puzzling topic in biology, psychology, and health sciences. Evolutionary theory predicts that energy-intensive behavior such as play can only evolve if there are considerable benefits. Prominent theories propose that locomotor play is (i) low cost, using surplus energy remaining after growth and maintenance, and (ii) beneficial because it trains motor skills. However, both theories are largely untested. Studying wild Assamese macaques, we combined behavioral observations of locomotor play and motor skill acquisition with quantitative measures of natural food availability and individual growth rates measured noninvasively via photogrammetry. Our results show that investments in locomotor play were indeed beneficial by accelerating motor skill acquisition but carried sizable costs in terms of reduced growth. Even under moderate natural energy restriction, investment in locomotor play accounted for up to 50% of variance in growth, which strongly contradicts the current theory that locomotor play only uses surplus energy remaining after growth and maintenance. Male immatures played more, acquired motor skills faster, and grew less than female immatures, leading to persisting size differences until the age of female maturity. Hence, depending on skill requirements, investment in play can take ontogenetic priority over physical development unconstrained by costs of play with consequences for life history, which strongly highlights the ontogenetic and evolutionary importance of play.

Description: Ultraviolet (UV) reception is useful for such basic behaviors as mate choice, foraging, predator avoidance, communication, and navigation, whereas violet reception improves visual resolution and subtle contrast detection. UV and violet reception are mediated by the short wavelength–sensitive (SWS1) pigments that absorb light maximally ( max ) at ~360 nm and ~395 to 440 nm, respectively. Because of strong nonadditive (epistatic) interactions among amino acid changes in the pigments, the adaptive evolutionary mechanisms of these phenotypes are not well understood. Evolution of the violet pigment of the African clawed frog ( Xenopus laevis , max = 423 nm) from the UV pigment in the amphibian ancestor ( max = 359 nm) can be fully explained by eight mutations in transmembrane (TM) I–III segments. We show that epistatic interactions involving the remaining TM IV–VII segments provided evolutionary potential for the frog pigment to gradually achieve its violet-light reception by tuning its color sensitivity in small steps. Mutants in these segments also impair pigments that would cause drastic spectral shifts and thus eliminate them from viable evolutionary pathways. The overall effects of epistatic interactions involving TM IV–VII segments have disappeared at the last evolutionary step and thus are not detectable by studying present-day pigments. Therefore, characterizing the genotype-phenotype relationship during each evolutionary step is the key to uncover the true nature of epistasis.

Description: Collaborative research has become the mainstay in knowledge production across many domains of science and is widely promoted as a means of cultivating research quality, enhanced resource utilization, and high impact. An accurate appraisal of the value of collaborative research efforts is necessary to inform current funding and research policies. We reveal contemporary trends in collaborative research spanning multiple subject fields, with a particular focus on interactions between nations. We also examined citation outcomes of research teams and confirmed the accumulative benefits of having additional authors and unique countries involved. However, when per capita citation rates were analyzed to disambiguate the effects of authors and countries, decreasing returns in citations were noted with increasing authors among large research teams. In contrast, an increasing number of unique countries had a persistent additive citation effect. We also assessed the placement of foreign authors relative to the first author in paper bylines of biomedical research articles, which demonstrated a significant citation advantage of having an international presence in the second-to-last author position, possibly occupied by foreign primary co-investigators. Our analyses highlight the evolution and functional impact of team dynamics in research and suggest empirical strategies to evaluate team science.

Description: Creating complex spatial objects from a flat sheet of material using origami folding techniques has attracted attention in science and engineering. In the present work, we use the geometric properties of partially folded zigzag strips to better describe the kinematics of known zigzag/herringbone-base folded sheet metamaterials such as Miura-ori. Inspired by the kinematics of a one–degree of freedom zigzag strip, we introduce a class of cellular folded mechanical metamaterials comprising different scales of zigzag strips. This class of patterns combines origami folding techniques with kirigami. Using analytical and numerical models, we study the key mechanical properties of the folded materials. We show that our class of patterns, by expanding on the design space of Miura-ori, is appropriate for a wide range of applications from mechanical metamaterials to deployable structures at small and large scales. We further show that, depending on the geometry, these materials exhibit either negative or positive in-plane Poisson’s ratios. By introducing a class of zigzag-base materials in the current study, we unify the concept of in-plane Poisson’s ratio for similar materials in the literature and extend it to the class of zigzag-base folded sheet materials.

Description: A diverse set of innate immune mechanisms protects cells from viral infections. The APOBEC3 family of DNA cytosine deaminases is an integral part of these defenses. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H would have the potential to destroy HIV-1 complementary DNA replication intermediates if not for neutralization by a proteasomal degradation mechanism directed by the viral protein Vif. At the core of this complex, Vif heterodimerizes with the transcription cofactor CBF-β, which results in fewer transcription complexes between CBF-β and its normal RUNX partners. Recent studies have shown that the Vif/CBF-β interaction is specific to the primate lentiviruses HIV-1 and SIV (simian immunodeficiency virus), although related nonprimate lentiviruses still require a Vif-dependent mechanism for protection from host species’ APOBEC3 enzymes. We provide a molecular explanation for this evolutionary conundrum by showing that CBF-β is required for expression of the aforementioned HIV-1–restrictive APOBEC3 gene repertoire. Knockdown and knockout studies demonstrate that CBF-β is required for APOBEC3 mRNA expression in the nonpermissive T cell line H9 and in primary CD4 + T lymphocytes. Complementation experiments using CBF-β separation-of-function alleles show that the interaction with RUNX transcription factors is required for APOBEC3 transcriptional regulation. Accordingly, the infectivity of Vif-deficient HIV-1 increases in cells lacking CBF-β, demonstrating the importance of CBF-β/RUNX–mediated transcription in establishing the APOBEC3 antiviral state. These findings demonstrate a major layer of APOBEC3 gene regulation in lymphocytes and suggest that primate lentiviruses evolved to hijack CBF-β in order to simultaneously suppress this potent antiviral defense system at both transcriptional and posttranslational levels.

Description: Organic carbonyl compounds represent a promising class of electrode materials for secondary batteries; however, the storage mechanism still remains unclear. We take Na 2 C 6 H 2 O 4 as an example to unravel the mechanism. It consists of alternating Na-O octahedral inorganic layer and -stacked benzene organic layer in spatial separation, delivering a high reversible capacity and first coulombic efficiency. The experiment and calculation results reveal that the Na-O inorganic layer provides both Na + ion transport pathway and storage site, whereas the benzene organic layer provides electron transport pathway and redox center. Our contribution provides a brand-new insight in understanding the storage mechanism in inorganic-organic layered host and opens up a new exciting direction for designing new materials for secondary batteries.

Description: The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.

Description: How do social systems make decisions with no single individual in control? We observe that a variety of natural systems, including colonies of ants and bees and perhaps even neurons in the human brain, make decentralized decisions using common processes involving information search with positive feedback and consensus choice through quorum sensing. We model this process with an urn scheme that runs until hitting a threshold, and we characterize an inherent tradeoff between the speed and the accuracy of a decision. The proposed common mechanism provides a robust and effective means by which a decentralized system can navigate the speed-accuracy tradeoff and make reasonably good, quick decisions in a variety of environments. Additionally, consensus choice exhibits systemic risk aversion even while individuals are idiosyncratically risk-neutral. This too is adaptive. The model illustrates how natural systems make decentralized decisions, illuminating a mechanism that engineers of social and artificial systems could imitate.

Description: A photonic integrated circuit (PIC) is the optical analogy of an electronic loop in which photons are signal carriers with high transport speed and parallel processing capability. Besides the most frequently demonstrated silicon-based circuits, PICs require a variety of materials for light generation, processing, modulation, and detection. With their diversity and flexibility, organic molecular materials provide an alternative platform for photonics; however, the versatile fabrication of organic integrated circuits with the desired photonic performance remains a big challenge. The rapid development of flexible electronics has shown that a solution printing technique has considerable potential for the large-scale fabrication and integration of microsized/nanosized devices. We propose the idea of soft photonics and demonstrate the function-directed fabrication of high-quality organic photonic devices and circuits. We prepared size-tunable and reproducible polymer microring resonators on a wafer-scale transparent and flexible chip using a solution printing technique. The printed optical resonator showed a quality ( Q ) factor higher than 4 x 10 5 , which is comparable to that of silicon-based resonators. The high material compatibility of this printed photonic chip enabled us to realize low-threshold microlasers by doping organic functional molecules into a typical photonic device. On an identical chip, this construction strategy allowed us to design a complex assembly of one-dimensional waveguide and resonator components for light signal filtering and optical storage toward the large-scale on-chip integration of microscopic photonic units. Thus, we have developed a scheme for soft photonic integration that may motivate further studies on organic photonic materials and devices.

Description: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD–induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD + cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.

Description: The Rashba effect is one of the most striking manifestations of spin-orbit coupling in solids and provides a cornerstone for the burgeoning field of semiconductor spintronics. It is typically assumed to manifest as a momentum-dependent splitting of a single initially spin-degenerate band into two branches with opposite spin polarization. Combining polarization-dependent and resonant angle-resolved photoemission measurements with density functional theory calculations, we show that the two "spin-split" branches of the model giant Rashba system BiTeI additionally develop disparate orbital textures, each of which is coupled to a distinct spin configuration. This necessitates a reinterpretation of spin splitting in Rashba-like systems and opens new possibilities for controlling spin polarization through the orbital sector.

Description: Many insects use nectar as their principal diet and have mouthparts specialized in nectarivory, whereas most nectar-feeding vertebrates are opportunistic users of floral resources and only a few species show distinct morphological specializations. Specialized nectar-feeding bats extract nectar from flowers using elongated tongues that correspond to two vastly different morphologies: Most species have tongues with hair-like papillae, whereas one group has almost hairless tongues that show distinct lateral grooves. Recent molecular data indicate a convergent evolution of groove- and hair-tongued bat clades into the nectar-feeding niche. Using high-speed video recordings on experimental feeders, we show distinctly divergent nectar-feeding behavior in clades. Grooved tongues are held in contact with nectar for the entire duration of visit as nectar is pumped into the mouths of hovering bats, whereas hairy tongues are used in conventional sinusoidal lapping movements. Bats with grooved tongues use a specific fluid uptake mechanism not known from any other mammal. Nectar rises in semiopen lateral grooves, probably driven by a combination of tongue deformation and capillary action. Extraction efficiency declined for both tongue types with a similar slope toward deeper nectar levels. Our results highlight a novel drinking mechanism in mammals and raise further questions on fluid mechanics and ecological niche partitioning.

Description: Ecologists widely accept that the distribution of abundances in most communities is fairly flat but heavily dominated by a few species. The reason for this is that species abundances are thought to follow certain theoretical distributions that predict such a pattern. However, previous studies have focused on either a few theoretical distributions or a few empirical distributions. I illustrate abundance patterns in 1055 samples of trees, bats, small terrestrial mammals, birds, lizards, frogs, ants, dung beetles, butterflies, and odonates. Five existing theoretical distributions make inaccurate predictions about the frequencies of the most common species and of the average species, and most of them fit the overall patterns poorly, according to the maximum likelihood–related Kullback-Leibler divergence statistic. Instead, the data support a low-dominance distribution here called the "double geometric." Depending on the value of its two governing parameters, it may resemble either the geometric series distribution or the lognormal series distribution. However, unlike any other model, it assumes both that richness is finite and that species compete unequally for resources in a two-dimensional niche landscape, which implies that niche breadths are variable and that trait distributions are neither arrayed along a single dimension nor randomly associated. The hypothesis that niche space is multidimensional helps to explain how numerous species can coexist despite interacting strongly.

Description: Fragile X syndrome (FXS), the most common inherited form of intellectual disability disorder and a frequent cause of autism spectrum disorder (ASD), is characterized by a high prevalence of sensory symptoms. Perturbations in the anatomical connectivity of neocortical circuits resulting in their functional defects have been hypothesized to contribute to the underlying etiology of these disorders. We tested this idea by probing alterations in the functional and structural connectivity of both local and long-ranging neocortical circuits in the Fmr1 –/y mouse model of FXS. To achieve this, we combined in vivo ultrahigh-field diffusion tensor magnetic resonance imaging (MRI), functional MRI, and viral tracing approaches in adult mice. Our results show an anatomical hyperconnectivity phenotype for the primary visual cortex (V1), but a disproportional low connectivity of V1 with other neocortical regions. These structural data are supported by defects in the structural integrity of the subcortical white matter in the anterior and posterior forebrain. These anatomical alterations might contribute to the observed functional decoupling across neocortical regions. We therefore identify FXS as a "connectopathy," providing a translational model for understanding sensory processing defects and functional decoupling of neocortical areas in FXS and ASD.

Description: Entanglement is a key resource for quantum computers, quantum-communication networks, and high-precision sensors. Macroscopic spin ensembles have been historically important in the development of quantum algorithms for these prospective technologies and remain strong candidates for implementing them today. This strength derives from their long-lived quantum coherence, strong signal, and ability to couple collectively to external degrees of freedom. Nonetheless, preparing ensembles of genuinely entangled spin states has required high magnetic fields and cryogenic temperatures or photochemical reactions. We demonstrate that entanglement can be realized in solid-state spin ensembles at ambient conditions. We use hybrid registers comprising of electron-nuclear spin pairs that are localized at color-center defects in a commercial SiC wafer. We optically initialize 10 3 identical registers in a 40-μm 3 volume (with 0.95–0.07+0.05 fidelity) and deterministically prepare them into the maximally entangled Bell states (with 0.88 ± 0.07 fidelity). To verify entanglement, we develop a register-specific quantum-state tomography protocol. The entanglement of a macroscopic solid-state spin ensemble at ambient conditions represents an important step toward practical quantum technology.

Description: Estimates of extinction risk for Amazonian plant and animal species are rare and not often incorporated into land-use policy and conservation planning. We overlay spatial distribution models with historical and projected deforestation to show that at least 36% and up to 57% of all Amazonian tree species are likely to qualify as globally threatened under International Union for Conservation of Nature (IUCN) Red List criteria. If confirmed, these results would increase the number of threatened plant species on Earth by 22%. We show that the trends observed in Amazonia apply to trees throughout the tropics, and we predict that most of the world’s 〉40,000 tropical tree species now qualify as globally threatened. A gap analysis suggests that existing Amazonian protected areas and indigenous territories will protect viable populations of most threatened species if these areas suffer no further degradation, highlighting the key roles that protected areas, indigenous peoples, and improved governance can play in preventing large-scale extinctions in the tropics in this century.

Description: Although kinetic energy of a massive particle generally has quadratic dependence on its momentum, a flat, dispersionless energy band is realized in crystals with specific lattice structures. Such macroscopic degeneracy causes the emergence of localized eigenstates and has been a key concept in the context of itinerant ferromagnetism. We report the realization of a "Lieb lattice" configuration with an optical lattice, which has a flat energy band as the first excited state. Our optical lattice potential has various degrees of freedom in its manipulation, which enables coherent transfer of a Bose-Einstein condensate into the flat band. In addition to measuring lifetime of the flat band population for different tight-binding parameters, we investigate the inter-sublattice dynamics of the system by projecting the sublattice population onto the band population. This measurement clearly shows the formation of the localized state with the specific sublattice decoupled in the flat band, and even detects the presence of flat-band breaking perturbations, resulting in the delocalization. Our results will open up the possibilities of exploring the physics of flat bands with a highly controllable quantum system.

Description: Even though polycrystalline graphene has shown a surprisingly high tensile strength, the influence of inherent grain boundaries on such property remains unclear. We study the fracture properties of a series of polycrystalline graphene models of increasing thermodynamic stability, as obtained from a long molecular dynamics simulation at an elevated temperature. All of the models show the typical and well-documented brittle fracture behavior of polycrystalline graphene; however, a clear decrease in all fracture properties is observed with increasing annealing time. The remarkably high fracture properties obtained for the most disordered (less annealed) structures arise from the formation of many nonpropagating prefracture cracks, significantly retarding failure. The stability of these reversible cracks is due to the nonlocal character of load transfer after a bond rupture in very disordered systems. It results in an insufficient strain level on neighboring bonds to promote fracture propagation. Although polycrystallinity seems to be an unavoidable feature of chemically synthesized graphenes, these results suggest that targeting highly disordered states might be a convenient way to obtain improved mechanical properties.

Description: Polyploidy is a common mode of speciation and evolution in angiosperms (flowering plants). In contrast, there is little evidence to date that whole genome duplication (WGD) has played a significant role in the evolution of their putative extant sister lineage, the gymnosperms. Recent analyses of the spruce genome, the first published conifer genome, failed to detect evidence of WGDs in gene age distributions and attributed many aspects of conifer biology to a lack of WGDs. We present evidence for three ancient genome duplications during the evolution of gymnosperms, based on phylogenomic analyses of transcriptomes from 24 gymnosperms and 3 outgroups. We use a new algorithm to place these WGD events in phylogenetic context: two in the ancestry of major conifer clades (Pinaceae and cupressophyte conifers) and one in Welwitschia (Gnetales). We also confirm that a WGD hypothesized to be restricted to seed plants is indeed not shared with ferns and relatives (monilophytes), a result that was unclear in earlier studies. Contrary to previous genomic research that reported an absence of polyploidy in the ancestry of contemporary gymnosperms, our analyses indicate that polyploidy has contributed to the evolution of conifers and other gymnosperms. As in the flowering plants, the evolution of the large genome sizes of gymnosperms involved both polyploidy and repetitive element activity.

Description: The structure of DNA was determined in 1953 by x-ray fiber diffraction. Several attempts have been made to obtain a direct image of DNA with alternative techniques. The direct image is intended to allow a quantitative evaluation of all relevant characteristic lengths present in a molecule. A direct image of DNA, which is different from diffraction in the reciprocal space, is difficult to obtain for two main reasons: the intrinsic very low contrast of the elements that form the molecule and the difficulty of preparing the sample while preserving its pristine shape and size. We show that through a preparation procedure compatible with the DNA physiological conditions, a direct image of a single suspended DNA molecule can be obtained. In the image, all relevant lengths of A-form DNA are measurable. A high-resolution transmission electron microscope that operates at 80 keV with an ultimate resolution of 1.5 Å was used for this experiment. Direct imaging of a single molecule can be used as a method to address biological problems that require knowledge at the single-molecule level, given that the average information obtained by x-ray diffraction of crystals or fibers is not sufficient for detailed structure determination, or when crystals cannot be obtained from biological molecules or are not sufficient in understanding multiple protein configurations.

Description: The presence of numerous complex organic molecules (COMs; defined as those containing six or more atoms) around protostars shows that star formation is accompanied by an increase of molecular complexity. These COMs may be part of the material from which planetesimals and, ultimately, planets formed. Comets represent some of the oldest and most primitive material in the solar system, including ices, and are thus our best window into the volatile composition of the solar protoplanetary disk. Molecules identified to be present in cometary ices include water, simple hydrocarbons, oxygen, sulfur, and nitrogen-bearing species, as well as a few COMs, such as ethylene glycol and glycine. We report the detection of 21 molecules in comet C/2014 Q2 (Lovejoy), including the first identification of ethyl alcohol (ethanol, C 2 H 5 OH) and the simplest monosaccharide sugar glycolaldehyde (CH 2 OHCHO) in a comet. The abundances of ethanol and glycolaldehyde, respectively 5 and 0.8% relative to methanol (0.12 and 0.02% relative to water), are somewhat higher than the values measured in solar-type protostars. Overall, the high abundance of COMs in cometary ices supports the formation through grain-surface reactions in the solar system protoplanetary disk.

Description: Measuring small molecule interactions with membrane proteins in single cells is critical for understanding many cellular processes and for screening drugs. However, developing such a capability has been a difficult challenge. We show that molecular interactions with membrane proteins induce a mechanical deformation in the cellular membrane, and real-time monitoring of the deformation with subnanometer resolution allows quantitative analysis of small molecule–membrane protein interaction kinetics in single cells. This new strategy provides mechanical amplification of small binding signals, making it possible to detect small molecule interactions with membrane proteins. This capability, together with spatial resolution, also allows the study of the heterogeneous nature of cells by analyzing the interaction kinetics variability between different cells and between different regions of a single cell.

Description: Dominant climatic factors controlling the lifetime peak intensity of typhoons are determined from six decades of Pacific typhoon data. We find that upper ocean temperatures in the low-latitude northwestern Pacific (LLNWP) and sea surface temperatures in the central equatorial Pacific control the seasonal average lifetime peak intensity by setting the rate and duration of typhoon intensification, respectively. An anomalously strong LLNWP upper ocean warming has favored increased intensification rates and led to unprecedentedly high average typhoon intensity during the recent global warming hiatus period, despite a reduction in intensification duration tied to the central equatorial Pacific surface cooling. Continued LLNWP upper ocean warming as predicted under a moderate [that is, Representative Concentration Pathway (RCP) 4.5] climate change scenario is expected to further increase the average typhoon intensity by an additional 14% by 2100.

Description: Humans and many animals have forward-facing eyes providing different views of the environment. Precise depth estimates can be derived from the resulting binocular disparities, but determining which parts of the two retinal images correspond to one another is computationally challenging. To aid the computation, the visual system focuses the search on a small range of disparities. We asked whether the disparities encountered in the natural environment match that range. We did this by simultaneously measuring binocular eye position and three-dimensional scene geometry during natural tasks. The natural distribution of disparities is indeed matched to the smaller range of correspondence search. Furthermore, the distribution explains the perception of some ambiguous stereograms. Finally, disparity preferences of macaque cortical neurons are consistent with the natural distribution.

Description: Like modern microprocessors today, future processors of quantum information may be implemented using all-electrical control of silicon-based devices. A semiconductor spin qubit may be controlled without the use of magnetic fields by using three electrons in three tunnel-coupled quantum dots. Triple dots have previously been implemented in GaAs, but this material suffers from intrinsic nuclear magnetic noise. Reduction of this noise is possible by fabricating devices using isotopically purified silicon. We demonstrate universal coherent control of a triple-quantum-dot qubit implemented in an isotopically enhanced Si/SiGe heterostructure. Composite pulses are used to implement spin-echo type sequences, and differential charge sensing enables single-shot state readout. These experiments demonstrate sufficient control with sufficiently low noise to enable the long pulse sequences required for exchange-only two-qubit logic and randomized benchmarking.

Description: Type I modular polyketide synthases are responsible for potent therapeutic compounds that include avermectin (antihelinthic), rapamycin (immunosuppressant), pikromycin (antibiotic), and erythromycin (antibiotic). However, compound access and biosynthetic manipulation are often complicated by properties of native production organisms, prompting an approach (termed heterologous biosynthesis) illustrated in this study through the reconstitution of the erythromycin pathway through Escherichia coli . Using this heterologous system, 16 tailoring pathways were introduced, systematically producing eight chiral pairs of deoxysugar substrates. Successful analog formation for each new pathway emphasizes the remarkable flexibility of downstream enzymes to accommodate molecular variation. Furthermore, analogs resulting from three of the pathways demonstrated bioactivity against an erythromycin-resistant Bacillus subtilis strain. The approach and results support a platform for continued molecular diversification of the tailoring components of this and other complex natural product pathways in a manner that mirrors the modular nature of the upstream megasynthases responsible for aglycone polyketide formation.

Description: Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium -specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c 9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring’s ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.

Description: Large wild herbivores are crucial to ecosystems and human societies. We highlight the 74 largest terrestrial herbivore species on Earth (body mass ≥100 kg), the threats they face, their important and often overlooked ecosystem effects, and the conservation efforts needed to save them and their predators from extinction. Large herbivores are generally facing dramatic population declines and range contractions, such that ~60% are threatened with extinction. Nearly all threatened species are in developing countries, where major threats include hunting, land-use change, and resource depression by livestock. Loss of large herbivores can have cascading effects on other species including large carnivores, scavengers, mesoherbivores, small mammals, and ecological processes involving vegetation, hydrology, nutrient cycling, and fire regimes. The rate of large herbivore decline suggests that ever-larger swaths of the world will soon lack many of the vital ecological services these animals provide, resulting in enormous ecological and social costs.

Description: Highly crystalline mesoporous materials with oriented configurations are in demand for high-performance energy conversion devices. We report a simple evaporation-driven oriented assembly method to synthesize three-dimensional open mesoporous TiO 2 microspheres with a diameter of ~800 nm, well-controlled radially oriented hexagonal mesochannels, and crystalline anatase walls. The mesoporous TiO 2 spheres have a large accessible surface area (112 m 2 /g), a large pore volume (0.164 cm 3 /g), and highly single-crystal–like anatase walls with dominant (101) exposed facets, making them ideal for conducting mesoscopic photoanode films. Dye-sensitized solar cells (DSSCs) based on the mesoporous TiO 2 microspheres and commercial dye N719 have a photoelectric conversion efficiency of up to 12.1%. This evaporation-driven approach can create opportunities for tailoring the orientation of inorganic building blocks in the assembly of various mesoporous materials.

Description: The presence of seifertite, one of the high-pressure polymorphs of silica, in achondritic shocked meteorites has been problematic because this phase is thermodynamically stable at more than ~100 GPa, unrealistically high-pressure conditions for the shock events in the early solar system. We conducted in situ x-ray diffraction measurements at high pressure and temperatures, and found that it metastably appears down to ~11 GPa owing to the clear difference in kinetics between the metastable seifertite and stable stishovite formations. The temperature-insensitive but time-sensitive kinetics for the formation of seifertite uniquely constrains that the critical shock duration and size of the impactor on differentiated parental bodies are at least ~0.01 s and ~50 to 100 m, respectively, from the presence of seifertite.

Description: Motility is a basic feature of living microorganisms, and how it works is often determined by environmental cues. Recent efforts have focused on developing artificial systems that can mimic microorganisms, in particular their self-propulsion. We report on the design and characterization of synthetic self-propelled particles that migrate upstream, known as positive rheotaxis. This phenomenon results from a purely physical mechanism involving the interplay between the polarity of the particles and their alignment by a viscous torque. We show quantitative agreement between experimental data and a simple model of an overdamped Brownian pendulum. The model notably predicts the existence of a stagnation point in a diverging flow. We take advantage of this property to demonstrate that our active particles can sense and predictably organize in an imposed flow. Our colloidal system represents an important step toward the realization of biomimetic microsystems with the ability to sense and respond to environmental changes.

Description: Numerous climate change effects on biodiversity have been anticipated and documented, including extinctions, range shifts, phenological shifts, and breakdown of interactions in ecological communities, yet the relative balance of different climate drivers and their relationships to other agents of global change (for example, land use and land-use change) remains relatively poorly understood. This study integrated historical and current biodiversity data on distributions of 115 Mexican endemic bird species to document areas of concentrated gains and losses of species in local communities, and then related those changes to climate and land-use drivers. Of all drivers examined, at this relatively coarse spatial resolution, only temperature change had significant impacts on avifaunal turnover; neither precipitation change nor human impact on landscapes had detectable effects. This study, conducted across species’ geographic distributions, and covering all of Mexico, thanks to two large-scale biodiversity data sets, could discern relative importance of specific climatic drivers of biodiversity change.

Description: Highly migratory organisms present major challenges to conservation efforts. This is especially true for exploited anadromous fish species, which exhibit long-range dispersals from natal sites, complex population structures, and extensive mixing of distinct populations during exploitation. By tracing the migratory histories of individual Chinook salmon caught in fisheries using strontium isotopes, we determined the relative production of natal habitats at fine spatial scales and different life histories. Although strontium isotopes have been widely used in provenance research, we present a new robust framework to simultaneously assess natal sources and migrations of individuals within fishery harvests through time. Our results pave the way for investigating how fine-scale habitat production and life histories of salmon respond to perturbations—providing crucial insights for conservation.

Description: In one of the most celebrated examples of the theory of universal critical phenomena, the phase transition to the superfluid state of 4 He belongs to the same three-dimensional (3D) O(2) universality class as the onset of ferromagnetism in a lattice of classical spins with XY symmetry. Below the transition, the superfluid density s and superfluid velocity v s increase as a power law of temperature described by a universal critical exponent that is constrained to be identical by scale invariance. As the dimensionality is reduced toward 1D, it is expected that enhanced thermal and quantum fluctuations preclude long-range order, thereby inhibiting superfluidity. We have measured the flow rate of liquid helium and deduced its superfluid velocity in a capillary flow experiment occurring in single 30-nm-long nanopores with radii ranging down from 20 to 3 nm. As the pore size is reduced toward the 1D limit, we observe the following: (i) a suppression of the pressure dependence of the superfluid velocity; (ii) a temperature dependence of v s that surprisingly can be well-fitted by a power law with a single exponent over a broad range of temperatures; and (iii) decreasing critical velocities as a function of decreasing radius for channel sizes below R ~= 20 nm, in stark contrast with what is observed in micrometer-sized channels. We interpret these deviations from bulk behavior as signaling the crossover to a quasi-1D state, whereby the size of a critical topological defect is cut off by the channel radius.

Description: Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter -aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics.

Description: To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently.

Description: As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.

Description: Thousands of lives are lost every year in developing countries for failing to detect epidemics early because of the lack of real-time disease surveillance data. We present results from a large-scale deployment of a telephone triage service as a basis for dengue forecasting in Pakistan. Our system uses statistical analysis of dengue-related phone calls to accurately forecast suspected dengue cases 2 to 3 weeks ahead of time at a subcity level (correlation of up to 0.93). Our system has been operational at scale in Pakistan for the past 3 years and has received more than 300,000 phone calls. The predictions from our system are widely disseminated to public health officials and form a critical part of active government strategies for dengue containment. Our work is the first to demonstrate, with significant empirical evidence, that an accurate, location-specific disease forecasting system can be built using analysis of call volume data from a public health hotline.

Description: The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples ( n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.

Description: Ion transport–driven instabilities in electrodeposition of metals that lead to morphological instabilities and dendrites are receiving renewed attention because mitigation strategies are needed for improving rechargeability and safety of lithium batteries. The growth rate of these morphological instabilities can be slowed by immobilizing a fraction of anions within the electrolyte to reduce the electric field at the metal electrode. We analyze the role of elastic deformation of the solid electrolyte with immobilized anions and present theory combining the roles of separator elasticity and modified transport to evaluate the factors affecting the stability of planar deposition over a wide range of current densities. We find that stable electrodeposition can be easily achieved even at relatively high current densities in electrolytes/separators with moderate polymer-like mechanical moduli, provided a small fraction of anions are immobilized in the separator.

Description: In modern neuroscience, significant progress in developing structural scaffolds integrated with the brain is provided by the increasing use of nanomaterials. We show that a multiwalled carbon nanotube self-standing framework, consisting of a three-dimensional (3D) mesh of interconnected, conductive, pure carbon nanotubes, can guide the formation of neural webs in vitro where the spontaneous regrowth of neurite bundles is molded into a dense random net. This morphology of the fiber regrowth shaped by the 3D structure supports the successful reconnection of segregated spinal cord segments. We further observed in vivo the adaptability of these 3D devices in a healthy physiological environment. Our study shows that 3D artificial scaffolds may drive local rewiring in vitro and hold great potential for the development of future in vivo interfaces.

Description: Silicene is a monolayer allotrope of silicon atoms arranged in a honeycomb structure with massless Dirac fermion characteristics similar to graphene. It merits development of silicon-based multifunctional nanoelectronic and spintronic devices operated at room temperature because of strong spin-orbit coupling. Nevertheless, until now, silicene could only be epitaxially grown on conductive substrates. The strong silicene-substrate interaction may depress its superior electronic properties. We report a quasi-freestanding silicene layer that has been successfully obtained through oxidization of bilayer silicene on the Ag(111) surface. The oxygen atoms intercalate into the underlayer of silicene, resulting in isolation of the top layer of silicene from the substrate. In consequence, the top layer of silicene exhibits the signature of a 1 x 1 honeycomb lattice and hosts massless Dirac fermions because of much less interaction with the substrate. Furthermore, the oxidized silicon buffer layer is expected to serve as an ideal dielectric layer for electric gating in electronic devices. These findings are relevant for the future design and application of silicene-based nanoelectronic and spintronic devices.

Description: One of the limiting factors to high device performance in photovoltaics is the presence of surface traps. Hence, the understanding and control of carrier recombination at the surface of organic-inorganic hybrid perovskite is critical for the design and optimization of devices with this material as the active layer. We demonstrate that the surface recombination rate (or surface trap state density) in methylammonium lead tribromide (MAPbBr 3 ) single crystals can be fully and reversibly controlled by the physisorption of oxygen and water molecules, leading to a modulation of the photoluminescence intensity by over two orders of magnitude. We report an unusually low surface recombination velocity of 4 cm/s (corresponding to a surface trap state density of 10 8 cm –2 ) in this material, which is the lowest value ever reported for hybrid perovskites. In addition, a consistent modulation of the transport properties in single crystal devices is evidenced. Our findings highlight the importance of environmental conditions on the investigation and fabrication of high-quality, perovskite-based devices and offer a new potential application of these materials to detect oxygen and water vapor.

Description: Protection of populations comprising admixed genomes is a challenge under the Endangered Species Act (ESA), which is regarded as the most powerful species protection legislation ever passed in the United States but lacks specific provisions for hybrids. The eastern wolf is a newly recognized wolf-like species that is highly admixed and inhabits the Great Lakes and eastern United States, a region previously thought to be included in the geographic range of only the gray wolf. The U.S. Fish and Wildlife Service has argued that the presence of the eastern wolf, rather than the gray wolf, in this area is grounds for removing ESA protection (delisting) from the gray wolf across its geographic range. In contrast, the red wolf from the southeastern United States was one of the first species protected under the ESA and was protected despite admixture with coyotes. We use whole-genome sequence data to demonstrate a lack of unique ancestry in eastern and red wolves that would not be expected if they represented long divergent North American lineages. These results suggest that arguments for delisting the gray wolf are not valid. Our findings demonstrate how a strict designation of a species under the ESA that does not consider admixture can threaten the protection of endangered entities. We argue for a more balanced approach that focuses on the ecological context of admixture and allows for evolutionary processes to potentially restore historical patterns of genetic variation.

Description: The oceanic Pacific Plate started forming in Early Jurassic time within the vast Panthalassa Ocean that surrounded the supercontinent Pangea, and contains the oldest lithosphere that can directly constrain the geodynamic history of the circum-Pangean Earth. We show that the geometry of the oldest marine magnetic anomalies of the Pacific Plate attests to a unique plate kinematic event that sparked the plate’s birth at virtually a point location, surrounded by the Izanagi, Farallon, and Phoenix Plates. We reconstruct the unstable triple junction that caused the plate reorganization, which led to the birth of the Pacific Plate, and present a model of the plate tectonic configuration that preconditioned this event. We show that a stable but migrating triple junction involving the gradual cessation of intraoceanic Panthalassa subduction culminated in the formation of an unstable transform-transform-transform triple junction. The consequent plate boundary reorganization resulted in the formation of a stable triangular three-ridge system from which the nascent Pacific Plate expanded. We link the birth of the Pacific Plate to the regional termination of intra-Panthalassa subduction. Remnants thereof have been identified in the deep lower mantle of which the locations may provide paleolongitudinal control on the absolute location of the early Pacific Plate. Our results constitute an essential step in unraveling the plate tectonic evolution of "Thalassa Incognita" that comprises the comprehensive Panthalassa Ocean surrounding Pangea.

Description: Thermally rearranged (TR) polymers, which are considered the next-generation of membrane materials because of their excellent transport properties and high thermal and chemical stability, are proven to have significant drawbacks because of the high temperature required for the rearrangement and low degree of conversion during this process. We demonstrate that using a [3,3]-sigmatropic rearrangement, the temperature required for the rearrangement of a solid glassy polymer was reduced by 200°C. Conversions of functionalized polyimide to polybenzoxazole of more than 97% were achieved. These highly mechanically stable polymers were almost five times more permeable and had more than two times higher degrees of conversion than the reference polymer treated under the same conditions. Properties of these second-generation TR polymers provide the possibility of preparing efficient polymer membranes in a form of, for example, thin-film composite membranes for various gas and liquid membrane separation applications.

Description: A striking prediction in topological insulators is the appearance of the quantized Hall resistance when the surface states are magnetized. The surface Dirac states become gapped everywhere on the surface, but chiral edge states remain on the edges. In an applied current, the edge states produce a quantized Hall resistance that equals the Chern number C = ±1 (in natural units), even in zero magnetic field. This quantum anomalous Hall effect was observed by Chang et al . With reversal of the magnetic field, the system is trapped in a metastable state because of magnetic anisotropy. We investigate how the system escapes the metastable state at low temperatures (10 to 200 mK). When the dissipation (measured by the longitudinal resistance) is ultralow, we find that the system escapes by making a few very rapid transitions, as detected by large jumps in the Hall and longitudinal resistances. Using the field at which the initial jump occurs to estimate the escape rate, we find that raising the temperature strongly suppresses the rate. From a detailed map of the resistance versus gate voltage and temperature, we show that dissipation strongly affects the escape rate. We compare the observations with dissipative quantum tunneling predictions. In the ultralow dissipation regime, two temperature scales ( T 1 ~ 70 mK and T 2 ~ 145 mK) exist, between which jumps can be observed. The jumps display a spatial correlation that extends over a large fraction of the sample.

Description: Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.

Description: Molecular mechanisms controlling functional bacterial chromosome (nucleoid) compaction and organization are surprisingly enigmatic but partly depend on conserved, histone-like proteins HUαα and HUαβ and their interactions that span the nanoscale and mesoscale from protein-DNA complexes to the bacterial chromosome and nucleoid structure. We determined the crystal structures of these chromosome-associated proteins in complex with native duplex DNA. Distinct DNA binding modes of HUαα and HUαβ elucidate fundamental features of bacterial chromosome packing that regulate gene transcription. By combining crystal structures with solution x-ray scattering results, we determined architectures of HU-DNA nucleoproteins in solution under near-physiological conditions. These macromolecular conformations and interactions result in contraction at the cellular level based on in vivo imaging of native unlabeled nucleoid by soft x-ray tomography upon HUβ and ectopic HUα38 expression. Structural characterization of charge-altered HUαα-DNA complexes reveals an HU molecular switch that is suitable for condensing nucleoid and reprogramming noninvasive Escherichia coli into an invasive form. Collective findings suggest that shifts between networking and cooperative and noncooperative DNA-dependent HU multimerization control DNA compaction and supercoiling independently of cellular topoisomerase activity. By integrating x-ray crystal structures, x-ray scattering, mutational tests, and x-ray imaging that span from protein-DNA complexes to the bacterial chromosome and nucleoid structure, we show that defined dynamic HU interaction networks can promote nucleoid reorganization and transcriptional regulation as efficient general microbial mechanisms to help synchronize genetic responses to cell cycle, changing environments, and pathogenesis.

Description: Stabilizing superconductivity at high temperatures and elucidating its mechanism have long been major challenges of materials research in condensed matter physics. Meanwhile, recent progress in nanostructuring offers unprecedented possibilities for designing novel functionalities. Above all, thin films of cuprate and iron-based high-temperature superconductors exhibit remarkably better superconducting characteristics (for example, higher critical temperatures) than in the bulk, but the underlying mechanism is still not understood. Solving microscopic models suitable for cuprates, we demonstrate that, at an interface between a Mott insulator and an overdoped nonsuperconducting metal, the superconducting amplitude is always pinned at the optimum achieved in the bulk, independently of the carrier concentration in the metal. This is in contrast to the dome-like dependence in bulk superconductors but consistent with the astonishing independence of the critical temperature from the carrier density x observed at the interfaces of La 2 CuO 4 and La 2– x Sr x CuO 4 . Furthermore, we identify a self-organization mechanism as responsible for the pinning at the optimum amplitude: An emergent electronic structure induced by interlayer phase separation eludes bulk phase separation and inhomogeneities that would kill superconductivity in the bulk. Thus, interfaces provide an ideal tool to enhance and stabilize superconductivity. This interfacial example opens up further ways of shaping superconductivity by suppressing competing instabilities, with direct perspectives for designing devices.

Description: Recent advances in materials, mechanics, and electronic device design are rapidly establishing the foundations for health monitoring technologies that have "skin-like" properties, with options in chronic (weeks) integration with the epidermis. The resulting capabilities in physiological sensing greatly exceed those possible with conventional hard electronic systems, such as those found in wrist-mounted wearables, because of the intimate skin interface. However, most examples of such emerging classes of devices require batteries and/or hard-wired connections to enable operation. The work reported here introduces active optoelectronic systems that function without batteries and in an entirely wireless mode, with examples in thin, stretchable platforms designed for multiwavelength optical characterization of the skin. Magnetic inductive coupling and near-field communication (NFC) schemes deliver power to multicolored light-emitting diodes and extract digital data from integrated photodetectors in ways that are compatible with standard NFC-enabled platforms, such as smartphones and tablet computers. Examples in the monitoring of heart rate and temporal dynamics of arterial blood flow, in quantifying tissue oxygenation and ultraviolet dosimetry, and in performing four-color spectroscopic evaluation of the skin demonstrate the versatility of these concepts. The results have potential relevance in both hospital care and at-home diagnostics.

Description: Motor units are the fundamental elements responsible for muscle movement. They are formed by lower motor neurons and their muscle targets, synapsed via neuromuscular junctions (NMJs). The loss of NMJs in neurodegenerative disorders (such as amyotrophic lateral sclerosis or spinal muscle atrophy) or as a result of traumatic injuries affects millions of lives each year. Developing in vitro assays that closely recapitulate the physiology of neuromuscular tissues is crucial to understand the formation and maturation of NMJs, as well as to help unravel the mechanisms leading to their degeneration and repair. We present a microfluidic platform designed to coculture myoblast-derived muscle strips and motor neurons differentiated from mouse embryonic stem cells (ESCs) within a three-dimensional (3D) hydrogel. The device geometry mimics the spinal cord–limb physical separation by compartmentalizing the two cell types, which also facilitates the observation of 3D neurite outgrowth and remote muscle innervation. Moreover, the use of compliant pillars as anchors for muscle strips provides a quantitative functional readout of force generation. Finally, photosensitizing the ESC provides a pool of source cells that can be differentiated into optically excitable motor neurons, allowing for spatiodynamic, versatile, and noninvasive in vitro control of the motor units.

Description: European governments are struggling with the biggest refugee crisis since World War II, but there exists little evidence regarding how the management of the asylum process affects the subsequent integration of refugees in the host country. We provide new causal evidence about how one central policy parameter, the length of time that refugees wait in limbo for a decision on their asylum claim, affects their subsequent economic integration. Exploiting exogenous variation in wait times and registry panel data covering refugees who applied in Switzerland between 1994 and 2004, we find that one additional year of waiting reduces the subsequent employment rate by 4 to 5 percentage points, a 16 to 23% drop compared to the average rate. This deleterious effect is remarkably stable across different subgroups of refugees stratified by gender, origin, age at arrival, and assigned language region, a pattern consistent with the idea that waiting in limbo dampens refugee employment through psychological discouragement, rather than a skill atrophy mechanism. Overall, our results suggest that marginally reducing the asylum waiting period can help reduce public expenditures and unlock the economic potential of refugees by increasing employment among this vulnerable population.

Description: Forsterite (Mg 2 SiO 4 ) is one of the major planetary materials, and its behavior under extreme conditions is important to understand the interior structure of large planets, such as super-Earths, and large-scale planetary impact events. Previous shock compression measurements of forsterite indicate that it may melt below 200 GPa, but these measurements did not go beyond 200 GPa. We report the shock response of forsterite above ~250 GPa, obtained using the laser shock wave technique. We simultaneously measured the Hugoniot and temperature of shocked forsterite and interpreted the results to suggest the following: (i) incongruent crystallization of MgO at 271 to 285 GPa, (ii) phase transition of MgO at 285 to 344 GPa, and (iii) remelting above ~470 to 500 GPa. These exothermic and endothermic reactions are seen to occur under extreme conditions of pressure and temperature. They indicate complex structural and chemical changes in the system MgO-SiO 2 at extreme pressures and temperatures and will affect the way we understand the interior processes of large rocky planets as well as material transformation by impacts in the formation of planetary systems.

Description: Stimuli-responsive metal-organic frameworks (MOFs) have gained increasing attention recently for their potential applications in many areas. We report the design and synthesis of a water-stable zirconium MOF (Zr-MOF) that bears photoresponsive azobenzene groups. This particular MOF can be used as a reservoir for storage of cargo in water, and the cargo-loaded MOF can be further capped to construct a mechanized MOF through the binding of β-cyclodextrin with the azobenzene stalks on the MOF surface. The resulting mechanized MOF has shown on-command cargo release triggered by ultraviolet irradiation or addition of competitive agents without premature release. This study represents a simple approach to the construction of stimuli-responsive mechanized MOFs, and considering mechanized UiO-68-azo made from biocompatible components, this smart system may provide a unique MOF platform for on-command drug delivery in the future.

Description: Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth.

Description: Marine phytoplankton may adapt to ocean change, such as acidification or warming, because of their large population sizes and short generation times. Long-term adaptation to novel environments is a dynamic process, and phenotypic change can take place thousands of generations after exposure to novel conditions. We conducted a long-term evolution experiment (4 years = 2100 generations), starting with a single clone of the abundant and widespread coccolithophore Emiliania huxleyi exposed to three different CO 2 levels simulating ocean acidification (OA). Growth rates as a proxy for Darwinian fitness increased only moderately under both levels of OA [+3.4% and +4.8%, respectively, at 1100 and 2200 μatm partial pressure of CO 2 ( P co 2 )] relative to control treatments (ambient CO 2 , 400 μatm). Long-term adaptation to OA was complex, and initial phenotypic responses of ecologically important traits were later reverted. The biogeochemically important trait of calcification, in particular, that had initially been restored within the first year of evolution was later reduced to levels lower than the performance of nonadapted populations under OA. Calcification was not constitutively lost but returned to control treatment levels when high CO 2 –adapted isolates were transferred back to present-day control CO 2 conditions. Selection under elevated CO 2 exacerbated a general decrease of cell sizes under long-term laboratory evolution. Our results show that phytoplankton may evolve complex phenotypic plasticity that can affect biogeochemically important traits, such as calcification. Adaptive evolution may play out over longer time scales (〉1 year) in an unforeseen way under future ocean conditions that cannot be predicted from initial adaptation responses.

Description: Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba , we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system.

Description: The physical and chemical properties of Earth’s mantle, as well as its dynamics and evolution, heavily depend on the phase composition of the region. On the basis of experiments in laser-heated diamond anvil cells, we demonstrate that Fe,Al-bearing bridgmanite (magnesium silicate perovskite) is stable to pressures over 120 GPa and temperatures above 3000 K. Ferric iron stabilizes Fe-rich bridgmanite such that we were able to synthesize pure iron bridgmanite at pressures between ~45 and 110 GPa. The compressibility of ferric iron–bearing bridgmanite is significantly different from any known bridgmanite, which has direct implications for the interpretation of seismic tomography data.

Description: As a novel and efficient surface analysis technique, graphene-enhanced Raman scattering (GERS) has attracted increasing research attention in recent years. In particular, chemically doped graphene exhibits improved GERS effects when compared with pristine graphene for certain dyes, and it can be used to efficiently detect trace amounts of molecules. However, the GERS mechanism remains an open question. We present a comprehensive study on the GERS effect of pristine graphene and nitrogen-doped graphene. By controlling nitrogen doping, the Fermi level ( E F ) of graphene shifts, and if this shift aligns with the lowest unoccupied molecular orbital (LUMO) of a molecule, charge transfer is enhanced, thus significantly amplifying the molecule’s vibrational Raman modes. We confirmed these findings using different organic fluorescent molecules: rhodamine B, crystal violet, and methylene blue. The Raman signals from these dye molecules can be detected even for concentrations as low as 10 –11 M, thus providing outstanding molecular sensing capabilities. To explain our results, these nitrogen-doped graphene-molecule systems were modeled using dispersion-corrected density functional theory. Furthermore, we demonstrated that it is possible to determine the gaps between the highest occupied and the lowest unoccupied molecular orbitals (HOMO-LUMO) of different molecules when different laser excitations are used. Our simulated Raman spectra of the molecules also suggest that the measured Raman shifts come from the dyes that have an extra electron. This work demonstrates that nitrogen-doped graphene has enormous potential as a substrate when detecting low concentrations of molecules and could also allow for an effective identification of their HOMO-LUMO gaps.

Description: Electron cryomicroscopy (cryo-EM) has significantly advanced our understanding of molecular structure in biology. Recent innovations in both hardware and software have made cryo-EM a viable alternative for targets that are not amenable to x-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy. Cryo-EM has even become the method of choice in some situations where x-ray crystallography and NMR spectroscopy are possible but where cryo-EM can determine structures at higher resolution or with less time or effort. Rotary adenosine triphosphatases (ATPases) are crucial to the maintenance of cellular homeostasis. These enzymes couple the synthesis or hydrolysis of adenosine triphosphate to the use or production of a transmembrane electrochemical ion gradient, respectively. However, the membrane-embedded nature and conformational heterogeneity of intact rotary ATPases have prevented their high-resolution structural analysis to date. Recent application of cryo-EM methods to the different types of rotary ATPase has led to sudden advances in understanding the structure and function of these enzymes, revealing significant conformational heterogeneity and characteristic transmembrane α helices that are highly tilted with respect to the membrane. In this Review, we will discuss what has been learned recently about rotary ATPase structure and function, with a particular focus on the vacuolar-type ATPases.

Description: DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat–containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown. We identify nuclear respiratory factor 1 and peroxisome proliferator–activated receptor coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5'-monophosphate (AMP)–activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.

Description: Emulation of biological synapses is an important step toward construction of large-scale brain-inspired electronics. Despite remarkable progress in emulating synaptic functions, current synaptic devices still consume energy that is orders of magnitude greater than do biological synapses (~10 fJ per synaptic event). Reduction of energy consumption of artificial synapses remains a difficult challenge. We report organic nanowire (ONW) synaptic transistors (STs) that emulate the important working principles of a biological synapse. The ONWs emulate the morphology of nerve fibers. With a core-sheath–structured ONW active channel and a well-confined 300-nm channel length obtained using ONW lithography, ~1.23 fJ per synaptic event for individual ONW was attained, which rivals that of biological synapses. The ONW STs provide a significant step toward realizing low-energy–consuming artificial intelligent electronics and open new approaches to assembling soft neuromorphic systems with nanometer feature size.

Description: Metal-free carbon-based electrocatalysts for dye-sensitized solar cells (DSSCs) are sufficiently active in Co(II)/Co(III) electrolytes but are not satisfactory in the most commonly used iodide/triiodide (I – /I 3 – ) electrolytes. Thus, developing active and stable metal-free electrocatalysts in both electrolytes is one of the most important issues in DSSC research. We report the synthesis of edge-selenated graphene nanoplatelets (SeGnPs) prepared by a simple mechanochemical reaction between graphite and selenium (Se) powders, and their application to the counter electrode (CE) for DSSCs in both I – /I 3 – and Co(II)/Co(III) electrolytes. The edge-selective doping and the preservation of the pristine graphene basal plane in the SeGnPs were confirmed by various analytical techniques, including atomic-resolution transmission electron microscopy. Tested as the DSSC CE in both Co(bpy) 3 2+/3+ (bpy = 2,2'-bipyridine) and I – /I 3 – electrolytes, the SeGnP-CEs exhibited outstanding electrocatalytic performance with ultimately high stability. The SeGnP-CE–based DSSCs displayed a higher photovoltaic performance than did the Pt-CE–based DSSCs in both SM315 sensitizer with Co(bpy) 3 2+/3+ and N719 sensitizer with I – /I 3 – electrolytes. Furthermore, the I 3 – reduction mechanism, which has not been fully understood in carbon-based CE materials to date, was clarified by an electrochemical kinetics study combined with density functional theory and nonequilibrium Green’s function calculations.

Description: The rapid growth of deformable and stretchable electronics calls for a deformable and stretchable power source. We report a scalable approach for energy harvesters and self-powered sensors that can be highly deformable and stretchable. With conductive liquid contained in a polymer cover, a shape-adaptive triboelectric nanogenerator (saTENG) unit can effectively harvest energy in various working modes. The saTENG can maintain its performance under a strain of as large as 300%. The saTENG is so flexible that it can be conformed to any three-dimensional and curvilinear surface. We demonstrate applications of the saTENG as a wearable power source and self-powered sensor to monitor biomechanical motion. A bracelet-like saTENG worn on the wrist can light up more than 80 light-emitting diodes. Owing to the highly scalable manufacturing process, the saTENG can be easily applied for large-area energy harvesting. In addition, the saTENG can be extended to extract energy from mechanical motion using flowing water as the electrode. This approach provides a new prospect for deformable and stretchable power sources, as well as self-powered sensors, and has potential applications in various areas such as robotics, biomechanics, physiology, kinesiology, and entertainment.

Description: Polyethylene (PE) is the largest-volume synthetic polymer, and its chemical inertness makes its degradation by low-energy processes a challenging problem. We report a tandem catalytic cross alkane metathesis method for highly efficient degradation of polyethylenes under mild conditions. With the use of widely available, low-value, short alkanes (for example, petroleum ethers) as cross metathesis partners, different types of polyethylenes with various molecular weights undergo complete conversion into useful liquid fuels and waxes. This method shows excellent selectivity for linear alkane formation, and the degradation product distribution (liquid fuels versus waxes) can be controlled by the catalyst structure and reaction time. In addition, the catalysts are compatible with various polyolefin additives; therefore, common plastic wastes, such as postconsumer polyethylene bottles, bags, and films could be converted into valuable chemical feedstocks without any pretreatment.

Description: Bismuth vanadate (BiVO 4 ) has been widely regarded as a promising photoanode material for photoelectrochemical (PEC) water splitting because of its low cost, its high stability against photocorrosion, and its relatively narrow band gap of 2.4 eV. However, the achieved performance of the BiVO 4 photoanode remains unsatisfactory to date because its short carrier diffusion length restricts the total thickness of the BiVO 4 film required for sufficient light absorption. We addressed the issue by deposition of nanoporous Mo-doped BiVO 4 (Mo:BiVO 4 ) on an engineered cone-shaped nanostructure, in which the Mo:BiVO 4 layer with a larger effective thickness maintains highly efficient charge separation and high light absorption capability, which can be further enhanced by multiple light scattering in the nanocone structure. As a result, the nanocone/Mo:BiVO 4 /Fe(Ni)OOH photoanode exhibits a high water-splitting photocurrent of 5.82 ± 0.36 mA cm –2 at 1.23 V versus the reversible hydrogen electrode under 1-sun illumination. We also demonstrate that the PEC cell in tandem with a single perovskite solar cell exhibits unassisted water splitting with a solar-to-hydrogen conversion efficiency of up to 6.2%.

Description: The causes of Late Pleistocene megafaunal extinctions (60,000 to 11,650 years ago, hereafter 60 to 11.65 ka) remain contentious, with major phases coinciding with both human arrival and climate change around the world. The Americas provide a unique opportunity to disentangle these factors as human colonization took place over a narrow time frame (~15 to 14.6 ka) but during contrasting temperature trends across each continent. Unfortunately, limited data sets in South America have so far precluded detailed comparison. We analyze genetic and radiocarbon data from 89 and 71 Patagonian megafaunal bones, respectively, more than doubling the high-quality Pleistocene megafaunal radiocarbon data sets from the region. We identify a narrow megafaunal extinction phase 12,280 ± 110 years ago, some 1 to 3 thousand years after initial human presence in the area. Although humans arrived immediately prior to a cold phase, the Antarctic Cold Reversal stadial, megafaunal extinctions did not occur until the stadial finished and the subsequent warming phase commenced some 1 to 3 thousand years later. The increased resolution provided by the Patagonian material reveals that the sequence of climate and extinction events in North and South America were temporally inverted, but in both cases, megafaunal extinctions did not occur until human presence and climate warming coincided. Overall, metapopulation processes involving subpopulation connectivity on a continental scale appear to have been critical for megafaunal species survival of both climate change and human impacts.

Description: Directional liquid transportation is important for a variety of biological processes and technical applications. Although surface engineering through asymmetric chemical modification or geometrical patterning facilitates effective liquid manipulation and enables water droplet self-transportation on synthetic surfaces, self-transportation of oil droplets poses a major challenge because of their low surface tension. We report oil droplet self-transportation on oleophobic surfaces that are microtextured with radial arrays of undercut stripes. More significantly, we observe three modes of oil motion on various sample surfaces, namely, inward transportation, pinned, and outward spreading, which can be switched by the structure parameters, including stripe intersection angle and width. Accompanying theoretical modeling provides an in-depth mechanistic understanding of the structure–droplet motion relationship. Finally, we reveal how to optimize the texture parameters to maximize oil droplet self-transportation capability and demonstrate spontaneous droplet movement for liquids down to a surface tension of 22.4 mN/m. The surfaces presented here open up new avenues for power-free liquid transportation and oil contamination self-removal applications in various analytical and fluidic devices.

Description: Ultrafast spin manipulation for opto–spin logic applications requires material systems that have strong spin-selective light-matter interaction. Conventional inorganic semiconductor nanostructures [for example, epitaxial II to VI quantum dots and III to V multiple quantum wells (MQWs) are considered forerunners but encounter challenges such as lattice matching and cryogenic cooling requirements. Two-dimensional halide perovskite semiconductors, combining intrinsic tunable MQW structures and large oscillator strengths with facile solution processability, can offer breakthroughs in this area. We demonstrate novel room-temperature, strong ultrafast spin-selective optical Stark effect in solution-processed (C 6 H 4 FC 2 H 4 NH 3 ) 2 PbI 4 perovskite thin films. Exciton spin states are selectively tuned by ~6.3 meV using circularly polarized optical pulses without any external photonic cavity (that is, corresponding to a Rabi energy of ~55 meV and equivalent to applying a 70-T magnetic field), which is much larger than any conventional system. The facile halide and organic replacement in these perovskites affords control of the dielectric confinement and thus presents a straightforward strategy for tuning light-matter coupling strength.

Description: Insects have evolved diverse methods of camouflage that have played an important role in their evolutionary success. Debris-carrying, a behavior of actively harvesting and carrying exogenous materials, is among the most fascinating and complex behaviors because it requires not only an ability to recognize, collect, and carry materials but also evolutionary adaptations in related morphological characteristics. However, the fossil record of such behavior is extremely scarce, and only a single Mesozoic example from Spanish amber has been recorded; therefore, little is known about the early evolution of this complicated behavior and its underlying anatomy. We report a diverse insect assemblage of exceptionally preserved debris carriers from Cretaceous Burmese, French, and Lebanese ambers, including the earliest known chrysopoid larvae (green lacewings), myrmeleontoid larvae (split-footed lacewings and owlflies), and reduviids (assassin bugs). These ancient insects used a variety of debris material, including insect exoskeletons, sand grains, soil dust, leaf trichomes of gleicheniacean ferns, wood fibers, and other vegetal debris. They convergently evolved their debris-carrying behavior through multiple pathways, which expressed a high degree of evolutionary plasticity. We demonstrate that the behavioral repertoire, which is associated with considerable morphological adaptations, was already widespread among insects by at least the Mid-Cretaceous. Together with the previously known Spanish specimen, these fossils are the oldest direct evidence of camouflaging behavior in the fossil record. Our findings provide a novel insight into early evolution of camouflage in insects and ancient ecological associations among plants and insects.

Description: Weyl semimetals are of great interest because they provide the first realization of the Weyl fermion, exhibit exotic quantum anomalies, and host Fermi arc surface states. The separation between Weyl nodes of opposite chirality gives a measure of the robustness of the Weyl semimetal state. To exploit the novel phenomena that arise from Weyl fermions in applications, it is crucially important to find robust separated Weyl nodes. We propose a methodology to design robust Weyl semimetals with well-separated Weyl nodes. Using this methodology as a guideline, we search among the material parameter space and identify by far the most robust and ideal Weyl semimetal candidate in the single-crystalline compound tantalum sulfide (Ta 3 S 2 ) with new and novel properties beyond TaAs. Crucially, our results show that Ta 3 S 2 has the largest k -space separation between Weyl nodes among known Weyl semimetal candidates, which is about twice larger than the measured value in TaAs and 20 times larger than the predicted value in WTe 2 . Moreover, all Weyl nodes in Ta 3 S 2 are of type II. Therefore, Ta 3 S 2 is a type II Weyl semimetal. Furthermore, we predict that increasing the lattice by 〈4% can annihilate all Weyl nodes, driving a novel topological metal-to-insulator transition from a Weyl semimetal state to a topological insulator state. The robust type II Weyl semimetal state and the topological metal-to-insulator transition in Ta 3 S 2 are potentially useful in device applications. Our methodology can be generally applied to search for new Weyl semimetals.

Description: The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER + (estrogen receptor–positive)/PR + human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER + /PR + breast cancers should be explored.

Description: Global climate models simulate a robust increase of global mean precipitation of about 1.5 to 2% per kelvin surface warming in response to greenhouse gas (GHG) forcing. Here, it is shown that the sensitivity to aerosol cooling is robust as well, albeit roughly twice as large. This larger sensitivity is consistent with energy budget arguments. At the same time, it is still considerably lower than the 6.5 to 7% K –1 decrease of the water vapor concentration with cooling from anthropogenic aerosol because the water vapor radiative feedback lowers the hydrological sensitivity to anthropogenic forcings. When GHG and aerosol forcings are combined, the climate models with a realistic 20th century warming indicate that the global mean precipitation increase due to GHG warming has, until recently, been completely masked by aerosol drying. This explains the apparent lack of sensitivity of the global mean precipitation to the net global warming recently found in observations. As the importance of GHG warming increases in the future, a clear signal will emerge.

Description: There is a growing awareness that biodiversity not only drives ecosystem services but also affects evolutionary dynamics. However, different theories predict contrasting outcomes on when do evolutionary processes occur within a context of competition. We tested whether functional diversity can explain diversification patterns. We tracked the survival and diversification of a focal bacterial species ( Pseudomonas fluorescens ) growing in bacterial communities of variable diversity and composition. We found that high functional diversity reduced the fitness of the focal species and, at the same time, fostered its diversification. This pattern was linked to resource competition: High diversity increased competition on a portion of the resources while leaving most underexploited. The evolved phenotypes of the focal species showed a better use of underexploited resources, albeit at a cost of lower overall growth rates. As a result, diversification alleviated the impact of competition on the fitness of the focal species. We conclude that biodiversity can stimulate evolutionary diversification, provided that sufficient alternative niches are available.

Description: We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3 , MAZ , ERG , and SHMT1 . The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3 , MAZ , and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Description: Nonviral gene therapy holds great promise but has not delivered treatments for clinical application to date. Lack of safe and efficient gene delivery vectors is the major hurdle. Among nonviral gene delivery vectors, poly(β-amino ester)s are one of the most versatile candidates because of their wide monomer availability, high polymer flexibility, and superior gene transfection performance both in vitro and in vivo. However, to date, all research has been focused on vectors with a linear structure. A well-accepted view is that dendritic or branched polymers have greater potential as gene delivery vectors because of their three-dimensional structure and multiple terminal groups. Nevertheless, to date, the synthesis of dendritic or branched polymers has been proven to be a well-known challenge. We report the design and synthesis of highly branched poly(β-amino ester)s (HPAEs) via a one-pot "A2 + B3 + C2"–type Michael addition approach and evaluate their potential as gene delivery vectors. We find that the branched structure can significantly enhance the transfection efficiency of poly(β-amino ester)s: Up to an 8521-fold enhancement in transfection efficiency was observed across 12 cell types ranging from cell lines, primary cells, to stem cells, over their corresponding linear poly(β-amino ester)s (LPAEs) and the commercial transfection reagents polyethyleneimine, SuperFect, and Lipofectamine 2000. Moreover, we further demonstrate that HPAEs can correct genetic defects in vivo using a recessive dystrophic epidermolysis bullosa graft mouse model. Our findings prove that the A2 + B3 + C2 approach is highly generalizable and flexible for the design and synthesis of HPAEs, which cannot be achieved by the conventional polymerization approach; HPAEs are more efficient vectors in gene transfection than the corresponding LPAEs. This provides valuable insight into the development and applications of nonviral gene delivery and demonstrates great prospect for their translation to a clinical environment.

Description: On 29 June 2015, Liberia’s respite from Ebola virus disease (EVD) was interrupted for the second time by a renewed outbreak ("flare-up") of seven confirmed cases. We demonstrate that, similar to the March 2015 flare-up associated with sexual transmission, this new flare-up was a reemergence of a Liberian transmission chain originating from a persistently infected source rather than a reintroduction from a reservoir or a neighboring country with active transmission. Although distinct, Ebola virus (EBOV) genomes from both flare-ups exhibit significantly low genetic divergence, indicating a reduced rate of EBOV evolution during persistent infection. Using this rate of change as a signature, we identified two additional EVD clusters that possibly arose from persistently infected sources. These findings highlight the risk of EVD flare-ups even after an outbreak is declared over.

Description: Newly discovered fossils of the Middle Triassic reptile Atopodentatus unicus call for a radical reassessment of its feeding behavior. The skull displays a pronounced hammerhead shape that was hitherto unknown. The long, straight anterior edges of both upper and lower jaws were lined with batteries of chisel-shaped teeth, whereas the remaining parts of the jaw rami supported densely packed needle-shaped teeth forming a mesh. The evidence indicates a novel feeding mechanism wherein the chisel-shaped teeth were used to scrape algae off the substrate, and the plant matter that was loosened was filtered from the water column through the more posteriorly positioned tooth mesh. This is the oldest record of herbivory within marine reptiles.

Description: The dynamics of ocean-terminating outlet glaciers are an important component of ice-sheet mass balance. Using satellite imagery for the past 40 years, we compile an approximately decadal record of outlet-glacier terminus position change around the entire East Antarctic Ice Sheet (EAIS) marine margin. We find that most outlet glaciers retreated during the period 1974–1990, before switching to advance in every drainage basin during the two most recent periods, 1990–2000 and 2000–2012. The only exception to this trend was in Wilkes Land, where the majority of glaciers (74%) retreated between 2000 and 2012. We hypothesize that this anomalous retreat is linked to a reduction in sea ice and associated impacts on ocean stratification, which increases the incursion of warm deep water toward glacier termini. Because Wilkes Land overlies a large marine basin, it raises the possibility of a future sea level contribution from this sector of East Antarctica.

Description: The influence of the circadian clock on sleep scheduling has been studied extensively in the laboratory; however, the effects of society on sleep remain largely unquantified. We show how a smartphone app that we have developed, ENTRAIN, accurately collects data on sleep habits around the world. Through mathematical modeling and statistics, we find that social pressures weaken and/or conceal biological drives in the evening, leading individuals to delay their bedtime and shorten their sleep. A country’s average bedtime, but not average wake time, predicts sleep duration. We further show that mathematical models based on controlled laboratory experiments predict qualitative trends in sunrise, sunset, and light level; however, these effects are attenuated in the real world around bedtime. Additionally, we find that women schedule more sleep than men and that users reporting that they are typically exposed to outdoor light go to sleep earlier and sleep more than those reporting indoor light. Finally, we find that age is the primary determinant of sleep timing, and that age plays an important role in the variability of population-level sleep habits. This work better defines and personalizes "normal" sleep, produces hypotheses for future testing in the laboratory, and suggests important ways to counteract the global sleep crisis.

Description: Health care–associated infections (HAIs) and drug-resistant pathogens have become a major health care issue with millions of reported cases every year. Advanced diagnostics would allow clinicians to more quickly determine the most effective treatment, reduce the nonspecific use of broad-spectrum antimicrobials, and facilitate enrollment in new antibiotic treatments. We present a new integrated system, polarization anisotropy diagnostics (PAD), for rapid detection of HAI pathogens. The PAD uses changes of fluorescence anisotropy when detection probes recognize target bacterial nucleic acids. The technology is inherently robust against environmental noise and economically scalable for parallel measurements. The assay is fast (2 hours) and performed on-site in a single-tube format. When applied to clinical samples obtained from interventional procedures, the PAD determined the overall bacterial burden, differentiated HAI bacterial species, and identified drug resistance and virulence status. The PAD system holds promise as a powerful tool for near-patient, rapid HAI testing.

Description: The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics.

Description: Mantle wedge regions in subduction zone settings show anomalously high electrical conductivity (~1 S/m) that has often been attributed to the presence of aqueous fluids released by slab dehydration. Laboratory-based measurements of the electrical conductivity of hydrous phases and aqueous fluids are significantly lower and cannot readily explain the geophysically observed anomalously high electrical conductivity. The released aqueous fluid also rehydrates the mantle wedge and stabilizes a suite of hydrous phases, including serpentine and chlorite. In this present study, we have measured the electrical conductivity of a natural chlorite at pressures and temperatures relevant for the subduction zone setting. In our experiment, we observe two distinct conductivity enhancements when chlorite is heated to temperatures beyond its thermodynamic stability field. The initial increase in electrical conductivity to ~3 x 10 –3 S/m can be attributed to chlorite dehydration and the release of aqueous fluids. This is followed by a unique, subsequent enhancement of electrical conductivity of up to 7 x 10 –1 S/m. This is related to the growth of an interconnected network of a highly conductive and chemically impure magnetite mineral phase. Thus, the dehydration of chlorite and associated processes are likely to be crucial in explaining the anomalously high electrical conductivity observed in mantle wedges. Chlorite dehydration in the mantle wedge provides an additional source of aqueous fluid above the slab and could also be responsible for the fixed depth (120 ± 40 km) of melting at the top of the subducting slab beneath the subduction-related volcanic arc front.

Description: Following an injury, a blood clot must form at the wound site to stop bleeding before skin repair can occur. Blood clots must satisfy a unique set of material requirements; they need to be sufficiently strong to resist pressure from the arterial blood flow but must be highly flexible to support large strains associated with tissue movement around the wound. These combined properties are enabled by a fibrous matrix consisting of the protein fibrin. Fibrin hydrogels can support large macroscopic strains owing to the unfolding transition of α-helical fibril structures to β sheets at the molecular level, among other reasons. Imaging protein secondary structure on the submicrometer length scale, we reveal that another length scale is relevant for fibrin function. We observe that the protein polymorphism in the gel becomes spatially heterogeneous on a micrometer length scale with increasing tensile strain, directly showing load-bearing inhomogeneity and nonaffinity. Supramolecular structural features in the hydrogel observed under strain indicate that a uniform fibrin hydrogel develops a composite-like microstructure in tension, even in the absence of cellular inclusions.