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Drug–target–drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

To realize a sustainable hydrogen economy, corrosion-resistant non-noble-metal catalysts are needed to replace noble-metal-based catalysts. The combination of passivation elements and catalytically active elements is crucial for simultaneously achieving high corrosion resistance and high catalytic activity. Herein, the self-selection/reconstruction characteristics of multi-element (nonary) alloys that can automatically redistribute suitable elements and rearrange surface structures under the target reaction conditions during the oxygen evolution reaction are investigated. The following synergetic effect (i.e., cocktail effect), among the elements Ti, Zr, Nb, and Mo, significantly contributes to passivation, whereas Cr, Co, Ni, Mn, and Fe enhance the catalytic activity. According to the practical water electrolysis experiments, the self-selected/reconstructed multi-element alloy demonstrates high performance under a similar condition with proton exchange membrane (PEM)-type water electrolysis without obvious degradation during stability tests. This verifies the resistance of the alloy to corrosion when used as an electrode under a practical PEM electrolysis condition.

Layered molybdenum disulphide (MoS2) crystals in combination with graphene create the opportunity for the development of heterostructures with tailored surface and structural properties for energy storage applications. Herein, 2D heterostructures are developed by growing MoS2 on epitaxial and self-standing nanoporous graphene (NPG) using chemical vapor deposition (CVD). The effect of substrate as well as different CVD growth parameters such as temperature, amount of sulfur and MoO3 precursors, and argon flow on the growth of MoS2 is systematically investigated. Interestingly, various structures of MoS2 such as monolayer triangular islands, spirals, standing sheets, and irregular stacked multilayered MoS2 are successfully developed. The growth mechanism is proposed using different advanced characterization techniques. The formation of a continuous wetting layer with grain boundaries over the surface prior to formation of any other structures is detected. As a proof of principle, MoS2/NPG is employed for the first time as anode material in potassium ion battery. The electrode delivers a specific capacity of 389 mAh g−1 with over 98% stability after 200 cycles. The porous structures clearly facilitate the ion transport which is beneficial for the ion battery. These encouraging results open new opportunities to develop hierarchical heterostructures of 2D-materials for next-generation energy storage technologies.

Li−O2 batteries are a promising electrochemical energy-storage system with a sufficient energy density for all electric vehicles, with a one-charge driving distance comparable to conventional petrol cars. However, the practical implementations of Li−O2 batteries face many scientific and technological challenges. Among these is the development of high-performance cathode materials that can provide high capacity, low charge/discharge overpotentials and stable cycling stability. Here, we report a nanoporous Ni cathode covered by N-doped graphene and self-grown catalyst for rechargeable Li−O2 batteries. The novel hybrid cathode shows relatively low charge/discharge overpotentials, high volumetric capacity and long cycling lifetime, which may pave a new way for practical implementation of economic nanoporous metals as binder-free cathodes for high-performance Li−O2 batteries.

Reduced graphene oxide (RGO) is an important graphene derivative for applications in photonics and optoelectronics because of the band gap created by chemical oxidation. However, most RGO materials made by chemically exfoliated graphite oxide are 2D flakes. Their optoelectronic performance deteriorates significantly as a result of weak light-matter interaction and poor electrical contact between stacking flakes. Here we report a bicontinuous 3D nanoporous RGO (3D np-RGO) with high optoelectronic performance for highly sensitive photodetectors. 3D np-RGO demonstrates a over 40 times higher light absorption than monolayer graphene materials and at least two orders of magnitude higher electron mobility than conventional RGO from discrete RGO flakes. The np-RGO with an optimal reduction state shows ultrahigh photoresponse of 3.10 3 104 A W−1 at room temperature, approximately four orders of magnitude higher than graphene and other graphene derivatives at similar levels of light intensity radiations, and the excellent external quantum efficiency of 1.04 3 107% better than commercial silicon photodetector. The ultrahigh capability of conversing photons to photocurrent originates from strongly enhanced light absorption, facilitated photocarrier transport, and tunable oxygenous defects and reduction states in the 3D interconnected bicontinuous RGO network.

Single-atom nickel dopants anchored to three-dimensional nanoporous graphene can be used as catalysts of the hydrogen evolution reaction (HER) in acidic solutions. In contrast to conventional nickel-based catalysts and graphene, this material shows superior HER catalysis with a low overpotential of approximately 50 mV and a Tafel slope of 45 mV dec(-1) in 0.5 M H2SO4 solution, together with excellent cycling stability. Experimental and theoretical investigations suggest that the unusual catalytic performance of this catalyst is due to sp-d orbital charge transfer between the Ni dopants and the surrounding carbon atoms. The resultant local structure with empty C-Ni hybrid orbitals is catalytically active and electrochemically stable.

Freestanding nanoporous N-doped graphene with encapsulated RuO2 nanoparticles is developed as a cathode for rechargeable Li-O2 batteries. The stabilized metal oxide catalyst reduces charge overpotentials enabling high-efficiency rechargeable Li-O2 batteries with a long cycling lifetime. This has important implications for the development of highly stable and catalytically active graphene-based cathodes for rechargeable Li-O2 batteries.

The "edge-free" monolayer MoS2 films supported by 3D nanoporous gold show high catalytic activities towards hydrogen evolution reaction (HER), originating from large out-of-plane strains that are geometrically required to manage the 3D curvature of bicontinuous nanoporosity. The large lattice bending leads to local semiconductor-to-metal transition of 2H MoS2 and the formation of catalytically active sites for HER.

Viral infections and their occult reactivation occasionally cause not only organ damage, but also exacerbation of acute graft-versus-host disease (aGVHD), which may increase transplantation-related mortality synergistically. To determine correlations between viral reactivation and transplantation-related complications, we performed various viral screening tests on the 30th day after allogeneic hematopoietic stem cell transplantation (HSCT), and assessed the clinical implications.Between August 2007 and January 2013, 49 patients (37 men, 12 women) underwent HSCT in our hospital. The stem cell sources were bone marrow (n = 21), peripheral blood (n = 13), and cord blood (n = 15). The presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpesvirus (HHV) 6, and HHV7 in plasma samples prospectively collected from HSCT recipients on day 30 after HSCT was assayed by quantitative polymerase chain reaction, and the correlations with transplantation-related complications were evaluated.The positivities of CMV, EBV, HHV6, and HHV7 were 44.9%, 22.4%, 53.1%, and 18.3%, respectively. We analyzed transplantation-related complications, and a significant correlation was found only between HHV6 and grade 2-4 aGVHD from day 30 to day 100 (P0.001). Using a receiver operating characteristic curve, the area under the curve was calculated as 0.86 (95% confidence interval [CI], 0.74-0.98) between the viral load (VL) of HHV6 and grade 2-4 aGVHD. The sensitivity and specificity were 79% and 93%, respectively, when a cutoff value of 87 copies/mL was used. In multivariate analysis using the Fine and Gray proportional hazards model, the clinically determined high-risk patients (P = 0.004; hazard ratio [HR], 3.69; 95% CI, 1.52-9.00) and the positivity of HHV6 (P0.001; HR, 9.957; 95% CI, 2.68-37.06) were extracted as independent risk factors for the cumulative incidence of grade 2-4 aGVHD on or after post-HSCT day 30. The only risk factor extracted for the elevation of HHV6 VL87 copies/mL was cord blood transplantation (P = 0.0032; odds ratio, 7.10; 95% CI, 1.98-30.00).All of the risk factors previously reported to predict severe aGVHD were obtained only during, but not after, HSCT. Our study suggests that the reactivation of HHV6 (≥ 87 copies/mL) at 30 days after HSCT is a possible predictive marker for grade 2-4 aGVHD on or after post-HSCT day 30.

Bicontinuous nanoporous N-doped graphene with tunable pore size is synthesized by nanoporous Ni-based chemical vapor deposition. The novel 3D graphene material shows an outstanding catalytic activity towards the oxygen reduction reaction with a low onset potential of -0.08 V and a high kinetic current density of 8.2 mA cm(-2) at -0.4 V.

We report three-dimensional (3D) nanoporous graphene with preserved 2D electronic properties, tunable pore sizes, and high electron mobility for electronic applications. The complex 3D network comprised of interconnected graphene retains a 2D coherent electron system of massless Dirac fermions. The transport properties of the nanoporous graphene show a semiconducting behavior and strong pore-size dependence, together with unique angular independence. The free-standing, large-scale nanoporous graphene with 2D electronic properties and high electron mobility holds great promise for practical applications in 3D electronic devices.

Alkanethiol-coated metal nanoparticles are fascinating materials for designing unconventional electronic and magnetic functions. Novel classes of magnetic nanosystems can be created using Pd and Pt nanoparticles and their alloys with a 3d transition metal using quantum size, interface and exchange enhancement effects. The charge transfer at the metal-organic interface and the quantum size effect render Pt and Pd nanoparticles magnetic with localised moments. The substitution of capping molecules with a TTF derivative having a long alkanethiol substituent decreases the totalspin concentration due to partial oxidation of the TTF units. Pd nanoparticles containing Co atoms as magnetic centres have significantly enhanced magnetic moments because of the exchange enhancement. Interestingly, in Pd nanoparticles of 2 nm in diameter containing only one Co atom per particle, the Co atom magnetises all of the Pd atoms in the particle. Therefore, the nanoparticles behave as a single nanoparticle magnet that shows blocking behaviour.

Imatinib at a daily dose of 400 mg is the standard treatment for chronic myelogenous leukemia in the chronic phase. However, the feasibility of this dose for small Japanese adults has not been clarified. We prospectively investigated the toxicity and efficacy of this dose in adult Japanese patients. Among the 89 evaluable patients with a median body weight of 62.8 kg, imatinib therapy was held in 40 subjects (45%), due to Grade 3-4 toxicities in 30 patients (75%) and Grade 2 toxicities at the discretion of the attending physician in 10 patients (25%). However, treatment was resumed and the dose was gradually increased until 62 of the 89 patients tolerated a maintenance dose of 400 mg. Older age and lower body weight were significant independent risk factors for discontinuation of imatinib. After a median follow-up period of 31 months, 84 patients were alive without progression. The complete cytogenetic response rate was 60 and 90% at 6 months and 1 year after starting imatinib, respectively. Older patients and those with a lower body weight were less likely to achieve a complete cytogenetic response. These findings suggest that the body weight has a significant influence on the toxicity and efficacy of imatinib in patients with a small body size, although dose reduction in proportion to weight may result in an inadequate response to imatinib.

This paper describes an automatic diagram input system which reads the handwritten piping and instrument diagram and recognizes the symbol, character, and line drawn on the diagram. The object is a handwritten diagram which is easily understandable by the knowledge of the designer under a very mild constraint. The symbols which are the object of recognition are of more than 200 kinds of various sizes. In addition, a large symbol with unspecified shape may be drawn, and there can be various kinds of lines. To cope with such complex diagrams containing a large amount of handwriting distortions, various diagram processing techniques are proposed. Examples are vector representation with a high accuracy, shaping of various distortions, and the two-stage segmentation, where line, symbol and character are separated hierarchically from the vectorized figure. Other examples are the symbol recognition combining a decision tree and pattern matching, and recognition dictionary based on automatic generation of distorted patterns. The developed diagram input system is a flexible system, in which new symbols can be additionally registered, and complex handwritten diagrams can be recognized. A test was made for the system using the actually written design diagrams. The result indicated a practically satisfactory performance, where the processing time is 3 to 8 min for an A3 sized diagram by a large-scale computer and the recognition rate is above 95 percent.

A superoxide anion generation rate upon exposure to myristate of 1.93 +/- 0.34 nmol/min/10(6) cells in neutrophils from elderly human donors was significantly less than a value of 3.02 +/- 0.48 nmol/min/10(6) neutrophils from young donors. Myristate activation resulted in equal increases of AA in both the young and the old indicating no effect of aging on the PLA2 pathway to response. By contrast, the PLD-induced generation of PA was significantly higher in the old than in the young. In addition, myristate induced a significant age-related enhancement in LPA generation, in the old but not in the young. The mass of LPA generated following activation was 3.5 nmol/ 2.5 x 10(7) cells/ml in the young while in the old it averaged 7.0 nmol/2.5 x 10(7) cells/ml. The inhibitory effects of LPA may explain the age-related impaired ability to generate superoxide anion following activation by myristate.

Summary. We encountered a patient with Philadelphia-negative chronic myeloid leukaemia, witht(7;11)(p15;p15), in whom acute leukaemia phase (acute myeloid leukaemia-M2 morphology) developed within a short period. We detected a novel gene fusion between NUP98 and HOXA11 both in the chronic phase and in the acute leukaemia phase in this case. Although it is well known that a fusion of NUP98–HOXA9 in myeloid malignancies is created by the t(7;11)(p15;p15), this case suggests the possibility that HOXA11 might be another partner gene for NUP98 in t(7;11)(p15;p15) leukaemia.

We report a 26-year-old man with Coats' disease associated with premacular fibrosis. As an initial treatment, the peripheral exduative area was treated with argon laser photocoagulation. Six weeks later, the premacular fibrosis was peeled off and the posterior vitreous membrane was also detached. The patient's visual acuity improved to 20/20. We also observed a change of the vitreous component before and after the treatment that was similar to posterior vitreous detachment (PVD). This is the first reported case in which a distinct vitreous change was observed after premacular fibrosis peeling in Coat's disease.

This paper describes the automatic input system for color drawing, which reads the printed circuit board pattern written with different colors for lands, vias and signal line patterns, and recognizes the elements to construct the input data for CAD. The object is a color drawing based on the traditional expression, which is drawn rather fairly in detail using color pencils, for use in the design of the printed circuit board pattern. In the processing of the color drawing, the discrimination of the color implies the discrimination of the elements in the drawing. Consequently, an exact color separation method for the image data is proposed. By the proposed processing, the color separation is realized easily in spite of the color variation, by constructing interactively the color separation map using a small computer. As the recognition of the figure element for each color, a correction method for the figure is proposed, which may contain modifications such as the noise of color pencil or the line disconnection due to overlapping of different colors. In the proposed method, the properties inherent to the printed circuit board pattern are utilized as the knowledge, and an intelligent figure processing is executed such as connection of vectors or shaping. As a result of a test using the implementation design drawing, an exact color separation was realized for the drawings of the layers drawn using four colors: red, blue, orange and green. The recognition rate for the figure is above 99.7 percent. The processing time for A1 drawing was approximately 12 min using a large-scale general-purpose computer. These figures are sufficient for application.