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Emicizumab binds to activated factor IX and factor X, reproducing the bridging function of the missing factor VIII. In a trial of emicizumab prophylaxis, emicizumab every 1 or 2 weeks led to a lower bleeding rate than no prophylaxis.

Inhibitors develop in many patients with hemophilia who receive recombinant factor VIII. Prophylaxis with emicizumab, an antibody that functionally replaces factor VIII in the clotting pathway, reduced the rate of bleeding events among patients with hemophilia with inhibitors.

Most flowering plants are able to form endosymbioses with arbuscular mycorrhizal fungi. In this mutualistic association, the fungus colonizes the root cortex and establishes elaborately branched hyphae, called arbuscules, within the cortical cells. Arbuscule development requires the cellular reorganization of both symbionts, and the resulting symbiotic interface functions in nutrient exchange. A plant symbiosis signaling pathway controls the development of the symbiosis. Several components of the pathway have been identified, but transcriptional regulators that control downstream pathways for arbuscule formation are still unknown. Here we show that DELLA proteins, which are repressors of gibberellic acid (GA) signaling and function at the nexus of several signaling pathways, are required for arbuscule formation. Arbuscule formation is severely impaired in a Medicago truncatula Mtdella1/Mtdella2 double mutant; GA treatment of wild-type roots phenocopies the della double mutant, and a dominant DELLA protein (della1 -Δ18) enables arbuscule formation in the presence of GA. Ectopic expression of della1 -Δ18 suggests that DELLA activity in the vascular tissue and endodermis is sufficient to enable arbuscule formation in the inner cortical cells. In addition, expression of della1 -Δ18 restores arbuscule formation in the symbiosis signaling pathway mutant cyclops/ipd3 , indicating an intersection between DELLA and symbiosis signaling for arbuscule formation. GA signaling also influences arbuscule formation in monocots, and a Green Revolution wheat variety carrying dominant DELLA alleles shows enhanced colonization but a limited growth response to arbuscular mycorrhizal symbiosis.

Monolayer graphene exhibits many spectacular electronic properties, with superconductivity being arguably the most notable exception. It was theoretically proposed that superconductivity might be induced by enhancing the electron–phonon coupling through the decoration of graphene with an alkali adatom superlattice [Profeta G, Calandra M, Mauri F (2012)Nat Phys8(2):131–134]. Although experiments have shown an adatom-induced enhancement of the electron–phonon coupling, superconductivity has never been observed. Using angle-resolved photoemission spectroscopy (ARPES), we show that lithium deposited on graphene at low temperature strongly modifies the phonon density of states, leading to an enhancement of the electron–phonon coupling of up toλ≃ 0.58. On part of the graphene-derivedπ*-band Fermi surface, we then observe the opening of a Δ ≃ 0.9-meV temperature-dependent pairing gap. This result suggests for the first time, to our knowledge, that Li-decorated monolayer graphene is indeed superconducting, withTc ≃ 5.9 K.

Ultrafast spectroscopies have become an important tool for elucidating the microscopic description and dynamical properties of quantum materials. In particular, by tracking the dynamics of nonthermal electrons, a material’s dominant scattering processes can be revealed. Here, we present a method for extracting the electron-phonon coupling strength in the time domain, using time- and angle-resolved photoemission spectroscopy (TR-ARPES). This method is demonstrated in graphite, where we investigate the dynamics of photoinjected electrons at the K̄ point, detecting quantized energy-loss processes that correspond to the emission of strongly coupled optical phonons. We show that the observed characteristic time scale for spectral weight transfer mediated by phonon-scattering processes allows for the direct quantitative extraction of electron-phonon matrix elements for specific modes.

The possibility of driving phase transitions in low-density condensates through the loss of phase coherence alone has far-reaching implications for the study of quantum phases of matter. This has inspired the development of tools to control and explore the collective properties of condensate phases via phase fluctuations. Electrically gated oxide interfaces1,2, ultracold Fermi atoms3,4 and cuprate superconductors5,6, which are characterized by an intrinsically small phase stiffness, are paradigmatic examples where these tools are having a dramatic impact. Here we use light pulses shorter than the internal thermalization time to drive and probe the phase fragility of the Bi2Sr2CaCu2O8+δ cuprate superconductor, completely melting the superconducting condensate without affecting the pairing strength. The resulting ultrafast dynamics of phase fluctuations and charge excitations are captured and disentangled by time-resolved photoemission spectroscopy. This work demonstrates the dominant role of phase coherence in the superconductor-to-normal state phase transition and offers a benchmark for non-equilibrium spectroscopic investigations of the cuprate phase diagram.

In the temperate climate of New Zealand, animals can be grazed outdoors all year round. The pasture is supplemented with conserved feed, with the amount being determined by seasonal pasture growth, genetics of the herd, and stocking rate. The large number of factors that affect production makes it impractical and expensive to use field trials to explore all the farm system options. A model of an in situ-grazed pasture system has been developed to provide a tool for developing and testing novel farm systems; for example, different levels of bought-in supplements and different levels of nitrogen fertilizer application, to maintain sustainability or environmental integrity and profitability. It consists of a software framework that links climate information, on a daily basis, with dynamic, mechanistic component-models for pasture growth and animal metabolism, as well as management policies. A unique feature is that the component models were developed and published by other groups, and are retained in their original software language. The aim of this study was to compare the model, called the whole-farm model (WFM) with a farm trial that was conducted over 3 yr and in which data were collected specifically for evaluating the WFM. Data were used from the first year to develop the WFM and data from the second and third year to evaluate the model. The model predicted annual pasture production, end-of-season cow liveweight, cow body condition score, and pasture cover across season with relative prediction error <20%. Milk yield and milksolids (fat + protein) were overpredicted by approximately 30% even though both annual and monthly pasture and supplement intake were predicted with acceptable accuracy, suggesting that the metabolic conversion of feed to fat, protein, and lactose in the mammary gland needs to be refined. Because feed growth and intake predictions were acceptable, economic predictions can be made using the WFM, with an adjustment for milk yield, to test different management policies, alterations in climate, or the use of genetically improved animals, pastures, or crops.

Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Purpose - A recent study confirmed that the particle size distribution of a metallic powder material has a major influence on the density of a part produced by selective laser melting (SLM). Although it is possible to get high density values with different powder types, the processing parameters have to be adjusted accordingly, affecting the process productivity. However, the particle size distribution does not only affect the density but also the surface quality and the mechanical properties of the parts. The purpose of this paper is to investigate the effect of three different powder granulations on the resulting part density, surface quality and mechanical properties of the materials produced.Design methodology approach - The scan surface quality and mechanical properties of three different particle size distributions and two layer thicknesses of 30 and 45 μm were compared. The scan velocities for the different powder types have been adjusted in order to guarantee a part density≥99.5 per cent.Findings - By using an optimised powder material, a low surface roughness can be obtained. A subsequent blasting process can further improve the surface roughness for all powder materials used in this study, although this does not change the ranking of the powders with respect to the resulting surface quality. Furthermore, optimised powder granulations lead generally to improved mechanical properties.Practical implications - The results of this study indicate that the particle size distribution influences the quality of AM metallic parts, produced by SLM. Therefore, it is recommended that any standardisation initiative like ASTM F42 should develop guidelines for powder materials for AM processes. Furthermore, during production, the granulation changes due to spatters. Appropriate quality systems have to be developed.Originality value - The paper clearly shows that the particle size distribution plays an important role regarding density, surface quality and resulting mechanical properties.

Determination of soil particle-size distribution (PSD) by sieving, hydrometer, and pipette methods as well as by laser diffraction (LD) suffers from inherent flaws, mainly due to the difficulty in defining the size of irregularly shaped particles. Therefore these methods yield only estimates of PSD. The objective of this study was to determine whether a functional relationship exists between the PSDs obtained by the combined sieve-pipette method and those obtained by LD. Samples from 42 California soils were analyzed. For the LD measurements a Beckman-Coulter LS-230 apparatus with a 750-nm laser beam that measures particles in the range of 0.04 to 2000 micrometer was used, employing the Mie theory for the PSD calculations. Values of 1.5 and 0.2 for the real part and the imaginary term of the refractive index (RI), respectively, gave satisfactory results for the optical model calculations. Volume percentage of the clay-size fraction obtained by LD was generally lower than mass percentage of the clay fraction derived by the pipette method. The opposite trend was noted for the silt-size fraction. Coefficients of determination for the regression equations for the clay, silt, and sand fractions determined by the two methods were 0.702, 0.689, and 0.821, respectively. Good agreement between measured and calculated LD values for one size class was accompanied by poor agreement between measured and calculated values for the other. The LD method provides a continuous PSD curve, which enables a detailed data analysis and a flexible application of different particle-size dependent classification systems.