Science Advances

The intractability of homogeneous α-satellite arrays has impeded understanding of human centromeres. Artificial centromeres are produced from higher-order repeats (HORs) present at centromere edges, although the exact sequences and chromatin conformations of centromere cores remain unknown. We use high-resolution chromatin immunoprecipitation (ChIP) of centromere components followed by clustering of sequence data as an unbiased approach to identify functional centromere sequences. We find that specific dimeric α-satellite units shared by multiple individuals dominate functional human centromeres. We identify two recently homogenized α-satellite dimers that are occupied by precisely positioned CENP-A (cenH3) nucleosomes with two ~100-base pair (bp) DNA wraps in tandem separated by a CENP-B/CENP-C-containing linker, whereas pericentromeric HORs show diffuse positioning. Precise positioning is largely maintained, whereas abundance decreases exponentially with divergence, which suggests that young α-satellite dimers with paired ~100-bp particles mediate evolution of functional human centromeres. Our unbiased strategy for identifying functional centromeric sequences should be generally applicable to tandem repeat arrays that dominate the centromeres of most eukaryotes.
The maximum planetesimal radius in the asteroid belt versus time, for three different values of the turbulent viscosity α. Here α = 2 × 10 −6 represents the strength of turbulence caused by streaming instabilities and Kelvin-Helmholtz instabilities in a sedimented mid-plane layer of chondrules, α = 10 −4 represents the turbulence strength in a dead zone stirred by active surface layers and α = 10 −3 the turbulence strength caused directly by the magnetorotational instability. Turbulent stirring of chondrules sets the scale-height and midplane density of the chondrule layer and hence dictates the planetesimal growth rate. The formation time of the first embryo depends strongly on the degree of stirring. 
Figure S4: The evolution of eccentricity e and inclination i of 800 planetesimals with mass M = 10 24 g located at 1 AU with a surface density of 10 g/cm 2. The eccentricity and the inclination are normalised by their Hill values [2M p /(3M )] 1/3. Results are qualitatively similar to Figure 2 of Stewart & Ida (2000). As in Figure S3, a time-step parameter of c dt = 0.1 provides a good compromise between precision and speed; hence we use c dt = 0.1 for planetesimal stirring in the planetesimal growth simulations. 
Figure S5: Phase points covering planetesimal orbits with inclinations i = 0, i = 0.0016, i = 0.0032 and i = 0.0064. We construct phase arrays to cover both the full planetesimal orbit and the scale-height of the chondrule layer (here H p = 0.02H). The height in the planetesimal orbit is normalised by the maximum height for the given inclination. The dotted line indicates the scale-height of the chondrule mid-plane layer, clearly resolved for all choices of the inclination. 
Figure S11: Cumulative size distribution after 3 Myr of coagulation within a population of planetesimals of initial diameters 100 km (50 km in radius), as shown by the cross. The size distribution is much steeper than the current observed size distribution in the asteroid belt. The results presented here are agree to within a few percent with Figure 5 of Morbidelli et al. (2009) (21) and Figure 5 of Weidenschilling (2011) (57), except for D > 1000 km where we have a slight underproduction of embryos. Note that we set the column density of planetesimals equal to that of solids in the Minimum Mass Solar Nebula of Hayashi (1981), while Weidenschilling (2011) uses approximately twice that value. 
Chondrules are millimeter-sized spherules that dominate primitive meteorites (chondrites) originating from the asteroid belt. The incorporation of chondrules into asteroidal bodies must be an important step in planet formation, but the mechanism is not understood. We show that the main growth of asteroids can result from gas-drag-assisted accretion of chondrules. The largest planetesimals of a population with a characteristic radius of 100 km undergo run-away accretion of chondrules within ~3 Myr, forming planetary embryos up to Mars sizes along with smaller asteroids whose size distribution matches that of main belt asteroids. The aerodynamical accretion leads to size-sorting of chondrules consistent with chondrites. Accretion of mm-sized chondrules and ice particles drives the growth of planetesimals beyond the ice line as well, but the growth time increases above the disk life time outside of 25 AU. The contribution of direct planetesimal accretion to the growth of both asteroids and Kuiper belt objects is minor. In contrast, planetesimal accretion and chondrule accretion play more equal roles for the formation of Moon-sized embryos in the terrestrial planet formation region. These embryos are isolated from each other and accrete planetesimals only at a low rate. However, the continued accretion of chondrules destabilizes the oligarchic configuration and leads to the formation of Mars-sized embryos and terrestrial planets by a combination of direct chondrule accretion and giant impacts.
The one-dimensional (1D) Fermi gas with repulsive short-range interactions provides an important model of strong correlations and is often amenable to exact methods. However, in the presence of confinement, no exact solution is known for an arbitrary number of strongly interacting fermions. Here, we propose a novel ansatz for generating the lowest-energy wavefunctions of the repulsive 1D Fermi gas in a harmonic potential near the Tonks-Girardeau (TG) limit of infinite interactions. We specialize to the case of a single impurity interacting with $N$ majority particles, where we may derive analytic forms of the approximate wavefunctions. Comparing with exact numerics, we show that the overlap between the wavefunctions from our ansatz and the exact ones in the ground-state manifold exceeds 0.9997 for $N\leq8$. Moreover, the overlap for the ground-state wavefunction extrapolates to 0.9999 as $N\to\infty$. Thus our ansatz is essentially indistinguishable from numerically exact results in both the few- and many-body limits. In the large $N$ limit, we find that the impurity probability density in the ground state is only slightly perturbed by the infinitely repulsive interactions, while the quasiparticle residue vanishes as the many-body limit is approached, reflecting the Anderson orthogonality catastrophe. We derive an effective Heisenberg spin-chain model for the regime near the TG limit, within which our ansatz is exact. Here, we find that the impurity eigenstates in the spin basis correspond to discrete Chebyshev polynomials. The energy of states in excited manifolds is calculated using a dynamical SO(2,1) symmetry, which provides an exact relation between states related by a scaling transformation. We finally show how our results for the wavefunctions and the energy spectrum can be detected in cold atomic gases via collective-mode, tunneling, and radio-frequency experiments.
Experimental setup used to study first-and second-order azimuthal interference. A solid state Millenia X laser at 532 nm illuminates a digital micro-mirror device (DMD). The DMD displays a series of Kolmogorov phase screens at a rate of 1.4 kHz and acts as a source of pseudothermal light. An aperture with two angular slits and a phase pattern with specific OAM values are encoded onto a spatial light modulator (SLM). The positive and negative diffraction orders, which correspond to a positive and negative OAM values, respectively, are coupled into single-mode fibers (SMFs). Single photon counting modules and a coincidence circuit are used for joint detection of photons.
Experimental evidence for the azimuthal HBT effect (a) and (b), and for correlations in OAM and angular position (c) and (d). (a) and(b) show that ∆G (2) plotted as a function of the OAM value displayed in arm 2, for a fixed OAM value displayed in arm 1, shows interference fringes. The bar in dark blue shows the center of the interference pattern for singles counts (see Fig. 2 (c)), whereas the purple bar shows the center of the displayed interference pattern. (c) shows that strong correlations are measured when same OAM values are displayed on both SLMs. A similar behavior is observed for correlations in the angular position variable (d).
Example frame sent to DMD containing 24 binary holograms encoded in bit plane slices 
Example DMD holograms and resulting beams measured before the image plane. 
shows images of the pseudo-thermal light with the detector before the image plane, in addition to an example hologram used to create the beam. Note that the randomness within the beam increases as the value of r 0 is reduced. Derivation of Azimuthal Pseudothermal Interference.
Interference governs a wide variety of fundamental effects in physics and it is considered one of the most fascinating phenomena in nature. Interest in distinguishing between interference effects produced by classical or quantum superpositions was largely motivated by the observations of Hanbury Brown and Twiss (HBT). In addition, the rich physics produced by the interference of random optical waves --- such as those produced by pseudothermal light --- has been extensively studied. For example, it has been recognized that optical vortices are ubiquitous in random light, and that the phase distribution around these optical singularities imprints a spectrum of orbital angular momentum (OAM) onto the light field. Here, we study the azimuthal properties of pseudothermal light and how intensity fluctuations induce azimuthal coherence, leading to complex interference structures. Azimuthal interference with high visibility is observed in intensity correlations. We find that these correlations depend on OAM, despite the fact that the OAM modes are defined only by a helical phase structure. This novel form of interference can be considered as the azimuthal analog of the HBT effect. We believe the azimuthal HBT effect can potentially be useful in the exploration of novel astrophysics that involves measuring the OAM of light, an important task that could for example lead to discovery of rotating black holes. The presence of correlations both in angular position and also OAM of pseudothermal light permits these interference effects. A study of correlations that resemble azimuthal Einstein-Podolsky-Rosen (EPR) correlations is presented.
Critical and noncritical control parameters for a two dimensional geometrically frustrated lattice of magnetic moments. Black circles indicate Ce atoms in the quasikagome plane of CeRhSn. Uniaxial pressure parallel to the a axis (p a ) deforms the equilateral triangular units and will reduce the geometrical frustration, whereas pressure perpendicular to the plane (p c ) leaves frustration unchanged.
Evidence of a frustration-induced QCP in CeRhSn. (A) Thermal expansion coefficient divided by temperature α/T versus temperature measured along the a-and c directions, as indicated by red and blue symbols. The inset shows the Grüneisen parameter Γ=BV m β/C, where B=105 GPa is the bulk modulus of isostructural UCoAl (39), V m =1.36x10 -4 m 3 /mol is the molar volume, β=2α a +α c is the volume thermal expansion and C denotes specific heat. The black dotted line indicates a power-law divergence. (B) Specific heat divided by temperature C /T as a function of temperature. Solid and open circles indicate data measured at zero field and at 2 T applied parallel to the a-axis, respectively. Up to 2 T there is no appreciable nuclear Schottky contribution visible even at lowest measured temperatures.  
Divergence of the magnetic Grüneisen parameter Γ H . Γ H /H as a function of temperature at various magnetic fields applied parallel to the c axis.  
Spin flop crossover in the spin liquid state of CeRhSn. (A) Magnetic Grüneisen ratio Γ H as a function of magnetic field applied parallel to the a axis. The inset shows a temperature versus magnetic field phase diagram, where the gray dotted line has been obtained from inflection points of Γ H (H) and the blue and red lines indicate anomalies in the field dependence of the electronic specific heat. (B) Electronic specific heat divided by temperature C el /T versus magnetic field applied parallel to the a-axis at constant temperatures. The nuclear contribution has been subtracted from the raw data. C el /T data at 0.15, 0.2, 0.3 and 0.6 K are shifted vertically for clarity by 0.15, 0.3, 0.45 and 0.6 J/mol K 2 , respectively. The blue and red dotted lines indicate the positions of specific heat anomalies.  
Possible scenario for the metamagnetic crossover in CeRhSn. T-H-Q phase diagram with a spin-flop transition between two magnetically ordered states (8). The parameter Q indicates the strength of quantum fluctuations induced by geometrical frustration. A line of bicritical points (BCP, in red) separates two distinct magnetically ordered states. The quantum bicritical point (QBCP) is the point where T BCP approaches zero temperature. The purple solid and dotted lines indicate H m and the metamagnetic crossover, respectively. The isostructural heavy fermion antiferromagnet YbAgGe is positioned near the QBCP and its T-H phase diagram near H m is illustrated by solid green lines (8). In this material, field induced quantum critical behavior arises from the nearby QBCP. Paramagnetic CeRhSn displays a zero-field QCP induced by Q (solid red circle) and field-driven metamagnetic crossover (dotted purple line) of spin flop nature.  
Geometrical frustration describes situations where interactions are incompatible with the lattice geometry and stabilizes exotic phases such as spin liquids. Whether geometrical frustration of magnetic interactions in metals can induce unconventional quantum critical points is an active area of research. We focus on the hexagonal heavy fermion metal CeRhSn where the Kondo ions are located on distorted kagome planes stacked along the c axis. Low-temperature specific heat, thermal expansion and magnetic Gr\"uneisen parameter measurements prove a zero-field quantum critical point. The linear thermal expansion, which measures the initial uniaxial pressure derivative of the entropy, displays a striking anisotropy. Critical and noncritical behaviors along and perpendicular to the kagome planes, respectively, prove that quantum criticality is driven by geometrical frustration. We also discovered a spin-flop-type metamagnetic crossover. This excludes an itinerant scenario and suggests that quantum criticality is related to local moments in a spin-liquid like state.
Scheme of the memcomputing architecture used in this work to solve the subset-sum problem. The central spectrum has been obtained by the discrete Fourier transform of the experimental output of a network of 6 memprocessors encoding the set G = {130, −130, −146, −166, −44, 118} with fundamental frequency f0 = 100 Hz. 
Memcomputing is a novel non-Turing paradigm of computation that uses interacting memory cells (memprocessors for short) to store and process information on the same physical platform. It was recently proved mathematically that memcomputing machines have the same computational power of non-deterministic Turing machines. Therefore they can solve NP-complete problems in polynomial time and, using the appropriate architecture, with resources that only grow polynomially with the input size. The reason for this computational power stems from three main properties inspired by the brain and shared by any universal memcomputing machine: intrinsic parallelism, functional polymorphism and information overhead, namely the capability of storing more information than the number of memory elements by using the collective state of the memprocessor network. Here, we show an experimental demonstration of an actual memcomputing architecture that solves the NP-complete version of the subset-sum problem in only one step and is composed of a number of memprocessors that scales linearly with the size of the problem. We have fabricated this architecture using standard microelectronic technology so that it can be easily realized in any laboratory setting, whether academic or industrial. Even though the particular machine presented here is eventually limited by noise, it represents the first proof-of-concept of a machine capable of working with the collective state of interacting memory cells, unlike the present-day single-state machines built using the von Neumann architecture.
Flow measurements. (A) Volumetric flow through a single 101 nm nanopore at 77K in the gas phase of helium when the pressure differential is decreased in a stepwise fashion. The red line is a fit of the function Q f (t, P f ) = Qi(Pi) + ∆Qe −t/τ used to extract the equilibrium value. (B) Similar measurements in the 6 nm diameter nanopore for the superfluid phase of helium when the temperature is increased in a stepwise fashion. The red line is obtained in the same fashion as in (A). 
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 $\mathrm{O}(2)$ universality class as the onset of ferromagnetism in a lattice of classical spins with $XY$ symmetry. Below the transition, the superfluid density $\rho_s$ and superfluid velocity $v_s$ increase as power laws of temperature described by a universal critical exponent constrained to be equal by scale invariance. As the dimensionality is reduced towards one dimension (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~nm to 3~nm. As the pore size is reduced towards the 1D limit, we observe: {\it i)} a suppression of the pressure dependence of the superfluid velocity; {\it ii)} a temperature dependence of $v_{s}$ that surprisingly can be well-fitted by a powerlaw with a single exponent over a broad range of temperatures; and {\it iii)} decreasing critical velocities as a function of radius for channel sizes below $R \simeq 20$~nm, in stark contrast with what is observed in micron sized channels. We interpret these deviations from bulk behaviour as signaling the crossover to a quasi-1D state whereby the size of a critical topological defect is cut off by the channel radius.
We report superconductivity and magnetism in a new family of topological semimetals, the ternary half Heusler compounds $R$PdBi ($R$ : rare earth). In this series, tuning of the rare earth $f$-electron component allows for simultaneous control of both lattice density via lanthanide contraction, as well as the strength of magnetic interaction via de Gennes scaling, allowing for a unique tuning of both the normal state band inversion strength, superconducting pairing and magnetically ordered ground states. Antiferromagnetism with ordering vector (0.5,0.5,0.5) occurs below a Ne\'eel temperature that scales with de Gennes factor $dG$, while a superconducting transition is simultaneously linearly suppressed. With superconductivity appearing in a system with non-centrosymmetric crystallographic symmetry, the possibility of spin-triplet Cooper pairing with non-trivial topology analogous to that predicted for the normal state electronic structure provides a unique and rich opportunity to realize both predicted and new exotic excitations in topological materials.
The emergence of nematic electronic states accompanied by a structural phase transition is a recurring theme in many correlated electron materials, including the high-temperature copper oxide- and iron-based superconductors. We provide evidence for nematic electronic states in the iron-chalcogenide superconductor FeSe0.4Te0.6 from quasi-particle scattering detected in spectroscopic maps. The symmetry-breaking states persist above Tc into the normal state. We interpret the scattering patterns by comparison with quasi-particle interference patterns obtained from a tight-binding model, accounting for orbital ordering. The relation to superconductivity and the influence on the coherence length are discussed.
Persistent optical gating of a TI channel. (a) Longitudinal resistance as a function of time during UV and visible illumination. For t < 1900 s, a series of 30 s exposures to UV light (purple highlighting) followed by 120 s dark periods illustrates the persistence of the optical gating effect as the sample's chemical potential is tuned across the charge neutrality point. For t > 1900 s, a series of red light exposures (pink highlighting) reverses the effect. The exposure times were chosen for clarity given the differing kinetics of the two effects. The backside of the sample was held at 0 V for the duration of the experiment. (b) Schematic of measurement setup, showing Van der Pauw indices of the electrical contacts. (c) Schematic of the band structure of (Bi,Sb)2Te3, showing the effect of optical illumination on the chemical potential μ of the TI layer (dotted line and arrows).
Charge carrier response to electrostatic and optical gating. (a) Longitudinal resistivity ρ xx (blue) and Hall coefficient R H 
Optical and electrostatic tuning of weak antilocalization. Magnetoconductance ∆ G of a (Bi,Sb,) 2 Te 3 /SrTiO 3 
Spectral and temperature dependence. (a) Spectral dependence of the optical gating effect. The relative change in longitudinal resistance ∆ R (blue) is shown due to identically timed exposures to different energies of light. Before each exposure, red and UV light were used to reset the chemical potential to a similar starting position in the p -type regime such that ∆ R maps roughly to chemical potential shift ∆ μ (see inset). The transmission spectrum (red) of an identically-annealed SrTiO 3 substrate is shown for comparison. Both measurements were conducted at 5.2 K. (b) Temperature 
Writing and imaging p-n junctions in a TI. (a) Scanning reflectance image of a (Bi,Sb) 2 Te 3 channel. (b,c) Photocurrent images of the same region showing the longitudinal 
Topological insulators (TIs) have attracted much attention due to their spin-polarized surface and edge states, whose origin in symmetry gives them intriguing quantum-mechanical properties. Robust control over the chemical potential of TI materials is important if these states are to become useful in new technologies, or as a venue for exotic physics. Unfortunately, chemical potential tuning is challenging in TIs in part because the fabrication of electrostatic top-gates tends to degrade material properties and the addition of chemical dopants or adsorbates can cause unwanted disorder. Here, we present an all-optical technique which allows persistent, bidirectional gating of a (Bi,Sb)2Te3 channel by optically manipulating the distribution of electric charge below its interface with an insulating SrTiO3 substrate. In this fashion we optically pattern p-n junctions in a TI material, which we subsequently image using scanning photocurrent microscopy. The ability to dynamically write and re-write mesoscopic electronic structures in a TI may aid in the investigation of the unique properties of the topological insulating phase. The optical gating effect may be adaptable to other material systems, providing a more general mechanism for reconfigurable electronics.
The world-wide trade-risk network for non-fuel minerals, represented as a multiplex trade network V ij r ( t ), where each layer corresponds to one mineral resource, (A) copper, (B) lithium, and (C) platinum group metals. We study the network topology of each of these layers and compute both regional (node-based, i.e. country-specific) and global (network-based) measures. We study the relationships between supply risk, price volatility, network centrality, and trade barriers for the US and EU (world regions highlighted in green in the world map). 
TradeRisk versus price volatility for the EU and the US. Each point represents a mineral resource. The country-specific TradeRisk indicator for (A) EU and (B) US is significantly correlated with both the average yearly price volatility of the specific mineral, and with the composite supply risk, indicated by color. Resources with high CSR r tend to be on the right hand side. We also show the correlation coefficients ρ σ and ρ CSR of the price volatility with TradeRisk and composite supply risk, respectively, together with the p -values to reject the null hypothesis that the true correlation coefficient is zero. 
Ranks of TradeRisk in the EU and US. Each point represents a single resource. Rank 1 is given to the resource with the highest TradeRisk in the given region, rank 2 for the second highest TradeRisk, and so on. Resources where information is only available for either the EU or the US are shown outside the plot area. Major metals are shown by black boxes, minerals that are byproducts are shown as gray circles, other minerals as light-gray diamonds. It is clearly visible that those minerals that have a high TradeRisk in both regions are mined as byproducts, whereas the major metals exhibit intermediate values of TradeRisk. 
In the wake of the 2008 financial crisis the role of strongly interconnected markets in fostering systemic instability has been increasingly acknowledged. Trade networks of commodities are susceptible to deleterious cascades of supply shocks that increase systemic trade-risks and pose a threat to geopolitical stability. On a global and a regional level we show that supply risk, scarcity, and price volatility of non-fuel mineral resources are intricately connected with the structure of the world-trade network of or spanned by these resources. On the global level we demonstrate that the scarcity of a resource, as measured by its trade volume compared to extractable reserves, is closely related to the susceptibility of the trade network with respect to cascading shocks. On the regional level we find that to some extent the region-specific price volatility and supply risk can be understood by centrality measures that capture systemic trade-risk. The resources associated with the highest systemic trade-risk indicators are often those that are produced as byproducts of major metals. We identify significant shortcomings in the management of systemic trade-risk, in particular in the EU.
Miniaturized, monolithically integrated, fully wireless temperature-sensing motes with ultrasound powering and data communication. (A) A deconstructed schematic illustration of the major components of a mote, including a CMOS temperature sensor chip with two exposed Al pads, a microscale PZT transducer covered in Au on both sides, an anisotropic conductive film (ACF), and a Cu layer. (B) An SEM image of the mote, where the PZT transducer is monolithically integrated on the surface of the sensor chip (photo credit: Jeffrey Elloian, Columbia University). The mote is 300 m wide, 380 m long, and 570 m thick (0.065 mm 3 ); it weighs 0.3 mg. (C) A picture of a mote placed on a U.S. dime showing the relative size scale (photo credit: Chen Shi, Columbia University). (D) A mote placed at the tip of an 18-G needle (inner diameter, 0.84 mm, outer diameter, 1.28 mm; photo credit: Victoria Andino-Pavlovsky, Columbia University). (E) Seven motes loaded in a 1-ml syringe filled with PBS solution (photo credit: Victoria Andino-Pavlovsky, Columbia University). (F) The system diagram demonstrating the operating principles of such a mote. A Vantage 256 system (Verasonics Inc.) produces a customized ultrasound signal through an L12-3v probe. Such a signal provides power to and receives data from a mote. The embedded sensor chip contains a front-end block to convert the incoming AC signal from the on-chip transducer into a stable DC supply for the rest of the chip, a temperature-sensing block to perform temperature measurements, and a modulation block to transfer the temperature information back to the ultrasound source by actively modifying the input impedance of the integrated PZT transducer.
In vitro characterization with two motes embedded in chicken tissues. (A) An ultrasound image showing the mote embedded in chicken tissue (photo credit: Chen Shi, Columbia University). (B) Waveform of the ultrasound signal used to power up and communicate with the mote. (C) Acoustic backscattering data obtained at 37°C for 1.28 s showing the signal and RMS noise levels. (D) Temperature curves for two motes from 25° to 50°C.
In vivo characterization with motes implanted on the brain and in the hindlimb for measuring core body temperature. (A) The experimental setup with a mote implanted on the brain of a mouse (photo credit: Chen Shi, Columbia University). (B) A continuous temperature recording with the mote implanted on the brain compared to the reference temperature. (C) The experimental setup with a mote implanted in the hindlimb of a mouse (photo credit: Chen Shi, Columbia University). (D) A continuous temperature recording with the mote implanted in the hindlimb compared with the reference temperature.
In vivo characterization with motes implanted at the sciatic nerve for temperature monitoring during FUS stimulation. (A) The experimental setup for measuring the EMG responses in the leg of a mouse with FUS stimulation at the sciatic nerve (photo credit: Chen Shi, Columbia University). (B) EMG signals recorded with FUS stimulation at the sciatic nerve. (C) Implantation of two motes at the sciatic nerve (photo credit: Victoria Andino-Pavlovsky, Columbia University). Inset: Cartoon illustration of the implantation strategy. (D) Illustration of applying FUS from beneath the sciatic nerve (photo credit: Victoria Andino-Pavlovsky, Columbia University). (E) The experimental setup to measure temperature increases with FUS stimulation (photo credit: Chen Shi, Columbia University). (F) The temperature variations of two implanted motes under four different FUS stimulation intensities in comparison to their self-heating effects measured in vitro.
There has been increasing interest in wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. Here, we present such an implant that uses a conventional ultrasound imager for wireless powering and data communication and acts as a probe for real-time temperature sensing, including the monitoring of body temperature and temperature changes resulting from therapeutic application of ultrasound. The sub–0.1-mm ³ , sub–1-nW device, referred to as a mote, achieves aggressive miniaturization through the monolithic integration of a custom low-power temperature sensor chip with a microscale piezoelectric transducer fabricated on top of the chip. The small displaced volume of these motes allows them to be implanted or injected using minimally invasive techniques with improved biocompatibility. We demonstrate their sensing functionality in vivo for an ultrasound neurostimulation procedure in mice. Our motes have the potential to be adapted to the distributed and localized sensing of other clinically relevant physiological parameters.
Phonon excitations generated in a RIXS process. (A) Schematic of a two-step Cu L 3 edge RIXS process. The transition from initial |i⟩ to the intermediate state |m⟩ occurs upon absorption of an incident photon; a Cu 2p core electron is promoted to the 3d valence band. While the core hole is screened, the excited electron effectively causes the vibrations of the oxygen ions. A decay process leaves behind a phonon in the final state |f⟩ with probability depending on the EPC (24). (B) Schematic of the scattering geometry and the eigenvector for phonons with Q = (0.25, 0, 0). The yellow and blue "balls" represent copper and oxygen ions, respectively. Black arrows on the oxygen ions indicate the vibration directions. (C) A representative RIXS spectrum collected at 15 K on LESCO. The orange solid, green solid, and blue dashed lines represent scattering from elastic, phonon, and background contributions, respectively. The fitting components are described in the main text. a.u., arbitrary units.
Bond-stretching phonon mode in LESCO probed by RIXS. (A) Raw RIXS spectra collected at 15 K across the charge ordering wave vector. (B and C) RIXS intensity maps as a function of energy loss and h for temperatures as indicated. The red arrows in (A) and black open circles in (B) and (C) mark the phonon dispersion determined from fitting the spectra (see the main text). Color code indicates the RIXS intensity. To avoid the overwhelming elastic scattering at the charge ordering wave vector, we here present data taken along Q = (h, h tan φ) with φ = 4° and 0° for T = 15 and 200 K, respectively. r.l.u., reciprocal lattice units. (D and E) Elastic scattering and background subtracted spectra for h = 0.26 and 0.31. (F) Dimensionless parameter W ph /E ph as a function of h at 15 and 200 K. Solid lines are guides to the eye. Error bars, throughout the article, reflect SDs of the fits described in the main text.
Charge order is universal to all hole-doped cuprates. Yet, the driving interactions remain an unsolved problem. Electron-electron interaction is widely believed to be essential, whereas the role of electron-phonon interaction is unclear. We report an ultrahigh-resolution resonant inelastic x-ray scattering (RIXS) study of the in-plane bond-stretching phonon mode in stripe-ordered cuprate La 1.675 Eu 0.2 Sr 0.125 CuO 4 . Phonon softening and lifetime shortening are found around the charge ordering wave vector. In addition to these self-energy effects, the electron-phonon coupling is probed by its proportionality to the RIXS cross section. We find an enhancement of the electron-phonon coupling around the charge-stripe ordering wave vector upon cooling into the low-temperature tetragonal structure phase. These results suggest that, in addition to electronic correlations, electron-phonon coupling contributes substantially to the emergence of long-range charge-stripe order in cuprates.
Doping dependence of the energy band position and the DOS near E F. (A) The doping dependence of the band bottom (top) energy of the a (b) band. At K c = 0.080 ML, the a band begins to cross E F. (B) Integrated dI/dV values within the bias range of ±8 meV as a function of K c , which reflects the DOS near E F . 
QPI measurement of the a band and the spatial and temperature dependence of its gap. (A) Topographic image of the mapping area of size 100 × 100 nm 2 (K c = 0.124 ML). (B) Typical dI/dV map taken at V b = 10 mV. The set point for dI/dV map is as follows: V b = 50 mV, I = 150 pA, and DV = 3 mV. (C) FFT image of (B). (D) Intensity plot of the FFT linecuts through q = (0, 0); dashed curve is the parabolic fit. Note that the small gap is not observable here because of the large modulation (DV ). (E) A dI/dV linecut taken along the dashed arrow in Fig. 2D, showing a spatially uniform gap. Bars indicate the coherence peaks. (F) Temperature dependence of the gap taken on a different sample with K c ~ 0.12 ML. 
In iron-based superconductors, understanding the relation between superconductivity and electronic structure upon doping is crucial for exploring the pairing mechanism. Recently, it was found that, in iron selenide (FeSe), enhanced superconductivity (Tc of more than 40 K) can be achieved via electron doping, with the Fermi surface only comprising M-centered electron pockets. By using surface K dosing, scanning tunneling microscopy/spectroscopy, and angle-resolved photoemission spectroscopy, we studied the electronic structure and superconductivity of (Li0.8Fe0.2OH)FeSe in the deep electron-doped regime. We find that a Γ-centered electron band, which originally lies above the Fermi level (EF), can be continuously tuned to cross EF and contribute a new electron pocket at Γ. When this Lifshitz transition occurs, the superconductivity in the M-centered electron pocket is slightly suppressed, and a possible superconducting gap with a small size (up to ~5 meV) and a dome-like doping dependence is observed on the new Γ electron pocket. Upon further K dosing, the system eventually evolves into an insulating state. Our findings provide new clues to understand superconductivity versus Fermi surface topology and the correlation effect in FeSe-based superconductors.
Twofold SC gap resolved by QPI measurements. (A to J) The FT-QPI images derived from Fourier transformation to the QPI images at different energies with real-space area of 84 × 84 nm 2 (V set = 10 mV, I set = 50 pA). The inset in (F) shows the topography associated with the QPI measurements. (K to O) Control experimental FT-QPI results on another 2-QL Bi 2 Te 3 /FeTe 0.55 Se 0.45 heterostructure. The FT-QPI at 4.0 mV presented in (O) shows very clearly the feature of sixfold symmetry. (P) The averaged FT-QPI intensity per pixel in the q space of (G) and (H) within the band bounded by the two parallel dashed hexagons in (A) with increment of every 5°. The initial angle of f is defined from one G-K direction, as marked by a red arrow in (A). (Q) Schematic top view of the Te atom layer of Bi 2 Te 3 surface. (R) Schematic 2D hexagonal Fermi surface and the resultant angular dependence of the anisotropic SC gap. (S) Schematic image of SC gap structures with an oval Fermi surface; the color gives a qualitative distribution of the SC gap. 
Vortex image and vortex core states. (A) Zero-bias differential conductance map of a single vortex. The inset shows the topography measured near the vortex, and the vortex is elongated along the a axis. (B) Spectroscopic image of the vortex lattice consisted of elongated vortices measured at zero bias. This elongated vortex shape is very different from that in the bare FeTe 0.55 Se 0.45 because of distinct values of Fermi energies. (C and D) Tunneling spectra measured along a axis and perpendicular to a axis directions, respectively. The curves marked by the red arrow represent the spectrum measured at the center of the vortex core. It should be noted that the dark dashed lines in (A) only denote the directions of the spectra measurements but do not represent the spatial distance of the measurements. The spectra shown in (C) and (D) are taken along much longer lines than those shown in (A), and the real spatial distance for measuring spectra is given by the vertical dashed arrowed line on the left-hand side of each panel. All data in this figure are taken at T = 0.4 K and B = 0.7 T with V set = 10 mV and I set = 50 pA. 
Energy evolution of vortex image. (A) Topography of the view in an area (V bias = 1 V, I t = 10 pA, 140 × 140 nm 2 ). (B to H) Vortex image measured with different bias voltages (V set = 10 mV, I set = 50 pA) at 0.4 K and 0.7 T. Twofold symmetry of the vortex images appears at bias below the gap maximum around 2 meV (B to F). When the measuring voltage is beyond 2 meV (G and H), the vortex images become roughly isotropic dark discs, and the twofold symmetry is absent. This can be understood by the relative reduction of DOS within a certain region in the center compared with that outside that region. 
Topological superconductors are an interesting and frontier topic in condensed matter physics. In the superconducting state, an order parameter will be established with the basic or subsidiary symmetry of the crystalline lattice. In doped Bi2Se3 or Bi2Te3 with a basic threefold symmetry, it was predicted, however, that bulk superconductivity with order parameters of twofold symmetry may exist because of the presence of odd parity. We report the proximity effect–induced superconductivity in the Bi2Te3 thin film on top of the iron-based superconductor FeTe0.55Se0.45. By using the quasiparticle interference technique, we demonstrate clear evidence of twofold symmetry of the superconducting gap. The gap minimum is along one of the main crystalline axes following the so-called Δ4y notation. This is also accompanied by the elongated vortex shape mapped out by the density of states within the superconducting gap. Our results provide an easily accessible platform for investigating possible topological superconductivity in Bi2Te3/FeTe0.55Se0.45 heterostructures.
Phases composition before and after SPS sintering. (A to D) FESEM images of the free surface of melt-spun ribbons containing 0, 5, 15, and 25 wt % excess of Te, respectively. The red arrows in (B) to (D) show the dendritic boundaries in the ribbon, where single-phase Te distributed. (E) Displacement of a plunger as a function of temperature during SPS processing of melt-spun ribbons containing different excess amounts of Te. (F) XRD patterns of powders at different stages of processing. (G to I) Photos of graphite dies after SPS containing samples with 5, 15, and 25 wt % excess of Te. The material ejected during SPS is clearly seen. a.u., arbitrary units. 
The orientation of the sintered bulks. (A) XRD patterns of planes perpendicular to the pressure direction during SPS. (B) Relationship between the orientation factor F and the amount of excess Te. (C) FESEM images: Surface of a sample with no Te excess observed perpendicular to the pressing direction of SPS. (D) Surface of the same sample as in (C) but observed parallel to the pressing direction. (E) Surface of a sample containing 25 wt % excess of Te observed perpendicular to the pressing direction. (F) Surface of the same sample as in (E) but observed parallel to the pressing direction. The upper right corners show the relative directions marked in red. 
Microstructure of sintered bulks. (A) TEM image of a sample sintered from melt-spun ribbons containing 25 wt % excess of Te. The inset shows SAED of a narrow region (white circle) corresponding to the Bi 0.5 Sb 1.5 Te 3 matrix. (B) A view of grain boundaries with the inset displaying images of FFT of the numbered regions. (C) Moiré pattern with the width of 40 nm in the boundary region. (D) An image of IFFT of (C) showing dislocations. 
Thermal properties of sintered bulks. Total thermal conductivity measured (A) perpendicular to and (B) parallel to the pressing direction for samples sintered from melt-spun ribbons of composition Bi 0.5 Sb 1.5 Te 3+x wt % excess of Te (x = 0, 5, 10, 15, 20, and 25). k || and k ⊥ represent the total thermal conductivity measured parallel and perpendicular to the pressing direction, respectively. The red dashed line without symbol in (A) and (B) is the data of Kim et al. (16) for comparison. (C) Lattice thermal conductivity for the identical samples measured perpendicular to the pressing direction. The inset is the data of Kim et al. (16). (D) A relationship between the ratio of k || /k ⊥ and the orientation factor F for sintered samples of composition Bi 0.5 Sb 1.5 Te 3+x wt % excess of Te (x = 0, 5, 10, 15, 20, and 25). The line is the data of Shen et al. (18). 
Electrical properties of sintered bulks. (A) Electrical conductivity, (B) Seebeck coefficient, (C) the power factor, and (D) figure of merit ZT for samples sintered from melt-spun ribbons of composition Bi 0.5 Sb 1.5 Te 3+x wt % excess of Te (x = 0, 5, 10, 15, 20, and 25) measured perpendicular to (solid lines with solid symbols, marked by "⊥") and parallel to (dashed lines with open symbols, marked by "//") the pressing direction. The suffix F means that the ZT is calculated using measurements of the electronic transport properties perpendicular to and the thermal conductivity k parallel to the pressing direction, as done for samples with x = 20 and x = 25 designated by open triangles and open hexagons connected by solid curves. The red dashed line without symbol in (A) and (B) is the data of Kim et al. (16) for comparison. 
Several prominent mechanisms for reduction in thermal conductivity have been shown in recent years to improve the figure of merit for thermoelectric materials. Such a mechanism is a hierarchical all-length-scale architecturing that recognizes the role of all microstructure elements, from atomic to nano to microscales, in reducing (lattice) thermal conductivity. In this context, there have been recent claims of remarkably low (lattice) thermal conductivity in Bi0.5Sb1.5Te3 that are attributed to seemingly ordinary grain boundary dislocation networks. These high densities of dislocation networks in Bi0.5Sb1.5Te3 were generated via unconventional materials processing with excess Te (which formed liquid phase, thereby facilitating sintering), followed by spark plasma sintering under pressure to squeeze out the liquid. We reproduced a practically identical microstructure, following practically identical processing strategies, but with noticeably different (higher) thermal conductivity than that claimed before. We show that the resultant microstructure is anisotropic, with notable difference of thermal and charge transport properties across and along two orthonormal directions, analogous to anisotropic crystals. Thus, we believe that grain boundary dislocation networks are not the primary cause of enhanced ZT through reduction in thermal conductivity. Instead, we can reproduce the purported high ZT through a favorable but impractical and incorrect combination of thermal conductivity measured along the pressing direction of anisotropy while charge transport measured in the direction perpendicular to the anisotropic direction. We believe that our work underscores the need for consistency in charge and thermal transport measurements for unified and verifiable measurements of thermoelectric (and related) properties and phenomena.
Rising sea levels will have overwhelmingly negative impacts on coastal communities globally. With previous research focused on how sea-level rise (SLR) affects storm-induced flooding, we show that SLR will also increase both the frequency and the intensity of tsunami-induced flooding, another significant coastal hazard associated with sea-level extremes. We developed probabilistic tsunami inundation maps for Macau, a densely populated coastal city located in the South China Sea, under current sea-level, 0.5-m SLR, and 1-m SLR conditions, using an extensive Monte Carlo tsunami inundation simulation. Our results indicate that conservative amounts of SLR of 0.5 m (by 2060) and 1 m (by 2100) would dramatically increase the frequency of tsunami-induced flooding incidences by a factor of 1.2 to 2.4 and 1.5 to 4.7, respectively.
Crystal structure, band structure, and metal-insulator transition of LMO. (A) Projection of four unit cells onto the ac plane, where the MoO 6 octahedra hosting the conducting zigzag chains (oriented out of this plane along the b axis) are highlighted in purple. Blue sphere, Mo; red/pink, O; green, Li. (B) In each unit cell, there are double zigzag chains made of corner-sharing octahedra. The octahedra at the top of the figure have had all nonessential oxygen atoms removed. The corner oxygen shared by adjacent in-chain octahedra is denoted in red, while interchain oxygen is denoted in pink. (C) Simplified Fermi surface of LMO showing the weakly dispersive, quasi-1D bands along the a axis due to the weak interchain hopping energy (top panel), which, nevertheless, causes an energy gap around the Fermi surface (schematic green curves in the lower panel). The small energy gap easily allows excitation of electron-hole pairs, i.e., excitons. (D) In-chain resistivity versus temperature showing a metal-insulator transition around T min ~ 25 K, below which the insulating form of the resistivity can be well fitted by a power law (see section S4C and fig. S11). Crystallographic drawings were produced using VESTA (44).
Asymmetric MR of LMO within the ac plane. (A) Notation of angles for magnetic fields rotated within the three principal planes of the coordinate system specified in Fig. 1A. (B) Normalized ADMR curves obtained at various temperatures as a constant magnetic field of 13 T is rotated within the ac plane. The ADMR evolves from symmetric (about the a or the c axis) at high temperatures to asymmetric at low temperatures. Data are shifted vertically for clarity. Here, current is injected along the a axis. (C) Left panel: Mirror reflection of the ADMR curves at T = 37 K [in (A)] about the c axis. Right panel: Corresponding reflection plot at T = 4.2 K. The shaded region indicates the degree of asymmetry between these two curves. (D) Evolution of the asymmetric MR with temperature. The solid circles represent the degree of asymmetry in the ADMR, quantified by taking the normalized integrated area inside the red and blue curves in (B) defined as  ≡ (A LHS − A RHS )/(A LHS + A RHS ). Inset: Blowup of the same figure between 10 and 40 K, to highlight the growth of the asymmetry below T min . The dashed line is a fit to a simple parabolic temperature dependence. (E) Similar ADMR sweeps as in Fig. 2B, but for the current along the b axis, showing a similar asymmetry at low temperatures. (F) At a fixed temperature (T = 1.2 K), the asymmetry in the ADMR grows with increasing field.
Origin of the asymmetry and determination of the critical angle. (A) Field sweeps of the MR at 1.2 K are measured at various angles within the ac plane, showing the evolution of the peak field with angle. The angle of the dashed thick curve is ~6° from the c axis. The maximal MR at B = 2, 5, 10, 15, 20, 25, and 30 T are denoted by empty symbols and correspond to the peaks in (B). Inset: Expanded plot of the region of the MR curves contained below the dashed line in the main panel. (B) Same data as in (A), replotted for fixed field strengths. Each is vertically shifted for better visibility. Comparison with Fig. 2F shows almost identical behavior. (C) Same data as in (A) with the field values scaled by |cos|. The actual scaling factor, i.e., the ratio between B scaled and B, is depicted in fig. S7. Inset: Expanded plot of the dashed rectangle in the main panel. (D) The resultant peak field values obtained from Fig. 3C plotted as a function of angle within the ac plane. At the critical angle  CR , the negative MR is maximally suppressed.
Identification of the critical angle. (A) Blowup of the unit cell of LMO showing the alignment of the critical angle  CR (purple arrow) with the polar axis of the MoO 6 octahedra. (B) Rotation of the unit cell's frame of reference to the polar axis. (C) A pair of MoO 6 octahedra showing the orientation of the d yz orbitals along this polar axis. A dark exciton, composed of d yz (in green) and d xz (not shown) orbitals, is formed in adjacent octahedra residing in two zigzag chains within a unit cell. Both orbitals have the same quantization axis (again indicated by the purple arrow). Crystallographic drawings were produced using VESTA (44).
We report on an emerging symmetry axis in the magnetoresistance of bulk single crystals of quasi–one-dimensional Li 0.9 Mo 6 O 17 below Tmin = 25 K, the temperature at which the electrical resistivity experiences a minimum. Detailed angle-dependent magnetoresistance sweeps reveal that this symmetry axis is induced by the development of a negative magnetoresistance, which is suppressed only for magnetic fields oriented along the poles of the MoO 6 octahedra that form the conducting chains. We show that this unusual negative magnetoresistance is consistent with the melting of dark excitons, composed of previously omitted orbitals within the t2g manifold that order below Tmin . The unveiled symmetry axis in directional magnetic fields not only provides evidence for the crystallization of these dark excitons but also sheds new light on the long-standing mystery of the metal-insulator transition in Li 0.9 Mo 6 O 17 .
Polarizable materials attract attention in catalysis because they have a free parameter for tuning chemical reactivity. Their surfaces entangle the dielectric polarization with surface polarity, excess charge, and orbital hybridization. How this affects individual adsorbed molecules is shown for the incipient ferroelectric perovskite KTaO 3 . This intrinsically polar material cleaves along (001) into KO- and TaO 2 -terminated surface domains. At TaO 2 terraces, the polarity-compensating excess electrons form a two-dimensional electron gas and can also localize by coupling to ferroelectric distortions. TaO 2 terraces host two distinct types of CO molecules, adsorbed at equivalent lattice sites but charged differently as seen in atomic force microscopy/scanning tunneling microscopy. Temperature-programmed desorption shows substantially stronger binding of the charged CO; in density functional theory calculations, the excess charge favors a bipolaronic configuration coupled to the CO. These results pinpoint how adsorption states couple to ferroelectric polarization.
Topological photonic crystals (TPhCs) provide robust manipulation of light with built-in immunity to fabrication tolerances and disorder. Recently, it was shown that TPhCs based on weak topology with a dislocation inherit this robustness and further host topologically protected lower-dimensional localized modes. However, TPhCs with weak topology at optical frequencies have not been demonstrated so far. Here, we use scattering-type scanning near-field optical microscopy to verify mid-bandgap zero-dimensional light localization close to 100 THz in a TPhC with nontrivial Zak phase and an edge dislocation. We show that because of the weak topology, differently extended dislocation centers induce similarly strong light localization. The experimental results are supported by full-field simulations. Along with the underlying fundamental physics, our results lay a foundation for the application of TPhCs based on weak topology in active topological nanophotonics, and nonlinear and quantum optic integrated devices because of their strong and robust light localization.
A novel bioorthogonal reaction-promoted hyperpolarization tagging strategy. (A) Illustration of spin-hyperpolarized tagging via bioorthogonal chemistry. Bioorthogonal ligation between reactive partners X and Y incorporates the hyperpolarized chemical motif (red) within the target molecule (yellow). (B) 15 N 4-1,2,4,5-tetrazine as a molecular tag and its dual roles in hyperpolarization and bioorthogonal ligation. First, the 15 N nuclei in 15 N 4-1,2,4,5-tetrazine are hyperpolarized by SABRE-SHEATH, and then, the hyperpolarized tetrazine undergoes rapid IEDDA with a strained azadienophile, leading to the hyperpolarized 15 N 2-cycloaddition product and hyperpolarized 15 N 2 gas. 
Tetrazine hyperpolarization. (A) Structures of studied 15 N 4-1,2,4,5-tetrazines 1a and 1b. (B) Single-shot hyperpolarized spectra of tetrazines 1a and 1b at magnetization or singlet modes, with peak identifications, observed enhancement (e), and polarization level (p). Depending on the magnetic field at which hyperpolarization was induced, inphase signal (magnetization) or antiphase signal (singlet) was observed. Enhancement values (e) and polarization levels (p) were obtained by comparison of the hyperpolarized spectrum to a thermal reference spectrum of the respective 15 N 4-1,2,4,5-tetrazine. a.u., arbitrary units; ppm, parts per million. (C) T 1 and T s lifetime curves for 1a and 1b. Measurement at 0.3 mT. Sample as a solution of 15 N 4-1,2,4,5-tetrazine (1.5 mM), pyridine (1.0 mM), and Ir(COD)(IMes)Cl [COD, 1,5-cyclooctadiene; IMes, 1,3-bis(2,4,6-trimethylphenyl) imidazol-2-ylidene; 0.15 mM] 0.15 mM] in methanol-d 4 (400 ml). 
Hyperpolarized magnetic resonance (HP-MR) is a powerful, sensitive, and noninvasive approach to visualize molecular structure, function, and dynamics in vitro and in vivo. Current applications of HP-MR mostly rely on hyperpolarization of target compounds in dedicated hyperpolarizers because biomolecules can typically not be hyperpolarized directly in vivo. The injected hyperpolarized probes often undergo multiple metabolic pathways in living systems, and it remains challenging to localize and identify specific targets with high chemical selectivity. To address these current limitations in HP-MR, we report a novel hyperpolarization tagging strategy that integrates bioorthogonal chemistry and hyperpolarization to achieve the specific hyperpolarization of targets. This strategy is demonstrated by studies of hyperpolarized ¹⁵N4-1,2,4,5-tetrazines, which undergo rapid and selective cycloaddition with cyclooctyne to provide hyperpolarized ¹⁵N2-containing cycloaddition products and hyperpolarized ¹⁵N2 gas. This work not only suggests great potential of ¹⁵N4-1,2,4,5-tetrazines as molecular tags in HP-MR imaging (HP-MRI) but also supports the production of hyperpolarized para-¹⁵N2 gas, a biologically and medically innocuous gas with great potential for HP-MRI. This bioorthogonal reaction–based hyperpolarization tagging strategy enables a new class of in vitro and in vivo applications.
Radical-mediated 1,2-difunctionalization of olefins is a well-established synthetic technique widely used in the rapid construction of structurally diverse molecular entities. However, radical-mediated 1,3-difunctionalization reactions are rare, and the substrates are generally limited to strained skeletons. Here, we report a practical approach for 1,3-difunctionalization of available β,γ-unsaturated ketones via a radical cascade process including visible light-irradiated radical addition, thermodynamic stability-driven 1,2-carbonyl migration from unactivated all-carbon quaternary center, and terminal C-radical varied transformations. Various highly functionalized alkyl skeletons with different valuable functional groups at positions 1 and 3 and the carbonyl group at position 2 have been synthesized through a radical chain pathway or Cu-catalyzed Ritter-type reaction. Moreover, this protocol provides a real case of diversity-oriented radical rearrangement for drug discovery. We identified a previously unknown chemotype of dual inhibitors for hypoxia-inducible factor (HIF) and WNT signaling pathways from products. These small-molecule inhibitors could suppress HIF and WNT signaling-dependent HCT116 cell growth in 2D and 3D culture systems.
Fucosylation reactions catalyzed by fucosylation enzymes. (A) Structures of various disease-associated and human milk oligosaccharides. (B) Schematic depiction of fucosylation reactions catalyzed by FucTs and fucosidases. Typically, an FutA catalyzes the l-fucose transfer from a GDP-Fuc donor substrate to a LacNAc acceptor substrate via an 1,3-linkage, forming the Le x . -l-Fucosidases can also transfer a fucose moiety from the para-nitrophenyl -l-fucopyranoside (Fuc--pNP) to lactose, forming a 3-fucosyllactose.
Scheme for the product entrapment strategy and the established cell-based fucosylation assay for FACS screening. (A) Two kinds of fluorescently labeled LacNAc derivatives (1 and 2) were designed and synthesized for cell entrapment analysis. (B) Fluorescently labeled acceptor substrates are transported into the cell via LacY; fucose enters into the cell via a fucosyl transporter (FucP) and was converted into GDP-fucose donor substrate by GDP-fucose synthase (FKP). After incubation and washing, E. coli cells expressing fucosylation enzymes accumulate fluorescent trisaccharide enzyme products, as the LacY transport rate for such products is significantly reduced compared to their disaccharide substrate form. Thus, the fluorescence intensity accumulation inside cells carries information about the catalytic activity of the fucosylation enzymes being assayed/screened. These cells with FutA activity can be further isolated using FACS. (C) Visualization of fluorescence entrapment within FutA (+) and FutA (−) cells under an ultraviolet light. (D) Flow cytometry profiles of FutA (+) and FutA (−) cell fluorescence after 30-min incubation with 1.5 mM fucose, 0.5 mM bodipy-LacNAc, and coumarin-LacNAc, followed by a washing step. Green and blue signals represent cells retaining bodipy and coumarin fluorescently labeled oligosaccharides, respectively.
Analysis of FACS-based screening efficiency by competitive allele-specific TaqMan PCR. (A) The RBS-ATG spacing technique was used to create two populations of cells: (i) normal FutA (+) cells and (ii) FutA (+) cells with a weakened FutA activity resulting from reduced FutA expression [FutA (+) -RBS cells]. Cell mixtures of FutA (+) and FutA (+) -RBS were prepared and applied to one round of FACS sorting. The unsorted and sorted variant pools were quantified using competitive allele-specific TaqMan PCR, and then, enrichment factors were calculated according to FutA (+) cell ratios before and after sorting. (B) Flow cytometric screening of FutA (+) and FutA (+) -RBS cells. (C) Percentage of FutA (+) cells increased after sorting.
Structural insight into the improved catalytic activity of the best M32 mutant. (A) Backbone diagram of the M32 mutant (PDB code 5ZOI) with mutations accumulations during directed evolution. Mutated residues are depicted in yellow sticks. Helix 5 having the triple mutations D127N/R128E/H131I located between the NTD and CTD is colored in green. (B) Enhanced interaction toward the LacNAc acceptor in the M32 mutant. The S45F mutation of M32 resulted in a new clamp-like structure with W33 and W34 at the bottom of the substrate-binding pocket. Key aromatic residues and S45 are shown in green sticks, and substituted residue F45 was represented in yellow stick. (C) Local electrostatic surface of M32 active pocket (red, electronegative; blue, electropositive; contoured from −8 to 8 kT/e). These D127N/R128E/ H131I mutations showed a changed local electrostatic potential environment on the surface of hinge helix 5. (D) Root mean square fluctuation (RMSF) of wild-type FutA and M32 mutant residues from 122 to 148 region backbones in 100 ns constrained MD simulation. The segment of 122 to 148 residues are shown in cartoon.
Fucosylated glycoconjugates are involved in a variety of physiological and pathological processes. However, economical production of fucosylated drugs and prebiotic supplements has been hampered by the poor catalytic efficiency of fucosyltransferases. Here, we developed a fluorescence-activated cell sorting system that enables the ultrahigh-throughput screening (>10 ⁷ mutants/hour) of such enzymes and designed a companion strategy to assess the screening performance of the system. After three rounds of directed evolution, a mutant M32 of the α1,3-FucT from Helicobacter pylori was identified with 6- and 14-fold increases in catalytic efficiency ( kcat / Km ) for the synthesis of Lewis x and 3′-fucosyllactose, respectively. The structure of the M32 mutant revealed that the S45F mutation generates a clamp-like structure that appears to improve binding of the galactopyranose ring of the acceptor substrate. Moreover, molecular dynamic simulations reveal that helix α5, is more mobile in the M32 mutant, possibly explaining its high fucosylation activity.
FBP relieves 2-DG-mediated pregnancy loss. (A) The FBP levels in uterine tissues of pregnant mice treated with saline (1%, n = 8) or 2-DG (50 mg/kg per day, n = 8) were detected with FBP kits. (B to D) Photograph (red arrow: absorption point) of uterus from pregnant mice intraperitoneally injected with 1% saline (n = 8), 2-DG (50 mg/kg per day, n = 8), or 2-DG (50 mg/kg per day) plus FBP (500 mg/kg per day) (n = 8). The absorption rates or crown-rump length (CRL) of embryos from (B) were analyzed in (C) or (D), respectively. Data were presented as means ± SEM and analyzed by t test or one-way ANOVA test. *P < 0.05, **P < 0.01, and ***P < 0.001; NS, no significance.
FBP increases IL-27 expression in DSCs in a PKM2/ERK1/2/c-FOS-dependent manner. (A and B) Expression of p-c-fos, c-fos, p-ERK, or ERK in FBP (0.5 mM)-treated ESCs (n = 9) was analyzed by Western blotting. (C) The IL-27 levels in supernatants of FBP, FBP, and ERK1/2 inhibitor (U0126, 10 M) or FBP and c-fos inhibitor (T-5224, 20 mM)-treated ESCs (24 hours, n = 6) were detected by ELISA. (D) Sense proteins of FBP and G6P in ESCs were analyzed by the HuProt 20K protein array. (E) PPI network based on the STRING database between 69 proteins from (D), FOS, MAPK1, and IL27. (F to H) The expression of p-c-fos, c-fos, p-ERK, or ERK and secretion levels of IL-27 in a PKM2 activator (mitapivat, 10 M) or DMSO (Ctrl, 1‰)-treated ESCs (24 hours, n = 6) were analyzed by Western blotting and ELISA. (I to K) Expression of p-c-fos, c-fos, p-ERK, or ERK in uterus and IL-27 levels in USCs from pregnant mice (n = 8) treated with saline (1%) or 2-DG (50 mg/kg per day) were analyzed by Western blotting and ELISA. Data were presented as means ± SEM and analyzed by t test or one-way ANOVA test. *P < 0.05, **P < 0.01, and ***P < 0.001.
IL-27 induces decidual COX-2 + macrophage differentiation in vitro. (A and B) Expression of IL-27RA in DSCs (n = 9), trophoblast cells (Tros; n = 9), DLCs (n = 9), and decidual macrophages (dMφs) (n = 9) was analyzed by FCM. Statistical graph of (A) was shown in (B). (C and D) Expression of p-STAT3 and STAT3 in dMφs (n = 9) after coculture with ESCs pretreated with FBP (0.5 mM for 24 hours) or transfected with IL-27 overexpression plasmids (IL-27 over ) for 48 hours was detected by FCM, and the ratios of p-STAT3 to STAT3 were calculated. (E and F) Expression of COX-2 in peripheral blood monocytes (pMos) (n = 12), eMφs (n = 12), and dMφs (n = 12) was analyzed by FCM. Statistical graph of (E) was shown in (F). (G) Expression of COX-2 in dMφs (n = 9) cocultured with Ctrl or FBP (0.5 mM for 24 hours)-treated ESCs was detected by FCM. (H) Expression of COX-2 in dMφs (n = 9) cocultured with FBP (0.5 mM for 24 hours)-pretreated ESCs or IL-27 over ESCs for 48 hours was detected by FCM. Data were presented as means ± SEM or median and quartile and analyzed by t test, one-way ANOVA test, or Kruskal-Wallis test. *P < 0.05, **P < 0.01, and ***P < 0.001.
IL-27 maintains normal pregnancy in a uterine COX-2 + macrophage-dependent manner. (A) Expression of COX-2 in uMφs of WT (mated with male Il27ra −/− mice, n = 8) or Il27ra −/− pregnant mice (mated with male WT mice, n = 8) was detected by FCM. (B) Expression of COX-2 in uMφs of saline (1%, n = 8) or 2-DG (50 mg/kg per day, n = 8)-treated pregnant mice was detected by FCM. (C) Expression of differentiation molecules in uMφs of WT (n = 8) or Ptgs2 −/− pregnant mice (n = 8) was detected by FCM. (D to F) Photograph (red arrow: absorption point) of uterus, the CRL of embryos, or absorption rates from WT (n = 8) or Ptgs2 −/− pregnant mice (n = 8). (G) Differential proteins of supernatants between IL-27RA + dMφs and IL-27RA − dMφs were evaluated by the proteomic microarray. (H to J) Transcription levels of decidualizationrelated genes in uterus, depth of CK7 + trophoblast infiltration into uterus, and embryo absorption rates of Il27ra −/− pregnant mice (mated with male WT mice, n = 8) adopted with WT or Ptgs2 −/− macrophages. Data were presented as means ± SEM or median and quartile and analyzed by t test, Mann-Whitney U test, or one-way ANOVA test. *P < 0.05, **P < 0.01, and ***P < 0.001.
FBP administration induces COX-2 + dMφ differentiation and alleviates pregnancy loss. (A and B) The FBP levels in uterine tissues and blood plasma of normal pregnant mice (Ctrl, n = 8), spontaneous abortion-prone mice (SA; n = 8), or SA mice intraperitoneally injected with FBP (500 mg/kg per day, SA + FBP, n = 8) were detected. (C and D) The IL-27 levels in USCs of pregnant mice from Ctrl (n = 8), SA (n = 8), or SA + FBP (n = 8) group were analyzed by FCM. (E and F) The COX-2 levels in uMφ of pregnant mice from Ctrl (n = 8), SA (n = 8), or SA + FBP (n = 8) group were analyzed by FCM. (G) The mRNA levels of decidualization-related genes in uterus of pregnant mice from Ctrl (n = 8), SA (n = 8), or SA + FBP (n = 8) group were detected by RT-PCR. (H) Depth of CK7 + trophoblast infiltration into uterus of pregnant mice from Ctrl (n = 8), SA (n = 8), or SA + FBP (n = 8) group was observed by hematoxylin and eosin staining or immunofluorescence staining. (I and J) Photograph (red arrow: absorption point) of uterus and absorption rates of pregnant mice from Ctrl (n = 8), SA (n = 8), or SA + FBP (n = 8) group. Data were presented as means ± SEM and analyzed by one-way ANOVA test. *P < 0.05, **P < 0.01, and ***P < 0.001.
Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanisms underlying this process are still largely unknown. We found that the decidualization process is accompanied by the accumulation of fructose-1,6-bisphosphate (FBP). The combination of FBP with pyruvate kinase M stimulated IL-27 secretion by endometrial stromal cells in an ERK/c-FOS-dependent manner. IL-27 induced decidual COX-2+ M2-like macrophage differentiation, which promotes decidualization, trophoblast invasion, and maternal-fetal tolerance. Transfer of Ptgs2+/COX-2+ macrophages prevented fetal loss in Il27ra-deleted pregnant mice. FBP levels were low in plasma and decidual tissues of patients with unexplained recurrent spontaneous abortion. In therapeutic studies, FBP supplementation significantly improved embryo loss by up-regulation of IL-27-induced COX-2+ macrophage differentiation in a mouse model of spontaneous abortion. These findings collectively provide a scientific basis for a potential therapeutic strategy to prevent pregnancy loss.
Vaccines are instrumental and indispensable in the fight against the COVID-19 pandemic. Several recent SARS-CoV-2 variants are more transmissible and evade infection- or vaccine-induced protection. We constructed live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and showed that the lead candidate, designated sCPD9, protects Syrian hamsters from a challenge with ancestral virus. Here, we assessed immunogenicity and protective efficacy of sCPD9 in the Roborovski dwarf hamster, a nontransgenic rodent species that is highly susceptible to SARS-CoV-2 and severe COVID-19–like disease. We show that a single intranasal vaccination with sCPD9 elicited strong cross-neutralizing antibody responses against four current SARS-CoV-2 variants of concern, B.1.1.7 (Alpha), B.1.351 (Beta), B. (Gamma), and B.1.617.2 (Delta). The sCPD9 vaccine offered complete protection from COVID-19–like disease caused by the ancestral SARS-CoV-2 variant B.1 and the two variants of concern B.1.1.7 and B.1.351.
The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors. Here, we compared variants of concern (VOC) B.1.1.7 and B.1.351 to a recent B.1 SARS-CoV-2 isolate containing the D614G spike substitution in the rhesus macaque model. B.1.1.7 behaved similarly to D614G with respect to clinical disease and replication in the respiratory tract. Inoculation with B.1.351 resulted in lower clinical scores, lower lung virus titers, and less severe lung lesions. In bronchoalveolar lavages, cytokines and chemokines were up-regulated on day 4 in animals inoculated with D614G and B.1.1.7 but not with B.1.351. In nasal samples, cytokines and chemokines were up-regulated only in the B.1.1.7-inoculated animals. Together, our study suggests that circulation under diverse evolutionary pressures favors transmissibility and immune evasion rather than increased pathogenicity.
Images of the membranes tested in this study. (A) SEM image of the CNT membrane surface, showing CNT tips emerging from the polymer. Inset shows the membrane sample without magnification. (B) SEM image of the surface of the CNT membrane using an imaging technique that uses high voltage without sputter coating to reveal the CNTs below the membrane surface. (C) TEM image of the CNT membrane in planar view, showing CNT pore openings, indicated by red circles, emerging from CNTs below the membrane surface. 
Rejection of analytes in the aqueous separation tests, with molecular dimensions increasing from left to right. Rejection of dyes is shown with and without a background IS of 34 mM (NaCl) to examine the effects of Donnan exclusion versus steric exclusion on solute rejection. 
Gas transport properties of CNT membranes. (A) Graph of the relationship between He permeance and pressure showing pressure dependence. GPU, gas permeation units. (B) Graph of the relationship between analyte/He selectivity and viscosity (viscous flow selectivity shown as a dashed line), indicating that no correlation with viscous flow is present. Viscosities for gases are taken from Yampolskii and Freeman (27). (C) Graph of the relationship between analyte molecular weight and analyte/He selectivity at 138 kPa. Knudsen selectivity is shown on the dashed line. Analyte selectivities deviate substantially from Knudsen, particularly the hydrocarbons and CO 2 (shown in red data points). AMU, atomic mass units. 
We report the first characterization study of commercial prototype carbon nanotube (CNT) membranes consisting of sub–1.27-nm-diameter CNTs traversing a large-area nonporous polysulfone film. The membranes show rejection of NaCl and MgSO4 at higher ionic strengths than have previously been reported in CNT membranes, and specific size selectivity for analytes with diameters below 1.24 nm. The CNTs used in the membranes were arc discharge nanotubes with inner diameters of 0.67 to 1.27 nm. Water flow through the membranes was 1000 times higher than predicted by Hagen-Poiseuille flow, in agreement with previous CNT membrane studies. Ideal gas selectivity was found to deviate significantly from that predicted by both viscous and Knudsen flow, suggesting that surface diffusion effects may begin to dominate gas selectivity at this size scale.
Uncovering the mechanisms that establish naïve pluripotency in humans is crucial for the future applications of pluripotent stem cells including the production of human blastoids. However, the regulatory pathways that control the establishment of naïve pluripotency by reprogramming are largely unknown. Here, we use genome-wide screening to identify essential regulators as well as major impediments of human primed to naïve pluripotent stem cell reprogramming. We discover that factors essential for cell state change do not typically undergo changes at the level of gene expression but rather are repurposed with new functions. Mechanistically, we establish that the variant Polycomb complex PRC1.3 and PRDM14 jointly repress developmental and gene regulatory factors to ensure naïve cell reprogramming. In addition, small-molecule inhibitors of reprogramming impediments improve naïve cell reprogramming beyond current methods. Collectively, this work defines the principles controlling the establishment of human naïve pluripotency and also provides new insights into mechanisms that destabilize and reconfigure cell identity during cell state transitions.
Bacterial adhesins are modular cell-surface proteins that mediate adherence to other cells, surfaces, and ligands. The Antarctic bacterium Marinomonas primoryensis uses a 1.5-MDa adhesin comprising over 130 domains to position it on ice at the top of the water column for better access to oxygen and nutrients. We have reconstructed this 0.6-μm-long adhesin using a “dissect and build” structural biology approach and have established complementary roles for its five distinct regions. Domains in region I (RI) tether the adhesin to the type I secretion machinery in the periplasm of the bacterium and pass it through the outer membrane. RII comprises ~120 identical immunoglobulin-like β-sandwich domains that rigidify on binding Ca²⁺ to project the adhesion regions RIII and RIV into the medium. RIII contains ligand-binding domains that join diatoms and bacteria together in a mixed-species community on the underside of sea ice where incident light is maximal. RIV is the ice-binding domain, and the terminal RV domain contains several “repeats-in-toxin” motifs and a noncleavable signal sequence that target proteins for export via the type I secretion system. Similar structural architecture is present in the adhesins of many pathogenic bacteria and provides a guide to finding and blocking binding domains to weaken infectivity.
Our nearest neighbor, Proxima Centauri, hosts a temperate terrestrial planet. We detected in radial velocities evidence of a possible second planet with minimum mass mc sin ic = 5.8 ± 1.9M⊕ and orbital period P c = 5.21 - 0.22 + 0.26 years. The analysis of photometric data and spectro-scopic activity diagnostics does not explain the signal in terms of a stellar activity cycle, but follow-up is required in the coming years for confirming its planetary origin. We show that the existence of the planet can be ascertained, and its true mass can be determined with high accuracy, by combining Gaia astrometry and radial velocities. Proxima c could become a prime target for follow-up and characterization with next-generation direct imaging instrumentation due to the large maximum angular separation of ~1 arc second from the parent star. The candidate planet represents a challenge for the models of super-Earth formation and evolution.
Study design. This study included three modeling analyses: (i) spatial network model inference to construct the transmission dynamics and estimate key population variables and parameters by United Hospital Fund (UHF) neighborhood of residence and age group; (ii) city-level multivariant, age-structured modeling to simulate and estimate the changes in transmissibility and immune escape potential for B.1.526; and (iii) linear regression models to estimate variant-specific infection fatality risk (IFR), for B.1.526 and B.1.1.7, separately. Nine datasets (listed in the black open boxes) were used as model inputs or to evaluate the accuracy of model estimates (indicated for each dataset below). Models used are shown in the blue filled boxes and model outputs are listed in the blue open boxes (key estimates reported in detail in Results are bolded). Connections among the analyses are indicated by the arrows and associated annotations.
Model fit and key estimates. Top panels show model fit to weekly number of cases (A), ED visits (B), and deaths (C), for all ages combined. Bottom panels show key model-inference estimates of weekly number of infections including those not detected as cases (D), cumulative number of infections in NYC overall (E), and cumulative infection rate by neighborhood (F). Boxes show model estimates (thick horizontal lines and box edges show the median, 25th, and 75th percentiles; vertical lines extending from each box show 95% CrI) and red dots show corresponding observations. For the weekly estimates, week starts (month/day/year) are shown in the x-axis labels. Asterisk (*) in the map indicates the location of the Washington Heights-Inwood (WHts) neighborhood.
Changes in transmission rate. (A) Changes in neighborhood-level relative transmission rate. (B) Changes in citywide transmission rate. Vertical dashed lines indicate the earliest date B.1.526 was identified as reported in Annavajhala et al. (2) Labels of the x axis show the week starts (month/day/year).
Comparison of different combinations of changes in transmissibility and immune escape property for B.1.526. Left panels show the overall accuracy (A), relative RMSE (B), and correlation (C) of model estimates under different transmissibility and immune escape settings. White crosses (x) indicate the best-performing parameter combination. (D) Model estimates using the overall best-performing parameter combination (i.e., 1.5 to 3.5% initial prevalence, 15 to 25% higher transmissibility, and 0 to 10% immune escape). Lines and surrounding areas show model-simulated median estimates and interquartile range; dots show corresponding observations; colors indicate different variants as specified in the legend. Note that these model simulations used the same infection-detection rate, hospitalization rate, and IFR (i.e., average during November 2020 to April 2021); that is, they did not account for changes in case ascertainment or disease severity by week during this period, due to, e.g., increases in disease severity by the new variants. As such, there were larger deviations from the observations during later months of the simulation with more infections by the new variants.
Estimated IFR. Estimates are made for people (A) < 25 years old; (B) 25 to 44 years; (C) 45 to 64 years; (D) 65 to 74 years; (E) ≥ 75 years; and (F) all ages combined. Red lines show the estimated median IFR with surrounding areas indicating the 50% (darker color) and 95% (lighter color) CrI. For comparison, the gray bars show the number of deaths reported for each week from the week of 4 October 2020 to 25 April 2021. x-axis labels show the week starts (month/day/year).
To characterize the epidemiological properties of the B.1.526 SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) variant of interest, here we used nine epidemiological and population datasets and model-inference methods to reconstruct SARS-CoV-2 transmission dynamics in New York City, where B.1.526 emerged. We estimated that B.1.526 had a moderate increase (15 to 25%) in transmissibility, could escape immunity in 0 to 10% of previously infected individuals, and substantially increased the infection fatality risk (IFR) among adults 65 or older by >60% during November 2020 to April 2021, compared to estimates for preexisting variants. Overall, findings suggest that new variants like B.1.526 likely spread in the population weeks before detection and that partial immune escape (e.g., resistance to therapeutic antibodies) could offset prior medical advances and increase IFR. Early preparedness for and close monitoring of SARS-CoV-2 variants, their epidemiological characteristics, and disease severity are thus crucial to COVID-19 (coronavirus disease 2019) response.
Sodium channel Na V 1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na V 1.7 trafficking or membrane distribution along sensory axons, which can be a meter or more in length. We show here with single-molecule resolution the first live visualization of Na V 1.7 channels in dorsal root ganglia neurons, including long-distance microtubule-dependent vesicular transport in Rab6A-containing vesicles. We demonstrate nanoclusters that contain a median of 12.5 channels at the plasma membrane on axon termini. We also demonstrate that inflammatory mediators trigger an increase in the number of Na V 1.7-carrying vesicles per axon, a threefold increase in the median number of Na V 1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of Na V 1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of Na V 1.7 to inflammatory pain.
Comparison of multiproxy records from the Zoige Basin core ZB13-C2 with regional insolation of the past 1.74 Ma. (A) Mean June insolation at 30°N (red) (4). (B) Chinese speleothem  18 O calcite (gray) (5). (C) Arboreal pollen percentages AP% (~600-year resolution) from ZB13-C2 (this study), a drill core from the Tibetan Plateau consisting of lacustrine sediments. ZB, Zoige Basin. (D) Reconstructed mean temperature of the warmest month (MTWM) and (E) mean annual temperature (MAT) based on pollen data from ZB13-C2. The horizontal lines indicate the mean values of MTWM and MAT for the intervals of 0-0.62, 0.62-1.03, 1.03-1.54, and 1.54-1.74 Ma BP. Bootstrap sample-specific estimates of uncertainties are shown in fig. S4. (F) Sixty-year smoothed Rb/Sr ratio based on XRF scanning from ZB13-C2. (G) Carbonate percentage (~600-year resolution) determined by loss on ignition from ZB13-C2. The gray bars mark the two fluvial sandy layers.
Pollen percentage diagram of major taxa and biome reconstruction from the Zoige Basin core ZB13-C2. (A) Pollen percentage diagram. Tree taxa mainly include Picea, Pinus, Betula, and deciduous Quercus. Major meadow/steppe taxa consist of Cyperaceae, Artemisia, other Asteraceae, Poaceae, and Ranunculaceae. The consistent presence of aquatic pollen of Myriophyllum suggests that the study site was occupied by a shallow-intermediate lake over the past 1.74 Ma. The pollen zonation is based on CONISS results aided by a multivariate regression tree analysis, which shows the biggest changes at 1.54 and 0.62 Ma BP. (B) Combined biome. The biomes were combined into five types. The results indicate a less frequent occurrence of forest from 0.62 Ma BP onward.
Continuous wavelet and spectral results of arboreal pollen (AP%) from the Zoige Basin core ZB13-C2. (A) The continuous wavelet and (B) the multitaper method spectral results for the intervals of 0-1.74, 0-0.62, 0.62-1.54, and 1.54-1.74 Ma BP. The data were resampled at equally spaced 0.6-ka intervals and detrended before analysis. AP% generally shows powers of ~40, 20, 10.6 to 9.6, 8, 6.6, 5.2, and 4.4 to 4.1 ka. Black lines denote the 90% confidence level. The ~100-ka cycle becomes established in the past ~0.62 Ma, along with an intermittent ~20-ka cycle and a weak ~40-ka cycle.
Correlation of vegetation and temperature records from the Zoige Basin core ZB13-C2 with global and regional climate records over the past 1.74 Ma. (A) LR04 global benthic δ 18 O stack (blue) (10). The numbers denote the MIS. (B) Seawater  18 O (23) at ODP 1123 (gray), east of New Zealand, which is a direct indicator of ice volume. (C) CO 2 records are shown as follows: orange,  11 B-based data from the Caribbean (27) and eastern tropical Atlantic (31); blue squares, low-resolution  11 B record from the equatorial Atlantic (all with 2 error bars/envelopes) (29); purple circle, ice core CO 2 measurements from blue ice (30); purple line, ice core compilation (36). (D) Southern Ocean dust mass accumulation rate (MAR) (33). (E) Bulk carbonate  18 O at site U1308, north Atlantic (11). The dashed lines indicate the mean values for three intervals. (F) Estimates of SST at site DSDP 607 (20), north Atlantic, and tropical stack (21). (G) Reconstructed MAT and 9-point running mean (black line) from ZB13-C2 (this study). The dashed lines indicate the mean values of MAT for three intervals. (H) Reconstructed MTWM and 9-point running mean (black line) from ZB13-C2 (this study). The dashed lines indicate the mean values of MTWM for three intervals. (I) Arboreal pollen percentages (~600-year resolution) from ZB13-C2. Black line shows the 9-point running mean.
Schematic diagram of the forcings of Zoige Basin vegetation and climate change modes at orbital and millennial scales over the past 1.74 Ma. The dark colors in the bars represent the trends of the strength of the forcings (low-latitude insolation and ice volume). The triangles demonstrate the frequency and strength of northern Atlantic ice-rated debris (IRD) variabilities. The curves show the Zoige-filtered AP% values centered around 20-, 40-, 100-ka bands, and the millennial variabilities of AP% (green) and Rb/Sr ratio (brown) at the powers between 15 and 3 ka.
The Tibetan Plateau exerts a major influence on Asian climate, but its long-term environmental history remains largely unknown. We present a detailed record of vegetation and climate changes over the past 1.74 million years in a lake sediment core from the Zoige Basin, eastern Tibetan Plateau. Results show three intervals with different orbital- and millennial-scale features superimposed on a stepwise long-term cooling trend. The interval of 1.74–1.54 million years ago is characterized by an insolation-dominated mode with strong ~20,000-year cyclicity and quasi-absent millennial-scale signal. The interval of 1.54–0.62 million years ago represents a transitional insolation-ice mode marked by ~20,000- and ~40,000-year cycles, with superimposed millennial-scale oscillations. The past 620,000 years are characterized by an ice-driven mode with 100,000-year cyclicity and less frequent millennial-scale variability. A pronounced transition occurred 620,000 years ago, as glacial cycles intensified. These new findings reveal how the interaction of low-latitude insolation and high-latitude ice-volume forcing shaped the evolution of the Tibetan Plateau climate.
Measured EC 50 value and DMPK properties for representatives from six identified hit clusters. MW, molecular weight.
Progression of series 1 thienopyrimidine from screening hit to early lead. 
Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides.
CIM setup and pump turn-on schedules. (A) Experimental setup. The FPGA system includes 56 FPGAs in total (details are explained in section S5). ADC, analog-todigital converter; BHD, balanced homodyne detector; BPF, band pass filter; DAC, digital-to-analog converter; FS, fiber stretcher; FPGA, field-programmable gate array; LO, local oscillator; PMF, polarization-maintaining fiber; PSA, phase-sensitive amplifier. (B) Schedules of the normalized pump amplitude. Schedule 1, pump turn-on schedule designed to minimize the time to reach the reference score; schedules 2 and 3, those for obtaining high scores.
Amplitude evolution of the first 100 of 100,000 DOPO pulses when running MAX CUT problem of K100000. The unit of the vertical axis is the output of the digital-to-analog converter that digitized the amplitude of the signal from the balanced homodyne detector, where 14 bits (16,384) corresponds to 0.25 V.
MAX CUT score as a function of computation time obtained with the CIM (orange line) and SA (blue line). The data points exhibit the scores evaluated at the intermediate steps in the CIM and SA computation. The dotted line denotes the score obtained with SG (10,759,955).
Effective time to reach the SG score for various graph sizes. The orange (blue) circles show the computation time of the CIM (SA), and the orange (blue) dashed lines are linear (quadratic) auxiliary lines. To estimate the time of CIM, we took the average of the top 10 results of 500 runs.
Computers based on physical systems are increasingly anticipated to overcome the impending limitations on digital computer performance. One such computer is a coherent Ising machine (CIM) for solving combinatorial optimization problems. Here, we report a CIM with 100,512 degenerate optical parametric oscillator pulses working as the Ising spins. We show that the CIM delivers fine solutions to maximum cut problems of 100,000-node graphs drastically faster than standard simulated annealing. Moreover, the CIM, when operated near the phase transition point, provides some extremely good solutions and a very broad distribution. This characteristic will be useful for applications that require fast random sampling such as machine learning.
The molecule of this study, chrozophoridin. Left: Close-up of C. tinctoria fruits (collected in Alentejo, Portugal) and clothlets prepared with the juice of the fruits following the instructions in the Book of all color paints. Light green fruits were used in this study shortly after collection. Right: Molecular structures of the blue colorants, hermidin (from M. perennis), and chrozophoridin (from C. tinctoria). Photo credit: Paula Nabais, Universidade NOVA de Lisboa.
Causes of color in hermidin extracted from M. perennis. Conversion of colorless hermidin into the blue hermidin quinone and formation of dimeric structures as proposed by Lorenz et al. (23, 24).
Analysis of the thermodynamically favored atropoisomers of chrozophoridin, in solution. Molecules are depicted as sticks and colored by atom type. (A) A ring, B ring, and glucose ring are colored in red, orange, and green, respectively. Both 1 and 2 dihedrals and hydrogen bonds are also indicated. (B) Superposition of the A ring of the two molecules. Colored by element (atropisomer 1) and green (atropisomer 2). (C) UV-VIS spectra (water, pH 7, blue) for chrozophoridin compared with the predicted spectra [Boese-Martin for kinetics (BMK) functional] for atropisomers 1 (black) and 2 (green).
The molecular structure of the medieval watercolor known as folium has finally been solved in the 21st century. The interdisciplinary approach taken was the key to producing extracts that had been prepared following medieval instructions, and shows the blue/purple chromophore as the major dye in Chrozophora tinctoria fruits (shell). A multi-analytical characterization of its structure was made using HPLC-DAD-MS, GC-MS, NMR ( ¹ H, ¹³ C, COSY, HSQC, HMBC, INADEQUATE), and computational studies. The results demonstrate that the blue compound corresponds to 6′-hydroxy-4,4′-dimethoxy-1,1′-dimethyl-5′-{[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl]oxy}-[3,3′-bipyridine]-2,2′,5,6(1 H ,1′ H )-tetraone, a hermidin derivative, which we named chrozophoridin. Experimental data and computational modeling studies show that this mono-glycosylated dimer is represented by two stable isomers (atropisomers). This is an indispensable piece of knowledge for the characterization of this medieval dye in works of art such as medieval manuscript illuminations and for testing its stability and contributes to the preservation of our cultural heritage.
Synthesis of S-PEDOT by oxidative polymerization of the S-EDOT monomer.
AFM height images of S-PEDOT. (A) Surface morphologies of S-PEDOT thin films with different C S-EDOT . (B) Average particle size (D p ), number of particles (N p ), and surface roughness (R a ) dependencies of S-PEDOT thin films on C S-EDOT .
cAFM images of S-PEDOT. (A) Current mapping images of S-PEDOT thin films with different C S-EDOT . (B) Average nanocrystal size (D nc ), number of nanocrystals (N nc ), and average length between adjacent nanocrystals (L nc ) dependencies of S-PEDOT thin films on C S-EDOT .
Electrical conductivity and carrier transport properties of S-PEDOT. (A) Electrical conductivity dependency of S-PEDOT films measured by the four-point method on C S-EDOT . (B) Electrical conductivity and activation energy (E a ) dependencies of S-PEDOT films on L nc . (C) L nc , electrical conductivities at 77 K ( 77K ) and 293 K ( 293K ), and E a of S-PEDOT films with different C S-EDOT . The vertical and horizontal axes of (B) (top) correspond to the vertical axis of (A) and the horizontal axis of (B) (bottom), respectively.
Correlation between the hierarchical structure and properties of S-PEDOT. (A) Chemical structures of the S-EDOT monomer (primary structure) and S-PEDOT (secondary structure), the S-PEDOT nanocrystal (tertiary structure), and the distribution of S-PEDOT nanocrystals (quaternary structure). (B) Relation between C S-EDOT and M w . (C) Dependencies of X c and N nc on M w . (D) Dependencies of L nc and E a on N nc . (E) Relation between L nc and electrical conductivity.
Wet-processable and highly conductive polymers are promising candidates for key materials in organic electronics. Poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) is commercially available as a water dispersion of colloidal particles but has some technical issues with PSS. Here, we developed a novel fully soluble self-doped PEDOT (S-PEDOT) with an electrical conductivity as high as 1089 S cm ⁻¹ without additives (solvent effect). Our results indicate that the molecular weight of S-PEDOT is the critical parameter for increasing the number of nanocrystals, corresponding to the S-PEDOT crystallites evaluated by x-ray diffraction and conductive atomic force microscopic analyses as having high electrical conductivity, which reduced both the average distance between adjacent nanocrystals and the activation energy for the hopping of charge carriers, leading to the highest bulk conductivity.
Numerical-model predictions for three regimes of slab-sinking behavior. (A to C) Arrows denote velocity vectors and colors indicate potential temperature in snapshots at 150 My (for time series, see fig. S3). The 5% iso-contours of harzburgite (black) and basalt fraction (gray) are labeled. Domains with X LM > 0 are shown with dark red hatching. Slab-sinking behavior varies as a function of X LM (as annotated) between the cases shown. (D) Map of slabsinking regimes as a function of all parameters. Mantle parameters G and X LM are varied between big squares; slab parameters t and b are varied between small squares (that is, within each big square). Cases (A to C) are labeled. For G = −3 MPa/K, slabs are always predicted to stagnate at the 660 (not shown). Bottom scale: Mg/Si of the lower mantle, calculated from X LM [according to Workman and Hart (2)].  
Compositional mantle layering predicted by a global-scale thermochemical mantle-convection model (case A1) after ~4.57 Gy model time. (A) Relative to the asthenosphere, the shallow lower mantle is enhanced by basalt (see translucent bars). (B) Model snapshot of composition (see fig. S6 for time series).  
Improved constraints on lower-mantle composition are fundamental to understand the accretion, differentiation, and thermochemical evolution of our planet. Cosmochemical arguments indicate that lower-mantle rocks may be enriched in Si relative to upper-mantle pyrolite, whereas seismic tomography images suggest whole-mantle convection and hence appear to imply efficient mantle mixing. This study reconciles cosmochemical and geophysical constraints using the stagnation of some slab segments at ~1000-km depth as the key observation. Through numerical modeling of subduction, we show that lower-mantle enrichment in intrinsically dense basaltic lithologies can render slabs neutrally buoyant in the uppermost lower mantle. Slab stagnation (at depths of ~660 and ~1000 km) and unimpeded slab sinking to great depths can coexist if the basalt fraction is ~8% higher in the lower mantle than in the upper mantle, equivalent to a lower-mantle Mg/Si of ~1.18. Global-scale geodynamic models demonstrate that such a moderate compositional gradient across the mantle can persist can in the presence of whole-mantle convection.
Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.
Scaling down of semiconductor devices requires high-k dielectric materials to continue lowering the operating voltage of field-effect transistors (FETs) and storing sufficient charge on a smaller area. Here, we investigate the dielectric properties of epitaxial BaHf0.6Ti0.4O3 (BHTO), an alloy of perovskite oxide barium hafnate (BaHfO3) and barium titanate (BaTiO3). We found the dielectric constant, the breakdown field, and the leakage current to be 150, 5.0 megavolts per centimeter (MV cm-1), and 10-4 amperes per square centimeter at 2 MV cm-1, respectively. The results suggest that two-dimensional (2D) carrier density of more than n2D = 1014 per square centimeter (cm-2) could be modulated by the BHTO gate oxide. We demonstrate an n-type accumulation mode FET and direct suppression of more than n2D = 1014 cm-2 via an n-type depletion-mode FET. We attribute the large dielectric constant, high breakdown field, and low leakage current of BHTO to the nanometer scale stoichiometric modulation of hafnium and titanium.
Surface variations due to density variations up to degree and order 4. (A) Difference between measured and constant-density surface accelerations shown on the shape model and in terms of surface latitude and longitude, measured in terms of percent variation (top) and microgals (bottom). (B) Geopotential slope variations using both views.
The energetics and dynamics associated with close motion about Bennu. (A) Bennu's rotational Roche lobe, along with locations and type of its co-orbital equilibrium points. (B) Select trajectories lofted from the surface that fly close to the center manifolds.
Surface slopes on Bennu. (A) Slopes mapped to the Bennu surface (color scale) showing the intersection of the rotational Roche lobe (the fence; black lines) with the surface. (B) Longitudinally averaged slopes (top) and radius (bottom) as a function of Bennu latitude. The numbers shown in the plots are the average values within and outside of the Roche lobe.
The gravity field of a small body provides insight into its internal mass distribution. We used two approaches to measure the gravity field of the rubble-pile asteroid (101955) Bennu: (i) tracking and modeling the spacecraft in orbit about the asteroid and (ii) tracking and modeling pebble-sized particles naturally ejected from Bennu's surface into sustained orbits. These approaches yield statistically consistent results up to degree and order 3, with the particle-based field being statistically significant up to degree and order 9. Comparisons with a constant-density shape model show that Bennu has a heterogeneous mass distribution. These deviations can be modeled with lower densities at Bennu's equatorial bulge and center. The lower-density equator is consistent with recent migration and redistribution of material. The lower-density center is consistent with a past period of rapid rotation, either from a previous Yarkovsky-O'Keefe-Radzievskii-Paddack cycle or arising during Bennu's accretion following the disruption of its parent body.
The 20-cm-resolution GDTM of Bennu. (A, C, and E) Views of the rendered OLA model and (B, D, and F) corresponding images acquired by OSIRIS-REx Camera Suite (OCAMS) (2). Images in (B) and (D) were taken by the MapCam imager on 13 December 2018 at 1:01:48 UTC (subobserver location −5, 156°E) and 1:59:00 UTC (subobserver location −7, 232°E), respectively. The image in (F) was acquired by the PolyCam imager on 2 December 2018 at 8:18:29 UTC (off-limb subobserver location). Aside from albedo differences (bright boulders in the OCAMS images), the OLA model and the images are nearly indistinguishable. The model is Poissonreconstructed from the point cloud and rendered into an image. The pole axis is vertical and Bennu north (+z) is up in (A) to (D). The model can be viewed over Bennu's full rotation in movie S1.
A sectoral spherical harmonic analysis. The hemispheres show similar power in the degree-4 term that indicates the longitudinal ridges, but the southern hemisphere has a higher degree-2 term that represents material obscuring the ridges in the south. Fig. 2. The median radius of Bennu. Differences in shape between the northern and southern hemispheres are evident, with the northern hemisphere exhibiting higher curvature than the south.
The geopotential elevation of Bennu. (A) Global results median-averaged over all longitudes show that the equatorial region between +20° and −20° has a flat profile. (B) The linearly detrended elevation as a function of latitude over four 90° longitude sectors (centered where indicated in the legend and each vertically offset in +4-m elevation increments for clarity) indicates greater regularity in the south, with terrace-like features (indicated by arrows) extending over multiple adjacent sectors and exhibiting similar latitudinal spacing.
Binned SD of the GDTM as a measure of roughness. The SD between OLA returns is binned into (A) 30-cm and (B) 10-cm bins and medianed over all longitudes as a measure of surface roughness at these two scales. (C) The ratio of south and north SDs for 10-cm and 30-cm bins. The rapid changes in the roughness at poles are in part due to the smaller number of bins and in part to the presence of boulders.
Boulder locations and relationships with surrounding material. (A) Hemispherical views of the elevation of Bennu overplotted on the OLA GDTM. Boulders that are visibly retaining material on the upslope side are outlined in blue, whereas perched boulders are outlined in white. Local DTMs in (B) and (C) show examples of northern boulders that are dynamically emplaced, specifically toppled (B), and imbricated (piled on one another) (C). Local DTMs in (D) and (E) show examples of southern boulders that are stationary or may have moved with the surrounding surface: (D) a material-retaining boulder and (E) a perched boulder. Locations of the local DTMs on the GDTM are shown by the letters. Cyan arrows show the downslope direction. The blue star indicates the same location on each boulder view.
We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu's southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu's history.
6-Diazo-5-oxo- l -norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 ⁺ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl( S )-2-(( S )-2-acetamido-3-(1 H -indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104’s effect was CD8 ⁺ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
Comparison with other populations. Results of PCA of Korea1K and the 1KGP set of (A) worldwide populations and (B) East Asian samples. (C) The number of TE insertions with significantly different allele frequencies between the Korea1K set and the population. (D) The proportion of differential TE insertions. Colors indicate TE subtypes. Abbreviation for populations is same population code as 1KGP (ACB, African Caribbean; ASW, African Ancestry in Southwest USA; BEB, Bengali; CDX, Dai Chinese; CEU, Utah residents with Northern and Western European ancestry; CHB, Han Chinese; CHS, Southern Han Chinese; CLM, Colombian; ESN, Esan; FIN, Finnish; GBR, British; GIH, Gujarati; GWD, Gambian Mandinka; IBS, Iberian; ITU, Telugu; JPT, Japanese; KHV, Kinh Vietnamese; LWK, Luhya; MSL, Mende; MXL, Mexican Ancestry; PEL, Peruvian; PJL, Punjabi; PUR, Puerto Rican; STU, Tamil; TSI, Toscani; and YRI, Yoruba).
List of traits with index variants located in previously reported loci. Highlighted rows indicate unreported variants with higher significance values, located in the same linkage disequilibrium block with reported variants.
We present the initial phase of the Korean Genome Project (Korea1K), including 1094 whole genomes (sequenced at an average depth of 31×), along with data of 79 quantitative clinical traits. We identified 39 million single-nucleotide variants and indels of which half were singleton or doubleton and detected Korean-specific patterns based on several types of genomic variations. A genome-wide association study illustrated the power of whole-genome sequences for analyzing clinical traits, identifying nine more significant candidate alleles than previously reported from the same linkage disequilibrium blocks. Also, Korea1K, as a reference, showed better imputation accuracy for Koreans than the 1KGP panel. As proof of utility, germline variants in cancer samples could be filtered out more effectively when the Korea1K variome was used as a panel of normals compared to non-Korean variome sets. Overall, this study shows that Korea1K can be a useful genotypic and phenotypic resource for clinical and ethnogenetic studies.
Molecular structure and chain packing of nylon-11. (A and D) Schematics show packing of nylon-11 monomeric units in unpoled ′-phase nylon-11 viewed along the c axis and b axis, respectively. All molecules lie in a random orientation. (B and E) The crystal structures and molecular packing of the poled ′-phase. All the oxygen atoms point to the same direction. (C and F) Crystal structure of -phase nylon-11. The fully stretched molecules in trans configuration with sheets of strong hydrogen bonding gives the -phase a relatively well-ordered crystal structure. The yellow lines indicate intermolecular hydrogen bonding. Gray spheres, carbon atoms; red spheres, oxygen atoms; blue spheres, nitrogen atoms; white spheres, hydrogen atoms.
Nanowire morphology and x-ray analysis. (A) SEM image of the nanotemplate surface with 200 nm pores. Inset shows the template cross section. (B) SEM image of template-freed nanowires fabricated by the TANI method. (C) Left: XRD patterns of nanowires fabricated by the conventional template-wetting (black) and the TANI (red) methods. Top right: Changes in the average intensities of the XRD peak at 20° and 24.2° as a function of solution concentration. Bottom right: Changes in the crystallite sizes perpendicular to the (200) planes (D (200) ) of 5 wt % samples as a function of processing temperature. ■, middle line, and top and bottom boundaries indicate mean, median, and 75 and 25% values, respectively. a.u., arbitrary units. (D) XRD patterns of -phase nylon-11 film (black) and nanowires (NW) without (red) and within (orange) a nanoporous AAO template. Inset schematics display the morphology of sample and the direction of x-ray beam () with a scattering vector (q). (E) XRD patterns of calculated (black) and experimentally observed (red and orange) -phase nylon-11 nanowires. Calculated patterns I and II assumed random orientation of crystals with large (>100 nm) and small crystallite sizes (D 200 ) (~25 nm), respectively. Calculated pattern III assumed preferred crystal orientation with actual D 200 .
Surface potential analysis before and after rubbing process. (A and C) ′-phase and (B and D) -phase nanowires. (A and B) AFM topology and surface potential images before (left) and after (right) rubbing process. Dashed squares, rubbing area. Scale bars, 1 m. Blue dashed line, the data acquisition position for plotting. (C and D) Surface potential changes before (black square) and after (red circle) rubbing process.
Triboelectric generator performance. (A) Short-circuit output current densities of triboelectric generators with different combinations of materials: Al (black), ′-phase nanowire (orange), and -phase nanowire (red). (B) The power density of the same devices as a function of load resistance. The power density is calculated by multiplying the current density squared with the load resistance.
Dipole alignment in ferroelectric polymers is routinely exploited for applications in charge-based applications. Here, we present the first experimental realization of ideally ordered dipole alignment in α-phase nylon-11 nanowires. This is an unprecedented discovery as dipole alignment is typically only ever achieved in ferroelectric polymers using an applied electric field, whereas here, we achieve dipole alignment in as-fabricated nanowires of ‘non-ferroelectric’ α-phase nylon-11, an overlooked polymorph of nylon proposed 30 years ago but never practically realized. We show that the strong hydrogen bonding in α-phase nylon-11 serves to enhance the molecular ordering, resulting in exceptional intensity and thermal stability of surface potential. This discovery has profound implications for the field of triboelectric energy harvesting, as the presence of an enhanced surface potential leads to higher mechanical energy harvesting performance. Our approach therefore paves the way towards achieving robust, high-performance mechanical energy harvesters based on this unusual ordered phase of nylon-11.
FAM21 CPI removes CP from the Arp1/11 minifilament of dynactin. (A) Single dynactin complexes containing GFP-Arp1 and mCherry-CP were observed by TIRF microscopy. Quantification of the colocalization of green and red spots. Conditions: 40 nM dynactin preincubated with 2.7 M CPI or CPI* for 1 min was diluted 10-fold and then adsorbed on the coverslip surface. Scale bar, 5 m. (B) Distribution of dynactin subunits in gel filtration in the presence of CPI or CPI*. (C) Elution fractions containing dynactin were negatively stained and observed by EM. Two major classes of 3D reconstructions obtained in the presence of CPI appear to lack a specific density. (D) The previously obtained cryo-EM model of dynactin was fit into the negative-stain EM densities. The two CP subunits are in red; other dynactin subunits are in blue. ns, not significant.
Dynactin primes endosomal branched actin structures. (A) The filament elongated from dynactin provides a substrate for actin branches (TIRF microscopy). Dynactin (2 nM) was preincubated for 12 min in F-buffer with 270 nM CPI, 1 M profilin, and 0.8 M Alexa 568-actin (red, 15% labeled). The reaction was then diluted 20-fold in a solution containing 60 nM WASH VCA 60 nM Arp2/3, 0.4 M profilin, and 0.4 M Alexa 488-actin (green, 15% labeled) in F-buffer supplemented with 0.13% methylcellulose. Scale bar, 2 m. (B) Whole field of view from the experiment in (A) after 1500 s. Scale bar, 10 m. (C) Pyrene-actin polymerization assay. Conditions: Actin (2 M, 5% pyrene), profilin (3 M), native dynactin (10 nM), CPI (50 nM), Arp2/3 (20 nM), and VCA (70 nM). Addition of the CPI fragment is indicated by arrowheads. (D) Live spinning disk confocal microscopy of an MCF10A cell line stably expressing GFP-ARPC5 (Arp2/3), mCherry-DCTN6 (dynactin), and iRFP-WASH. Single confocal plane. Scale bar, 6 m. Middle: Zoomed still images extracted from the video (white box), elapsed time in seconds; scale bar, 1.2 m. Right: Kymograph; scale bars, vertical 1.2 m, horizontal 12 s. (E) MCF10A cells were depleted of dynactin through siRNAs targeting Arp1 or Arp11. Endosomal branched actin structures were estimated by the overlap of ARPC2 (Arp2/3) with VPS35 (retromer) upon latrunculin A (LatA) washout. Scale bar, 10 m.
Deficient uncapping alters endosomal structures. (A) Endogenous FAM21 was depleted from MCF10A control cells or stable MCF10A lines expressing GFP-FAM21 WT or CPI* using siRNAs. Endosomal branched actin structures were estimated by the overlap of ARPC2 (Arp2/3) with VPS35 (retromer). Scale bar, 10 m. (B) Endosomes were loaded at steady state with fluorescent transferrin. Endosomal size and the presence of tubules (arrowheads) were estimated from live-cell confocal imaging.
Uncapping by the WASH complex is required for cargo recycling. (A) Endogenous FAM21 was depleted from MCF10A control cells or stable MCF10A lines expressing GFP-FAM21 WT or CPI* using siRNAs. WASH complex subunits were analyzed by Western blots. (B) Levels of 1 integrin and quantification by densitometry. (C) 1-integrin recycling. Surface proteins that were biotinylated and internalized were allowed to recycle to the plasma membrane for the indicated time, before extracellular exposed biotin was removed. Streptavidin-captured protein was analyzed by 1-integrin Western blots. (D) Quantification by densitometry. (E) Mean square displacement (MSD) and aspect ratio volatility of single cells. (F) The glucose transporter GLUT1 localizes to perinuclear SNX27-positive endosomes and at the plasma membrane. Scale bar, 10 m. (G) Cell uptake of the glucose analog 2-NBDG.
Concentration of barbed ends in pyrene-actin assays.
Dendritic actin networks develop from a first actin filament through branching by the Arp2/3 complex. At the surface of endosomes, the WASH complex activates the Arp2/3 complex and interacts with the capping protein for unclear reasons. Here, we show that the WASH complex interacts with dynactin and uncaps it through its FAM21 subunit. In vitro, the uncapped Arp1/11 minifilament elongates an actin filament, which then primes the WASH-induced Arp2/3 branching reaction. In dynactin-depleted cells or in cells where the WASH complex is reconstituted with a FAM21 mutant that cannot uncap dynactin, formation of branched actin at the endosomal surface is impaired. Our results reveal the importance of the WASH complex in coordinating two complexes containing actin-related proteins.
The Zintl phases, Yb14MSb11 (M = Mn, Mg, Al, Zn), are now some of the highest thermoelectric efficiency p-type materials with stability above 873 K. Yb14MnSb11 gained prominence as the first p-type thermoelectric material to double the efficiency of SiGe alloy, the heritage material in radioisotope thermoelectric generators used to power NASA's deep space exploration. This study investigates the solid solution of Yb14Mg1-x Al x Sb11 (0 ≤ x ≤ 1), which enables a full mapping of the metal-to-semiconductor transition. Using a combined theoretical and experimental approach, we show that a second, high valley degeneracy (Nv = 8) band is responsible for the groundbreaking performance of Yb14MSb11 This multiband understanding of the properties provides insight into other thermoelectric systems (La3-x Te4, SnTe, Ag9AlSe6, and Eu9CdSb9), and the model predicts that an increase in carrier concentration can lead to zT > 1.5 in Yb14MSb11 systems.
The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l -adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l -adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 ( Casp11 −/− ), or Gsdmd inactivation ( Gsdmd I105N/I105N ) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.
One of the key factors that limit the high-power applications for a type II superconductor is the irreversibility line Hirr ( T ), which reflects the very boundary of resistive dissipation in the phase diagram of magnetic field versus temperature. In cuprate family, the Y-, Bi-, Hg-, and Tl-based systems have superconducting transition temperatures exceeding the liquid nitrogen boiling temperature (~77 K). However, the toxic elements Hg and Tl in the latter two systems strongly constrain the applications. The best perspective so far is relying on the YBa 2 Cu 3 O 7−δ ( Tc ≈ 90 K) system, which is nontoxic and has a relatively high irreversibility magnetic field. We report the study of a nontoxic superconductor (Cu,C)Ba 2 Ca 3 Cu 4 O 11+δ with Tc = 116 K. We found that the irreversibility magnetic field is extremely high, and it thus provides great potential for applications above the liquid nitrogen temperature.
Damage-induced fibrotic scarring limits tissue regeneration in mammals and is a leading cause of morbidity. In contrast, species like zebrafish can regenerate damaged tissues without excessive fibrosis. However, whether specific signaling pathways can both limit fibrosis and promote regeneration is unclear. Here, we show that interleukin-11 (Il-11)/Stat3 signaling has such a dual function. Zebrafish lacking Il-11 receptor function display severely compromised heart, fin, and scale regeneration. Deep phenotyping and transcriptional analysis of adult hearts and fins show that Il-11 signaling drives cellular reprogramming to orchestrate global and tissue-specific regenerative programs and broadly antagonizes hallmarks of adult mammalian scarring. Mechanistically, our data indicate that IL-11 signaling in endothelial cells antagonizes profibrotic transforming growth factor–β signaling and endothelial-to-mesenchymal transition, limiting scarring and promoting cardiomyocyte repopulation, after injury. Overall, our findings position damage-induced Il-11/Stat3 signaling in a key role limiting fibrosis and promoting regeneration, revealing novel targets for regenerative therapies. dedifferentiation, proliferation, and migration, allowing regeneration (13–17). Although scar formation clearly correlates negatively with regeneration, the existence of specific upstream mechanisms that both promote cellular reprogramming and limit scarring is unclear. In this study, through genetic loss-of-function approaches, lineage tracing, the examination of regeneration in various tissues and developmental stages, and combinatorial transcriptome profiling, we show that interleukin-11 (Il-11)/signal transducer and activator of transcription 3 (Stat3) signaling plays two roles: (i) It promotes cellular reprogramming by orchestrating regenerative programs, and (ii) it limits injury-induced mammalian-like scarring.
Top-cited authors
Jenna Jambeck
  • University of Georgia
Kara Lavender Law
  • Sea Education Association, Inc.
Roland Geyer
  • University of California, Santa Barbara
Thomas Lovejoy
  • George Mason University
Clinton N. Jenkins
  • Florida International University